Biol. Rev. (2010), pp. 000–000. doi: 10.1111/j.1469-185X ...

Biol. Rev. (2010), pp. 000–000. 1doi: 10.1111/j.1469-185X.2010.00124.x

Molluscan biological and chemical diversity:secondary metabolites and medicinalresources produced by marine molluscs

Kirsten Benkendorff∗School of Biological Sciences, Flinders University, GPO Box 2100 Adeliade, 5001, SA, Australia

(Received 4 March 2009; revised 10 December 2009; accepted 17 December 2009)

ABSTRACT

The phylum Mollusca represents an enormous diversity of species with eight distinct classes. This review provides ataxonomic breakdown of the published research on marine molluscan natural products and the medicinal productscurrently derived from molluscs, in order to identify priority targets and strategies for future research. Some marinegastropods and bivalves have been of great interest to natural products chemists, yielding a diversity of chemical classesand several drug leads currently in clinical trials. Molluscs also feature prominently in a broad range of traditional naturalmedicines, although the active ingredients in the taxa involved are typically unknown. Overall secondary metaboliteshave only been investigated from a tiny proportion (<1%) of molluscan species. At the class level, the number ofspecies subject to chemical studies mirrors species richness and our relative knowledge of the biology of differenttaxa. The majority of molluscan natural products research is focused within one of the major groups of gastropods,the opisthobranchs (a subgroup of Heterobranchia), which are primarily comprised of soft-bodied marine molluscs.Conversely, most molluscan medicines are derived from shelled gastropods and bivalves. The complete disregard forseveral minor classes of molluscs is unjustified based on their evolutionary history and unique life styles, which may haveled to novel pathways for secondary metabolism. The Polyplacophora, in particular, have been identified as worthy offuture investigation given their use in traditional South African medicines and their abundance in littoral ecosystems.As bioactive compounds are not always constitutively expressed in molluscs, future research should be targeted towardsbiosynthetic organs and inducible defence reactions for specific medicinal applications. Given the lack of an acquiredimmune system, the use of bioactive secondary metabolites is likely to be ubiquitous throughout the Mollusca andbroadening the search field may uncover interesting novel chemistry.

Key words: bioactivity, biodiversity, chemical defence, molluscan evolution, marine natural products, natural remedies,secondary metabolism, traditional medicine.

CONTENTS

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2(1) Molluscan biological diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2(2) Molluscan chemical diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

II. Taxonomic Distribution of Molluscan Metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6(1) Minor classes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6(2) Cephalopoda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8(3) Bivalvia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10(4) Gastropoda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

(a) Eogastropoda and non-heterobranch orthogastropods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10(b) Heterobranch gastropods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

* Address for correspondence: Tel: +61 8 8201 3959; Fax: +61 8 8201 3015; Email: [email protected]

Biological Reviews (2010) 000–000 © 2010 The Author. Journal compilation © 2010 Cambridge Philosophical Society

2 Kirsten Benkendorff

III. Molluscan Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12IV. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15V. Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

VI. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

I. INTRODUCTION

Throughout history, molluscs have provided a wide range ofhuman resources, including food, shells, dyes and medicines(e.g. Fig. 1). In many cultures shelled gastropods and bivalvesare regarded as a delicacy or healthy food and they alsofeature in a range of traditional natural remedies (e.g. Hu,1980; Herbert et al., 2003; Prabhakar & Roy, 2009). In mostcases there has been no scientific research undertaken tosubstantiate the health benefits of molluscs. However, thereis increasing interest in the bioactivity of mollusc extractsand secondary metabolites (see Cimino & Gavagnin, 2006).Currently, natural products isolated from molluscs and theirstructural analogues are particularly well represented in theanticancer compounds in clinical trials (Simmons et al., 2005).Nevertheless, it is presently unclear whether the productionof bioactive secondary metabolites is ubiquitous within thePhylum Mollusca.

The term mollusc is derived from the Latin word molluscus

meaning ‘soft’. Despite the presence of a shell in somemolluscan groups, all molluscs are essentially soft-bodied,making them vulnerable to predators and pathogens. Eventhose with a shell must regularly open the shell, or extendtheir muscular foot beyond it, for the purposes of feedingand locomotion. Thus the shell does not present a truephysical barrier to microbial infection. However, molluscsoften live in microbially rich habitats, such as soil andleaf litter on land and amongst marine benthic sedimentsand hard reef communities. The majority of molluscandiversity occurs in the sea, where even in the watercolumn there is an estimated 105 –106 microbial cells ml−1

(Whitman, Coleman & Wiebe, 1998). When any naturalor artificial surface is placed in the marine environment,bacteria rapidly settle, attach and form biofilms (Davis et al.,

1989), which can facilitate pathogenic invasion. However,like all invertebrates, molluscs do not have an acquiredimmunological memory (Sminia & Van Der Knaap, 1986;Hooper et al., 2007). This suggests that molluscs must haveevolved alternative defence strategies to protect themselvesagainst the onslaught of microbial invasion. Indeed, theirinnate immune system does appear to have a well-developedhumoral component with the biosynthesis of antimicrobialdefence factors (e.g. Tripp, 1975; Mitta et al., 2000b; Mitta,Vandenbulcke & Roch, 2000; Cellura et al., 2007; Li, Zhao& Song, 2009). Under the pressure of natural selection,a range of different antibacterial, antifungal, antiparasiticand antiviral secondary metabolites may have evolved inmolluscs, for circulation in the haemolymph, as well as forinclusion in mucus secretions on body surfaces. Molluscs havealso been shown to use secondary metabolites as part of theircommunication systems (e.g. Cimino et al., 1991; Zatylny

et al., 2002; Cummins et al., 2006), predatory behaviour (e.g.Roseghini et al., 1996; Craig, 2000; Kanda et al., 2003) anddefensive secretions (e.g. Ireland & Faulkner, 1978; Pawlik,Albizati & Faulkner, 1986; Marin et al., 1999; Kelly et al.,2003; Derby et al., 2007). Consequently, there should bemuch scope for future drug discovery within this phylum.

The continual discovery of novel drug leads from theenormous pool of available species requires a strategicapproach, such as the investigation of traditional medicinesand/or previously unstudied sources that are likely tohave independently evolved novel pathways for secondarymetabolism. As outlined by Cimino & Ghiselin (2001)chemical defence appears to have evolved differentlyin different types of organisms. Consequently, it couldbe predicted that distinct chemical structures will occurwithin molluscan groups that have evolved under differentenvironmental and biological pressures. The purpose of thisreview is to examine the current literature on molluscansecondary metabolites to identify major gaps in ourknowledge of molluscan chemistry. Combined with anassessment of molluscan evolution and medicinal resources,this could help refine future targets for natural productsresearch. The approach used here primarily involves ataxonomic classification of molluscan secondary metabolitesto highlight under-represented taxa. The bias towards certaintaxa is also compared to the distribution of species used inmedicinal remedies, to establish further limitations in ourknowledge on bioactive compounds from molluscs.

(1) Molluscan biological diversity

Molluscs are the second largest animal phylum on earth,constituting approximately 7% of living animals. Thereare currently around 52,000 named species of marinemolluscs (Bouchet, 2006) and an estimated diversity of100,000–200,000 species (Pechenik, 2000). Molluscs arerelatively well described compared to many other inver-tebrate phyla and the taxonomy is fairly well resolvedfor an enormous diversity of species from many regionsaround the world, despite some remaining unresolvedphylogenetic disputes (e.g. Haszprunar, 1996; Ponder &Lindberg, 1997; Colgan, Ponder & Eggler, 2000; reviewedby Ponder & Lindberg, 2008). Molluscs are diverse notonly in terms of their species richness, but also encom-pass a wide range of morphologies and ecological niches.Their habitats range from the highest alpine regions tothe deepest sea vents and they have adapted to a rangeof different life styles, including trophic niches encom-passing predatory, herbivorous, scavenging, detritivorous,filter-feeding and even some symbiotic photo- and chemo-autotrophs. Phylogenetically, molluscs have diversified into


Molluscan biological and chemical diversity 3

Fig. 1. Illustration of the diverse resources obtained from molluscs, such as edible whelks in the family Muricidae (Gastropoda);(A) The Australian muricid Dicathais orbita; (B) the Murex homeopathic remedy; (C) dyes and pigmented compounds isolated frommuricids by (D) silica chromatography. Chemical structures are shown for the secondary metabolites (E) murexine, a muscle-relaxingcholine ester; and the anticancer brominated indoles (F) tyrindoleninone; (G) 6-bromoisatin and (H) 6,6’-dibromoindirubin, whichis a minor pigment and structural isomer of (I) 6,6’-dibromoindigo, the well-known historical dye Tyrian purple.

seven or eight classes: Gastropoda, Bivalvia, Scaphopoda,Cephalopoda, Polyplacophora, Monoplacophora, Caud-ofoveata and Solenogastres. The Caudofoveata andSolenogastres are often combined into one paraphyleticgroup the Aplacophora (Haszprunar, 2000; Haszprunar,Schander & Halanych, 2008) and as these are both minorgroups they are treated together herein (Table 1, Fig. 2).

About 90% of molluscan diversity is found in one class,the Gastropoda, with an estimated 75,000 –150,000 species(Fig. 2). The Gastropoda have diversified into the widestrange of ecological niches, including all trophic niches andterrestrial, freshwater, marine benthic, pelagic and infaunalhabitats. The bivalves are the next most diverse class,with approximately 10,000–20,000 species (Fig. 2), foundin marine and freshwater habitats. These are primarily filter-feeding organisms, although some are deposit feeders and afew are carnivorous (the septibranchs). Some bivalve familieshave specifically adapted to house microbial symbiontswithin their gills or mantle tissue to allow autotrophicnutrition. The remaining five classes of molluscs are allmarine and relatively minor in terms of their species diversity(Fig. 2). Most cephalopods are highly adapted to an activepredatory lifestyle in benthic and pelagic habitats. Thepolyplacophorans (chitons) are essentially algal grazers onshallow rocky reefs and the Scaphopoda (tusk shells) are

Table 1. Published research on secondary metabolites from thedifferent classes of Mollusca, complied from Faulkner (1984a, b,1986, 1987, 1988, 1990, 1991, 1992b, 1993, 1994, 1995, 1996,1997, 1998, 1999, 2000, 2001, 2002), Blunt et al., (2003, 2004,2005, 2006, 2007, 2008, 2009), Alam & Thomson (1998), Baker& Murphy (1976, 1981) and additional searches using ChemicalAbstracts, Biological Abstracts and Medline. The number of speciesthat have been subject to natural products studies is provided, inaddition to the number of compounds isolated and the numberof research papers, accounting for overlap between the differentliterature sources. The per cent of species investigated in eachclass is calculated based on Avila’s (2006) estimate of the numberof species in each class (see Fig. 2)

Taxa Compounds Papers Species Per cent species

Aplacophora 0 0 0 0Monoplacophora 0 0 0 0Polyplacophora 49 11 10 1.5Scaphopoda <10 2 4 1.1Cephalopoda 24 11 13 1.3Bivalvia 190 146 61 0.3Gastropoda 948 878 817 1.0

infaunal microcarnivores occurring in soft sediment habitats.The Aplacophora have mostly been found from deep seaand continental shelf samples and are either carnivores or



Fig. 2. The estimated number of extant species in each class of the phylum Mollusca, from three different sources. The estimatednumber of species from Ponder & Lindberg (2008) is extracted from relevant chapters, with the exception of bivalves, for which nospecies richness estimate was available.

detritivores (Beesley, Ross & Wells, 1998). The enormousadaptive radiation in the biology of molluscs suggests thatthey are likely also to be diverse in terms of their chemistry(secondary metabolism).

(2) Molluscan chemical diversity

Marine molluscs have become the focus of many chemicalstudies aimed at isolating and identifying novel naturalproducts. As scant information is available on the chemistryof terrestrial and freshwater molluscs, this review focuseson marine species. In the last three decades over 1000research papers have been published on molluscan secondarymetabolites (Table 1, Avila, 2006). Alam & Thomson (1998)compiled a valuable reference book detailing 585 metabolitesisolated from marine molluscs. Prior to this, Baker & Murphy(1976, 1981) compiled information on 148 molluscanmetabolites in their two-volume book ‘Compounds fromMarine Organisms’. Faulkner (1984a, b, 1986, 1987, 1988,1990, 1991, 1992, 1993, 1994b, 1995, 1996, 1997, 1998,1999, 2000, 2001, 2002) included molluscs in his annualreview of marine natural products, reporting a total of 729compounds from 199 species. These reviews have beencontinued in recent years by Blunt et al. (2003, 2004, 2005,2006, 2007, 2008, 2009) reporting a further 190 distinctcompounds from 75 species. Cimino & Gavagnin (2006)provide a modern review of marine molluscan chemistry andbiotechnology, including chapters on secondary metabolitesfrom marine gastropods from Antarctica, Southern Africaand South America (Davies-Coleman, 2006); Australia andNew Zealand (Garson, 2006), Indo-Pacific (Wahidullah et al.,2006) and Japan (Miyamoto, 2006). These references offerexcellent opportunities to examine the chemical diversity

of marine molluscs (Table 1, Figs 3, 4), with respect tostructural diversity (Fig. 5) and the taxonomic distribution ofthe metabolites (Figs 6, 7).

Taking into consideration the chemical redundancybetween species, at least 977 distinct compounds havebeen isolated from just 251 species in the annual reviewsof marine natural products (Faulkner 1984a, b, 1986,1987, 1988, 1990, 1991, 1992b, 1993, 1994, 1995, 1996,1997, 1998, 1999, 2000, 2001, 2002; Blunt et al., 2003,2004, 2005, 2006, 2007, 2008, 2009). Similarly, Alam &Thomson (1998) report 585 compounds from just 135 speciesof marine molluscs. This implies that chemical diversityin molluscs exceeds their species diversity, although thischemical diversity encompasses many structurally relatedcompounds derived from the same biochemical pathways.The majority of compounds have only been isolated froma single species, although the same group of compoundsis often found in molluscs from the same family or genus,when related species are investigated. Infrequently, the samesecondary metabolites converge across diverse classes ofmolluscs (e.g. Roseghini et al., 1996; Derby et al., 2007). Thedistribution of compounds across taxonomic groups andspecies (Fig. 3 & 4) is primarily due to the fact that theassociated research effort is far from equal. The frequencydistribution histogram of the number of species reportedto contain multiple metabolites complied from Faulkner(1984a, b, 1986, 1987, 1988, 1990, 1991, 1992b, 1993,1994, 1995, 1996, 1997, 1998, 1999, 2000, 2001, 2002)and Blunt et al. (2003–2007) reveals a strong right-handskew, with a median number of two and a maximum of58 compounds isolated from a single species of mollusc(Fig. 4). The majority of species have only been subject to asingle study aimed at the isolation of novel natural products.



Fig. 3. The number of (A) species subject to chemical investigation and (B) distinct secondary metabolites isolated from each classin the phylum Mollusca, sourced from the indicated reviews and syntheses of marine natural products.

These studies typically yield a small group of structurallyrelated compounds (analogues). However, some species havebeen intensively studied, often by several different researchgroups working on collections from different biogeographicregions. These collections may yield distinct compounds,according to the isolation procedures and focus of the specificresearchers. For example, 25 compounds have been isolatedfrom the seahare Aplysia kurodai including terpenes, nitrogen-containing aliphatic compounds, macrolides and fatty acidderivatives. In 2008, a further eight novel metabolites wereisolated from this species (Blunt et al., 2009) collected fromnew locations.

The 58 compounds reported from the related speciesA. dactylomela (Fig. 4) are primarily terpenes derived from

the algal diets of these cosmopolitan grazing seahares. Thebivalve Patinopectin yessoensis contained the second highestnumber of compounds (33, Fig. 4) with a range of sterols andalgal toxins. Clearly dietary sources contribute significantlyto the chemical diversity found in molluscs. Nevertheless,evidence for de novo biosynthesis has been reported in severalmolluscan taxa (see reviews by Garson, 1993; Cimino &Ghiselin, 2001; Moore, 2006; Fontana, 2006). Evidence forthe biogenesis of secondary metabolites mostly stems fromfeeding experiments, which demonstrate the incorporationof radio-labeled precursors in certain groups of heterobranchmolluscs (reviewed by Cimino et al., 2004; Fontana, 2006).More recently, these experiments have been complementedby genetic studies (Fontana, 2006) or histochemistry (Westley



Fig. 4. Frequency distribution of the number of compounds found in molluscan species complied from Faulkner (1984a,b–2002)and Blunt et al.’s, (2003, 2004, 2005, 2006, 2007) annual reviews of marine natural products. Fifty-eight compounds have beenisolated from Aplysia dactylomela (inset with egg masses).

& Benkendorff, 2009) aimed at identifying the biosyntheticprocesses.

The secondary metabolites isolated from molluscs fall intoa wide range of structural classes, with some compoundsbeing more dominant in certain taxa. Fig. 5 shows therelative proportions of different compounds in the two majormolluscan classes compiled from Alam & Thomson (1998),Faulkner (1984a, b, 1986, 1987, 1988, 1990, 1991, 1992b,1993, 1994, 1995, 1996, 1997, 1998, 1999, 2000, 2001,2002) and Blunt et al. (2003, 2004, 2005, 2006, 2007). Allthe major types of secondary metabolites are representedin both classes of mollusc (Fig. 5). In the Gastropoda(Fig 5A) terpenes dominate, whereas only three terpeneswere reported from bivalves (Fig. 5B). Terpenes have beena major focus of research in soft-bodied grazing gastropods,which may acquire these compounds from their diet foruse in their own defence (e.g. Faulkner, 1984a, 1992a).Sterols are the dominants compounds reported from bivalves(Fig. 5B), but are the least frequently reported in gastropods(Fig. 5A). The relatively large research effort on sterols inbivalves is probably due to their importance in fisheriesand aquaculture, with interest focusing on biochemicalchanges over the reproductive cycle. Polyproprionates andalkaloids have been isolated in reasonably large numbersfrom both classes of molluscs, whereas aliphatic nitrogen-containing compounds are relatively uncommon (Fig. 5).Further discussion on the types of compounds found withincertain molluscan taxa is given below for each group. Thisincludes additional compounds found by extensive databasesearching that are not represented in general reviews onmarine natural products.

II. TAXONOMIC DISTRIBUTION OFMOLLUSCAN METABOLITES

The number of species subject to natural products researchin the different molluscan taxa (Figs 3A, 6A) is likely tobe influenced by their relative diversity (Fig. 2), as well astheir accessibility for research and how well their biology iscurrently understood. In general, the diversity of compoundsisolated from the different molluscan classes (Figs 3B, 6B)does mirror their relative species richness (Fig. 2), but eventhe two best studied classes (gastropods and bivalves) areonly represented by a tiny proportion of the available species(Table 1). Overall, less than 1% of named molluscan specieshave been investigated for their secondary metabolites.

(1) Minor classes

The Monoplacophorans and Aplacophorans have not beensubject to any chemical studies to date (Fig. 3, Table 1).This is not surprising considering the dearth of biologicalknowledge on these groups and the fact that they are all deep-sea organisms with relatively small body sizes (Beesley et al.,1998). The Monoplacophora, with few living representatives,triggered much excitement when extant specimens were firstdiscovered, as it was suggested that they are the closest to thehypothetical ancestral mollusc (e.g. Morton, 1979). However,more recent research indicates that the ancestral mollusc ismore aplacophoran-like (Haszprunar et al., 2008), althoughthis is not universally accepted (e.g. Ponder and Lindberg,1997). The Aplacophora are worm-shaped molluscs that donot have a shell, but rather are covered by a cuticle embeddedwith calcareous spicules (Beesley et al., 1998). Consequently,



Fig. 5. The relative proportion of secondary metabolites in different structural classes for (A) Gastropoda (N = 661) and (B) Bivalvia(N = 92) complied from complied from Alam & Thomson (1998), Faulkner (1984a, b, 1986, 1987, 1988, 1990, 1991, 1992b, 1993,1994, 1995, 1996, 1997, 1998, 1999, 2000, 2001, 2002) and Blunt et al.’s, (2003, 2004, 2005, 2006, 2007) annual reviews of marinenatural products. Miscellaneous refers to compounds of mixed biosynthetic origin.

they could be of great interest for investigations into theevolution of chemical defence mechanisms and may provideinteresting insights into the early evolution of biosyntheticpathways in the Mollusca. However, further research ontheir biology should ensure the collection of specimens isenvironmentally sustainable (Benkendorff, 2002). Additionalinformation on their biological attributes would furthercontribute to effective targeting of species for biodiscoveryresearch.

Two other minor classes of molluscs, the Polyplacophoraand Scaphopoda, have also been neglected in the naturalproducts literature (Fig. 3, Table 1). The Scaphopoda aredifficult subjects for research because they live completelyburied in sediment (Beesley et al., 1998). On the other hand,some species of Polyplacophora (chitons) are common onintertidal and shallow subtidal reefs. They can reach largesizes (>10 cm) and their biology is relatively well understood(e.g. Boyle, 1977; Otaiza & Santelices, 1985; Smith &

Otway, 1997). No interesting secondary metabolites fromthese molluscan classes have been reported in the variousreviews of marine natural products (Fig. 3B), although furtherdatabase searching revealed a handful of chemical studies(Table 1) on the sterols (Kind & Meigs, 1955; Teshima& Kanazawa, 1973, 1978; Voogt & Van Rheenen, 1974;Teshima et al., 1982), lipids (Lawrence, 1970; Hayashiet al., 1991), hydrocarbons (Yasuda & Fukamiya, 1977) andcarotene derivatives (Tsushima, Maoka & Matsuno, 1989) ofchitons. One study has also investigated the sterols and lipidsof scaphopods (Kandaswarmy & Rajulu, 1978) and at leasttwo further investigations have incorporated a scaphopodand/or chitons in comparative studies of sterols in molluscs(Teshima & Kanazawa, 1972; Idler et al., 1978).

Future studies aimed at isolating novel secondarymetabolites from these two molluscan classes would bestrongly justified based on their distinct biological attributes.The Scaphopoda are detritivores and microcarnivores with



Fig. 6. The number of (A) species subject to chemical investigation and (B) distinct secondary metabolites isolated from Eogastropodaand major groups within the Orthogastropoda, sourced from the indicated reviews and syntheses of marine natural products.

a tubular shell open at both ends (Poon, 1987). Theirfeeding habits involve extending cilia outside their shellsto probe the sediment, which could make them vulnerableto predators and pathogens. The Polyplacophora are algalgrazers protected by an eight-plate shell on their dorsalsurface, which is surrounded by a leathery girdle. Althoughtheir muscular foot on the ventral surface typically clingsvery tightly to the rocky substratum, they may be vulnerableto pathogens in biofilms and some predators, particularlywhen moving or detached. Such potential vulnerability couldhave led to the evolution of chemical defence strategies,particularly in some large slug-like species that have very

reduced or internal shell plates. Given the early divergenceof chitons from other molluscan classes, there is potential forthe discovery of novel secondary metabolites.

(2) Cephalopoda

Despite also being one of the minor classes in terms ofspecies richness (Fig. 2), the Cephalopoda have been subjectto several interesting chemical studies (Table 1, Fig. 3). Withthe exception of Nautilus spp., these predatory species are soft-bodied organisms, which have secondarily lost the protectionof the shell as an adaptation to an active pelagic life style.



Fig. 7. The number of (A) species subject to chemical investigation and (B) distinct secondary metabolites isolated from differentgroups within the Heterobranchia, sourced from the indicated reviews and syntheses of marine natural products.

Their highly evolved behaviour, camouflage and ability tomove fast was assumed to reduce the need for chemicaldefence against predators (e.g. Faulkner, 1992a), althoughthe secretion of ink is a cephalopod chemical defencemechanism (Derby et al., 2007). They also remain vulnerableto pathogens in the microbially rich marine environment.Furthermore, as active predators with venom glands tosubdue their prey, there is much scope for investigationinto the chemical composition of their venom secretions.Secondary metabolites isolated from cephalopod venom, todate, include tetrodotoxin (Scheumack et al., 1978), peptides(e.g. Songdahl & Shapiro, 1974; Kanda et al., 2003) andbiogenic amines (e.g. Roseghini et al., 1996). Given thehigh diversity of bioactive peptides found in the predatorycaenogastropods in the family Conidae (Olivera et al. 1990,

Myers et al., 1993), more research effort into the venomsand secretory glands of cephalopods is likely to be highlyrewarding.

In addition to the venoms, a range of other naturalproducts have been isolated from the Cephalopoda. Theseinclude cytotoxic tyrosinase from the ink of the cuttlefish Sepia

officinalis (Russo et al., 2003), as well as ovarian jelly peptides(Bernay et al., 2006), a sperm-attracting peptide (Zatylny et al.,

2002) and novel cardioactive peptide isolated from the brainof the common octopus Octopus vulgaris (Kanda & Minakata,2006). The compounds reported from cephalopods in Baker& Murphy (1981) include fairly simple, widely distributedcompounds, such as aromatic amino acids, noradrenalineand some benzoquinols. Overall, despite the relatively highrepresentation of species studied in this class (Table 1), there



has been fairly limited research into their biologically activeorganic molecules. There remains good potential for noveldiscoveries within cephalopods, and this is in part beingaddressed by a current Australian Research Council fundedcollaborative research project into the evolution of theirtoxicity (Norman, 2008).

(3) Bivalvia

The second largest molluscan class, the Bivalvia (Fig. 2),is relatively well represented in chemical studies (Fig. 3,Table 1). However, much of this research is associatedwith sterols (Fig. 5B) and bioaccumulated toxins responsiblefor paralytic shellfish poisoning (see reviews by Bricelj &Shumway, 1998; Llewellyn, Negri & Robertsin, 2006; Kita& Uemura, 2006; Ciminiello & Fattorusso, 2006), as opposedto defensive secondary metabolites. Some bivalves haveadapted to use their dietary toxins in their own defenceagainst predators (e.g. Kvitek & Bretz, 2005). Most bivalvescan also clamp their shells tightly shut to enclose the entireanimal, thus providing them with some physical protectionfrom predators. Nevertheless, as sedentary suspension-feeding organisms that pump large volumes of sea water andsuspended microorganisms through their gills, they are quitevulnerable to microbial infection, thus requiring chemicaldefence against pathogens. This has been demonstratedin recent research into the involvement of antimicrobialpeptides and proteins in the humoral immunity of bivalves(e.g. Mitta et al., 2000a, b; Cellura et al., 2007; Zhao et al.,2007; Li et al., 2009). Some interesting polyproprionatesand alkaloids (aromatic nitrogenous compounds) have alsobeen isolated from bivalves (Fig. 5B), although it is presentlyunclear if these play any defensive role.

The detection of antimicrobial defence factors inshelled molluscs such as bivalves has been influenced byrecent advances in our understanding of the biosynthesisand regulated expression of these bioactive compounds.Research on a mussel, Mytilus galloprovincialis, revealed adiversity of antimicrobial peptides (reviewed by Mitta et al.,2000b). Interestingly, some of these peptides are expressedconstitutively, whilst some are only induced after infectionwith bacteria (Mitta et al., 2000a; Cellura et al., 2007).Similarly, an antimicrobial protein from the scallop Argopecten

irradians is rapidly upregulated after bacterial challenge(Zhao et al., 2007). The possibility that bioactive secondarymetabolites are not always present in the humoral defencesystem in molluscs means that their bioactivity may beoverlooked in general screening programs. Strategic researchinto regulated defence mechanisms may provide noveldiscoveries in even the most well-studied molluscan taxa,including commercially important bivalves, which are inrelatively abundant supply for future drug development(Benkendorff, 2009).

(4) Gastropoda

Consistent with their high species diversity, the gastropodsare the most highly represented molluscan class in natural

products studies (Figs 3, 6, Table 1). Although a relativelylarge number of compounds have been isolated, the numberof species included in these studies still represents onlya tiny proportion of the possible pool of extant marinespecies in what is by far the largest class of molluscs(∼1%, Table 1). Given the large diversity of species, itis appropriate to break the gastropods into major groups(Fig. 6). The gastropods were traditionally divided into threesubclasses: Prosobranchia, Pulmonata and Opisthobranchia,but are now considered to fall into two major subclasses:Eogastropoda (true limpets- Patellogastropoda being theonly living representatives) and Orthogastropoda (Ponder &Lindberg, 1997; 2008), encompassing all other gastropods(recognized groups Vetigastropoda, Caenogastropoda andHeterobranchia treated as superorders). The pulmonatesand opisthobranchs share a common ancestor and arenow combined under one monophyletic group Euthyneura,which is included in the Heterobranchia (Thollesson,1999; Wagele et al., 2008).

(a) Eogastropoda and non-heterobranch orthogastropods

Taxonomic breakdown of the gastropod metabolites revealsthat only three species of patellogastropod limpets have beenstudied (Fig. 6A). Twenty-three structurally related fatty acidderivatives have been isolated from two of these species(Kawashima, 2005; Kawashima & Ohnishi, 2006), whilst thethird species yielded a defensive terpene (Pawlik et al., 1986).Further research into the chemistry of this ancestral class ofgastropods is justified, especially considering that limpets areonly protected by a shell on their top surface and are foundin very large numbers on most rocky intertidal shores.

In the Orthogastropoda, over 91% of the compoundshave been isolated from the marine heterobranchs(Fig. 6B). Only a single species has been studied fromthe Neritimorpha (=Neritopsina, Fig. 6A). Notably, fiveantimicrobial isoflavones have been isolated from this nerite(Sanduja et al., 1985), but it is uncertain whether these arede novo synthesised or acquired from their diet. As Nerita

spp. are microalgal grazers on rocky intertidal platforms,comparisons of the chemical composition of these herbivoresto their local diet would help resolve the origin of thesebioactive isoflavones. Nerites have a broad global distributionand some neritimorphs can be found in freshwater andterrestrial habitats. Studies on the chemical consistency ofextracts from species across different habitats and tropicaland temperate locations could add to the diversity ofsecondary metabolites recorded for this abundant group.

In early studies, Baker & Murphy (1976, 1981) report sevencompounds isolated from seven different vetigastropods.However, only an additional 12 compounds from threespecies have been reported in more recent annual reviews ofmarine natural products (Fig. 6B). Consequently, this species-rich group is hugely under-represented in chemical studies.Vetigastropoda contains extremely diverse families, such asthe Trochidae (topshells) and many large common speciesin the families Haliotidae, Turbinidae and Fissurellidae(see Geiger, Nutzel & Sasaki, 2008, for a comprehensive



review of this group). Chemical studies undertaken onthe turbinid snails revealed toxins, which are possiblydietary derived (Kigoshi et al., 2000), as well as fournovel cytostatic glycosphingolipids (Pettit, Tang & Knight,2005). The only documented chemical study on a trochid(Callistoma canaliculatum), yielded a novel toxin 6-bromo-2-mercaptotryptamine from hypobranchial gland secretions(Kelley et al., 2003). Interestingly, this compound also bearsremarkable structural similarity to the bromoindoxyl sulfateprecursors of Tyrian purple secreted from the hypobranchialglands of the caenogastropod family Muricidae (Fig. 1F-I; Baker & Sutherland, 1968; Cooksey, 2001; Westley &Benkendorff, 2008). The hypobranchial gland is a uniquelymolluscan feature (Beesley et al., 1998) and its functional rolein molluscs is not currently well understood (Westley, Vine &Benkendorff, 2006). However, histological investigations ingastropods have revealed it to be a complex organ containinga range of secretory cells (e.g. Fretter & Graham, 1994;Roller, Rickett & Stickle, 1995; Westely & Benkendorff,2009). Consequently, further investigation of the chemicalsecretions associated with this gland across a broad range ofmolluscs would be worthwhile.

In total, 40 species of caenogastopod are represented inthe annual reviews of marine natural products (Fig. 6A)and these have yielded 49 compounds (Fig. 6B). This isthe largest group of gastropods (Aktipis et. al., 2008) buthas been largely overlooked by natural products researchersdue to the presence of a protective shell. However, furtherliterature searches revealed that three classes of compoundsknown to occur in caenogastropods are under-representedin the annual reviews used to generate Fig. 6. Roseghiniet al. (1996) examined the distribution of five choline esters(e.g. Fig. 1E) and six biogenic amines in 55 species of thecaenogastropod subgroup Neogastropoda. Cooksey (2001)reviewed Tyrian purple (Fig. 1I) and related indoles isolatedfrom the hypobranchial glands of 17 species of Muricidae.Antimicrobial secondary metabolites from the egg masses of afurther eight species of Muricidae have also been investigated(Benkendorff, Bremner & Davis, 2000; 2001; Benkendorff,Pillai & Bremner, 2004), revealing 16 indole derivatives,many of which are brominated, as well as brominatedimidazoles and several small mercaptans. Evidence forthe biosynthesis of the brominated indoles is provided bybromoperoxidase activity in the hypobranchial glands ofTrunculariopsis (Murex) trunculus (Jannun & Coe, 1987) andDicathais orbita (Westley & Benkendorff, 2009).

Numerous reviews have been dedicated to the diversity,structure and pharmaceutical applications of conotoxinsfrom predatory marine cone shells (e.g. Olivera et al., 1990;Myers et al., 1993; Craig, 2000; Livett, Gayler & Khalil, 2004;Terlau & Olivera, 2004; Buczek, Bulaj & Olivera, 2005;Prommer, 2006). Recently identified neurotoxic peptidesare included in Blunt et al.’s, (2003, 2004, 2005, 2006,2007, 2008, 2009) reviews of marine natural products andcontribute significantly to the number of caenogastropodspecies and compounds in Fig 6, although they werenot included in earlier reports by Faulkner (1984b–2002),

and thus remain under-represented. Myers et al. (1993)provide sequence data for 37 peptides from eight distinctpharmacological and structural classes. There are 500–700species of Conus, and of the species studied so far, eachappears to produce between 40 and 200 different peptideswith little overlap among species (Myers et al., 1993; Terlau& Olivera, 2004; Livett et al., 2004), suggesting enormouschemical diversity within this one family of molluscs. Indeed acomplex library of up to 100,000 bioactive peptides has beenpredicted, each with specific physiological targets (Buczeket al., 2005).

(b) Heterobranch gastropods

There is a strong bias in the natural product literaturetowards research on marine heterobranch gastropods (Figs6, 7), in which the shell is often reduced or completely absent.Several reviews focus on the chemical ecology of these soft-bodied opisthobranchs ( Karuso, 1987; Cimino and Sodano,1989; Faulkner, 1992a; Avila, 1995; 2006; Cimino et al.,2001; Wagele, Ballesteros & Avila, 2006; Wahidullah et al.,2006; Miyamoto, 2006; Fontana, 2006). The taxonomyof Heterobranchia is yet to be fully resolved (Thollesson,1999; Wagele et al., 2008; Mordan & Wade, 2008), butfurther knowledge of their phylogenetic relationships will bebeneficial for understanding the full chemical diversity of thisgroup and the potential for shared biosynthetic pathwaysamong taxa. For example, the pulmonates are sister taxato the main opisthobranch radiation, which is consistentwith the prevalent biosynthesis of polyproprionates (Garson,1993; Cimino & Ghiselin, 2001; Moore, 2006; Fontana,2006) across a range of heterobranch taxa including theSiphonaridae (basommatophoran pulmonates), Plakobranchus

sp. (saccoglosan opisthobranch) and Pleurobranchus sp.(notospidean opisthobranch).

Within the heterobranchs there is clearly unequalrepresentation of the different orders in chemicalstudies (Fig. 7). Four relatively minor groups, Acochlidea,Rhodopemorpha, Thecosomata and Gymnosomata, havenot been subject to any chemical studies to date. Themajority of research on the Heterobranchia has concentratedon the largest and most charismatic marine group, theNudibranchia (Fig. 7), with over 386 compounds isolatedfrom 102 species. The Anaspidea (seahares e.g. Aplysia spp.and Dolabella spp.) are also well represented with 18 speciesyielding an amazing total of 247 compounds documentedin the annual reviews of marine natural products (Fig. 7).A broad range of compounds has been isolated from these‘seahares’ (Kamiya, Sakai & Jimbo, 2006), dominated byterpenes (Fig. 5), but also including sterols (e.g. Miyamotoet al., 1988, Yamaguchi et al., 1992), fatty acid derivatives(e.g. Spinella et al., 1997) and alkaloids (e.g. Kigoshi et al.,1990). A range of cytotoxic peptides (e.g. the dolastatins,reviewed by Poncet, 1999) and glycoproteins (e.g. Iijima,Kisugi and Yamazaki, 2003; Yamazaki, 1993) have alsobeen isolated from the Anaspidea, as well as severalproteinaceous sex pheromones (Cummins et al., 2006). Some



other heterobranch groups, such as the Cephalaspidea andSaccoglossa are also reasonably well represented in chemicalstudies (Fig. 7). In addition to a range of polyproprionates,the Cephalaspidea produce phenolic and alkaloid alarmpheromones isolated from a range of species includingNavanax inermis (e.g. Sleeper, Paul & Fenical, 1980), Haminoea

navicula (e.g. Cimino et al., 1991) and Bulla spp. (Marin et al.,1999), as well as cytotoxic peptides from Philinopsis spp. (e.g.Nakao et al., 2004). Chemical defence in the saccoglossanEylsia spp. is also the source of several cytotoxic peptides,the kahalalides (e.g. Hamann et al., 1996; Goetz, Nakao &Scheuer, 1997, Horgen et al., 2000) and diterpenes (Paul &Van Alstyne, 1988), which appear to be dietary derived.

Chemical studies on the marine pulmonate gastropodshave focused largely on the polyproprionates from the limpet-like Siphonaria spp. (Darias, Cueto & Dıaz-Marrero, 2006),although some novel fatty acid derivatives have also beenisolated from species in this genus (Carballeira et al., 2001).Polyproprionates have also been isolated from the intertidalsystellommatophoran slug Onchidium sp. (Rodriguez, Riguera& Debitus,1992), in addition to a mixture of pyrone esters(Ireland et al., 1984) and a novel peptide (Fernandez et al.,1996). Earlier studies on the defence secretions of its sistergenus Onchidella revealed a lipid-soluble compound onchidal(Ireland & Faulkner, 1978). No further studies have beenundertaken on the chemistry of this genus or any othersystellommatophorans. The much larger pulmonate groupEupulmonata is only represented by a few studies on thesterols and terpenes of Trimusculus sp. (e.g. Manker &Faulkner, 1996; San-Martin et al., 1996). The Eupulmonataincludes the large and diverse family Ellobiidae, whichare mostly marine; eupulmonates are otherwise primarilyterrestrial and thus are not included in annual reviews ofmarine natural products.

There are no equivalent reviews of the literatureon terrestrial invertebrate natural products and as aconsequence it is much more difficult to find chemicalstudies on terrestrial species. Extensive searches of scientificdatabases reveal very few studies on secondary metabolitesfrom terrestrial pulmonates, with a much greater focuson plant metabolites that may be useful as molluscicides.However, the mucoproteins produced by garden snails, Helix

spp., have been studied since the early 1900s (Levene, 1925)and there has been considerable interest in the bioactiveproperties of the mucus-associated lectins (reviewed byBonnemain, 2005). Some novel terpenes that inhibit HIV-1reverse transcriptase have been isolated from extracts ofthe giant African snail Achatina fulica (Patil et al., 1993)and cardioexcitatory peptides have been identified from thefreshwater snail Lymnaea stagnalis (Tensen et al., 1998). There isevidence that some terrestrial pulmonate snails can sequesterbioactive terpenes from their lichen diets (Hesbacher et al.,1995) and terrestrial slugs, such as Arion lusitanicus, have beenshown to sequester and detoxify alkaloids from a variety ofplants (Aguiar & Wink, 2005). These studies highlight thepotential for further discoveries within the natural productsand chemical ecology of terrestrial pulmonates.

III. MOLLUSCAN MEDICINES

Molluscs have long provided a source of medicinallyuseful products for many cultures around the world.Pliny the Elder described the use of certain molluscs,such as terrestrial pulmonates, in medicinal remedies fromAncient Rome (Bailey, 1929; Bonnemain, 2005). Bivalvemussels (Mytillidae) were used as therapy in ancient Crete(Kamm, 1997) and more recently have been subject toseveral patents as a source of antimicrobial (de Faire,1999; Roch et al., 2001) and antiviral (Rothman, 1984;Bichurina et al., 2001) peptides. Molluscs also feature ina number of traditional medicines (Fig. 8) from SouthAfrica (Herbert et al., 2003), India (Prabhakar & Roy, 2009)and China (Hu, 1980; Yeung, 1983). Several molluscan-derived therapies are listed on the Homeopathic MateriaMedica (Boericke, 1999, Fig. 8) and extracts from theNew Zealand green-lipped mussel, Perna canaliculus, areincluded in the Natural Medicines Comprehensive Database(www.naturaldatabase.com). Currently, several bioactivenatural products from molluscs are under developmentfor pharmaceutical drugs (Simmons et al., 2005; Fig. 8).Recently, Ziconotide, derived from the venom of predatorycone snails, was the first marine drug to be approved forclinical use (Prommer, 2006), as a treatment for chronic pain.Dolastatin 10, and synthetic analogues, from the aplysiidDolabella auriculata are currently in Phase II clinical trials asanticancer agents (Madden et al., 2000). Kahalalide F firstidentified from the saccoglossan Elysia rufescens (Lopez-Maciaet al., 2001), as well as ES-285 from the bivalve Mactromeris

polynyma have passed through Phase I clinical trials (DenBrock et al., 2005; Faircloth & Cuevas, 2006).

There appears to be no correlation between the numberof species from different molluscan taxa that are usedin medicines and the number of species that have beensubject to investigation in the natural products literature(r2 = 0.04). The lack of correlation is largely driven by theheterobranch molluscs, which rarely feature in molluscanmedicines (Fig. 8B), despite intensive chemical investigation(Fig. 7). Conversely, the Cephalopoda are used in a widerange of traditional medicines (Fig. 8A), but there arerelatively few chemical investigations (Fig. 3). Listings ofCephalopods in the Chinese Materia Medica include squidand cuttlefish (Sepia sp.) ‘‘bone’’, as well as the meat, ink andeggs from cuttlefish (Hu, 1980). Sepia ink is also listed in thehomeopathic Materia Medica for the treatment of depression(Cazalet, 2007). Four cephalopod species were listed in asurvey of South African medicines; the internal shells ofthe species Spirula spirula were the most expensive marineinvertebrate on sale at the traditional medicine market inDurban (Herbert et al., 2003). The medicinal applicationsof these species remain unknown and they are yet to besubjected to any detailed natural product investigations.Several species of chiton (Polyplacophora) were also amongstthe most valuable marine invertebrate taxa reported in asurvey of South African traditional medicines (Herbert et al.,2003). These chitons are reported to cause vaginal spasm in



Fig. 8. The number of taxa in (A) the different classes of Mollusca and (B) the Eogastropoda and major groups from theOrthogastropoda that are used in medicinal remedies. Taxa refers to distinct species, except for the Caenogastropoda, where thenumber of families is plotted due to related uses and limited information at the species level. Pharmaceuticals refers to compoundsderived from molluscs that are commercially available or in clinical trials, whereas all of the natural and traditional remediesare commercially available. Nutraceutical is a modern term derived from the combination of nutritional and pharmaceutical anddescribes natural extracts or products purified from foods with demonstrated pharmacological activity.

women and prevent bed wetting in children (Herbert et al.,2003), suggesting that future chemical investigation intobioactive metabolites could be worthwhile in this previouslyneglected class of molluscs (see Fig. 3).

In most cases there are no data to support the applicationof traditional and homeopathic remedies from molluscs.Indeed, there are few data to support the biological activity ofhomeopathic remedies in general and few have been testedfor safety and effectiveness using rigorous methodologies(Straus, 2000). One possible exception is the Murex remedy(Fig. 1B) derived from the purple dye secretion of muricidwhelks (Muridicae; Caenogastropoda), such as Trunculariopsis

trunculus, used to treat pain and ‘women’s problems’ includinguterine cancer, dysmenorrhoea, chronic endometritis,metrorrhagia, leucorrhoea, nymphomania, anxiety and

melancholic disposition (Cazalet, 2007; Boericke, 1995).A minor constituent of this dye, 6,6’ dibromoindirubin(Fig. 1H), has been shown to inhibit cell proliferationwith selectivity towards glycogen synthase kinase-3 (GSK-3)α/β receptors (Meijer et al., 2003; Magiatis & Skaltsounis,2006). The intermediate dye precursor tyrindoleninone(Fig. 1F) also appears to have selective cytotoxicity towardsseveral cancer cell lines (Vine et al., 2007; Benkendorff,McIver & Abbott, 2009) and the oxidation product 6’bromoisatin (Fig. 1G) is generally cytoxtoxic (Westley et al.,2006; Vine et al., 2007). The ultimate dye precursor isheld as a salt of choline esters. These choline esters (e.g.murexine, Fig. 1E) display potent neuromuscular blockingand muscle-relaxing activity, as well as nicotinic action(Whittaker, 1960; Baker & Duke, 1976; Roseghini et al.,



1996). These bioactive compounds could all potentiallycontribute to the homeopathic action of the Murex remedy.However, the composition of dye extracts from differentspecies of Muricidae can vary according to the presence ofdifferent ultimate precursors (Cooksey, 2001; Benkendorffet al., 2001). Neither the source species, nor the chemicalcomposition of the homeopathic tincture, are providedon the commercially available products. Serial dilutionis characteristic of homeopathy and even after 100 foldconcentration only traces of 6’ bromoisatin could bedetectedin some batches of the commercially available Murex remedyand there was no evidence of anticancer effects in eitherthe dilute or concentrated product (Benkendorff et al., 2009).Trace amounts of choline esters were found in some, but notall, batches of the commercial product suggesting that, withquality control, there could be chemical support for somehomeopathic applications. In a different line of research, lipidextracts from the muricid Rapana venosa have been shown tobe highly efficient in healing induced skin burns in Wistarrats (Badiu et al., 2008). Overall, there is much potential toderive medicines from the Muricidae.

Abalone (Haliotidae) is another family of gastropods thatis valued as a healthy delicacy and features prominently innatural remedies. In traditional Chinese medicine abaloneshell and powder is used as a liver tonic, to improve vision andto treat cataracts, hypertension, vertigo and limb convulsion(Yeung, 1983). Dried abalone power from New Zealandis sold as a nutraceutical (defined as products purified fromfoods with demonstrated protective or physiological benefits).Abalone powder is promoted for generally enhancing healthand sexual life, as well as supporting the immune systemand blood circulation, preventing anaemia and providingminerals, vitamins and omega 3 unsaturated fatty acids(Aroma New Zealand Ltd., 2007). Powder of abalone shell isalso incorporated into a patented formula for treating burnswithout pain and scaring (Lee, 1994). The haemolymph ofabalone has demonstrated antibacterial (Li, 1960; Vakalia& Benkendorff, 2005) and antiviral (Li, Prescott & Jahnes,1962A, Li et al., 1962B) properties against a range of humanpathogens in vitro. The antiviral fraction was shown to protectmice infected with poliovirus and influenza (Li et al., 1962A).These studies indicate that the active factors are likely to bemacromolecules such as glycoproteins. However, treatmentof the abalone haemolymph with heat or proteases to destroythe proteins caused no reduction in the antibacterial activity,whereas the lipophylic compounds extracted on a dianionresin column were found to be active (Benkendorff, K.,unpublished data). Further bioassay-guided fractionationis required to isolate and identify the active factors fromabalone.

Shelled gastropods from at least 13 families feature in theSouth African traditional medicine market (Herbert et al.,2003), although it is unclear what these are actually usedfor. In some cases they may be used as symbols or regaliaby traditional healers to bring good fortune or ward offmisfortune, rather than as curative medicines per se. Forexample, wrist bands consisting of the shells of Nerita albicilla

are common and cowrie shells (Cypraeidae) are incorporatedinto headbands and necklaces for sale at Durban markets(Herbert et al., 2003). Cowrie shells also feature in Chinesetraditional medicines (Hu, 1980) and have been patented foruse in dental fillings (Weil, 1994).

Some terrestrial and freshwater caenogastropods in thebasal group Architaenoglossa feature in traditional Indianmedicine. The eggs of terrestrial apple snails from thefamily Ampullariodoidae (Pila spp.) are used to treat rickets,whilst extracts from freshwater snails (Bellamya spp.) areused for inflammatory problems including asthma, arthritisand rheumatism, as well as a treatment for conjunctivitis(Prabhakar & Roy, 2009). As reviewed by Bonnemain (2005),the terrestrial land snail Helix spp. (Stylommatophora) hasbeen used in Western health care, from antiquity to thepresent. Traditionally extracts and mucus from these snailswere used to treat a range of ailments including hernias,tuberculosis, resistant colds bronchitis and other chronicchest diseases. Studies on the bioactive properties of themucus from Helix have revealed mucolytic and bacteriolyticactivities, as well as sedative or antispasmodic properties (seeBonnemain, 2005). Analysis of extracts of the mucus haverevealed a wide range of enzymes and glycosaminoglycans,as well as prostaglandins, which may contribute to itsbiological effects. Cryptomphalus (Helix) aspersa mucus isincorporated into a commercially available cosmaceuticalcalled BIOSKINCARE™, which is claimed to ‘‘repair scars,prevent and eliminate new stretch marks and firm breasts’’(BioSkinCare, 2009). Recent pharmacological studies onC. aspersa secretions support the skin-regenerative propertiesthrough evidence of anti-oxidant activity, stimulation offibroblast proliferation and extracellular matrix assembly,as well as regulation of metalloproteinase activities (Brievaet al., 2008).

Natural and traditional medicines from bivalve molluscs(Fig. 8A) primarily comprise ground shells, whole-bodypowders and mother of pearl from the subclassPteriomorphia, including oysters (Ostreina), pearl oysters(Pterioida), clams (Arcoida) and mussels (Mytiloida). Oystershell lysate from Ostrea edulis provides a bioavailable formof calcium carbonate for osteoporosis patients (Fujita et al.,1990) and is used in the homeopathic treatment of bonedeficiencies (Cazalet, 2007). Oyster shell has also been shownto prevent gastric ulcers in vivo using a rodent model (Nieet al., 1994). Oyster shell (Crassostrea gigas, Ostrea spp.) isused as a Chinese remedy to treat headaches, dizziness,palpitations, insomnia, sweating, leucorrhea and uterinebleeding (Yeung, 1983), whereas oyster extract powder(Crassostrea gigas) is promoted as a dietary supplementcontaining natural taurine and zinc for cardiovascular health,liver problems, arthritis, skin problems wound healing andresistance to infection (Aroma New Zealand Ltd., 2007).Several alkaloids have been isolated from Ostrea rivularis, atraditional Chinese medicine used to treat vertigo, tinnitus,pulmonary tuberculosis and to reduce phlegm (Ouyang,2006). Water extracts from oysters (Ostrea gingas syn. Crassostrea

gigas) were found to inhibit liver damage and stimulate



lipogenesis in rats (Kimura, Ohminami & Okuda, 1998).Taurine has been identified as the active ingredient inthe Chinese remedy Zhenzhu Jingmu from the serum ofpearl oyster Pinctada martensii gonads, causing constrictionsin guinea pig uterus and reducing bleeding time in mice(Xu, 1997). Mother of pearl and pearls (Pinctada spp.)provide another Chinese remedy (Hu, 1980), used as atopical eye ointment and to treat various skin conditions.A cream containing mother of pearl has been patented fordermatological and cosmetic use (Camprasse & Camprasse,1998). Additional Chinese remedies derived from the pearloyster Pteria margaritifera are used to treat headache, vertigo,dizziness, tinnitius and cataracts (Yeung, 1983). The arcidbivale (Arca inflata) is also listed as a Chinese remedy, used forgoitre, spleen, liver and gastric problems, as well as duodenalcancer (Yeung, 1983). Oyster and clam extracts have beenshown to have antibacterial and antiviral properties similarto abalone (Haliotis spp., Li et al., 1962b; Prescott et al., 1966;Olicard et al., 2005).

Natural remedies from the New Zealand green-lippedmussel (Perna canaliculus) species are generally promoted asanti-inflammatory agents, effective in halting the progressionof joint and connective tissue problems and relieving thesymptoms of arthritis. Several novel anti-inflammatoryomega 3 polyunsaturated fatty acids have been identifiedfrom P. canaliculus extracts (Treschow et al., 2007). A rangeof nutraceuticals are produced from this species includingmussel powder, a mussel extract claimed to have up to fivetimes greater anti-inflammatory properties than the powder(Aroma New Zealand Ltd., 2007) and a stabilized lipidextract (Lyprinol), which has been patented and proveneffective in a range of clinical trials for arthritis and asthma(Gibson, 2000; Halpern, 2000). The cost of these productsincreases accordingly; $AUD 150 kg−1 for the powder,$1600 kg−1 for the extract and around $16,000 kg−1 forLyprinol. Lyprinol has been shown to be effective in arodent model for prevention of inflammatory bowel disease(Tenikoff et al., 2005) and pharmaceutical preparationscontaining P. canaliculus extracts have been patented for usein treating side effects caused to gastro-intestinal mucosaafter oral ingestion of analgesics (McFarlane & Croft, 1984).To date, no species of Perna or other related bivalvesoutside New Zealand appear to have been tested for anti-inflammatory activity. However, a lipid extract from Mytilus

galloprovincialis was found to reduce the healing time forinduced skin burns in a rodent model, similarly to resultsfor the muricid Rapana venosa (Badiu et al., 2008). In India,shell powder from the freshwater mussels Lamellidens spp.and Parreysia spp. (Paleoheterodonta: Unionoidea) is used tocontrol blood pressure, giddiness and dehydration, whereas asoup prepared from the foot is used to treat cardiac aliments(Prabhakar & Roy, 2009). This is the only study that refers tomedicinal use of bivalves in the subclass Paleoheterodonta.The anticancer agent ES-285 from Mactromeris polynyma (DenBrok et al., 2005) represents the only medicinal study on thesubclass Heterodonta.

IV. CONCLUSIONS

(1) Natural products research aimed at the isolationand identification of novel secondary metaboliteshas only been undertaken on a small proportion ofmolluscan species to date. This research has beentraditionally biased towards soft-bodied heterobranchs(opisthobranchs) based on their apparent vulnerabilitydue to the lack of a physically protective shell. Thisapproach has been rewarding, with an extremelydiverse range of compounds revealed, including severaldrug leads in clinical trials.

(2) The under-representation of other molluscan taxa innatural products research appears to be unjustifiedgiven that most molluscan traditional medicines areactually derived from shelled molluscs. The bioactivityof many molluscan traditional medicines is yet to besubstantiated, but preliminary data available frombivalves, cephalopds and caenogastropods suggeststhat there is likely to be some chemical basis totheir medical applications. Further studies aimed atidentifying the bioactive factors in well-known culturedmolluscs, such as abalone, would be valuable giventheir wide use for a range of medicinal applications.

(3) Broadening the search field to encompass terrestrialgastropods and some minor molluscan classes couldalso be worthwhile given the possibility for divergentevolution of metabolic pathways and distinct selectivepressures for secondary metabolites. In particular,the polyplacophorans would be worthy of furtherinvestigation given their availability, the reasonablylarge size of some species and their apparent use intraditional South African medicines.

(4) Overall, there is a need for more targeted researchbased on specific hypotheses related to molluscanbioactivity and the defence systems of shelled molluscs,to maximize the success rates of future investigations.

V. ACKNOWLEDGEMENTS

I would like to thank Winston Ponder (Australian Museum)and Prof. G. Cimino (Italian National Council of Research)for useful comments and references that have contributed tothis review. I would also like to thank Chantel Westley, VickiEdwards, Casey Campleman, Warwick Noble and PatrickLaffy from the mollusc lab at Flinders University for usefulfeedback.

VI. REFERENCES

Aguiar, R. & Wink, M. (2005). How do slugs cope with toxicalkaloids? Chemoecology 15, 167–177.

Alam, M. & Thomson, R.H. (1998). Handbook of Natural Products

from Marine Invertebrates. Part 1 Phylum Mollusca. HarwoodAcademic Publishers, Australia.



AROMA NEW ZEALAND LTD. (2007). Company Profileand Product Specification. Accessed online www.aromanz.com13/09/2007.

Aktipis, S. W., Giribet, G., Lindberg, D.R. & Ponder, W.F.(2008) Gastropoda: An overview and analysis. Pp 201–238 InPonder, W.F. & Lindberg, D.R. (Ed) Phylogeny and Evolution of

the Molluscs. University of California Press, Berkley.Avila, C. (1995). Natural products of opisthobranch molluscs: a

biological review. Oceanography and Marine Biology Annual Review 33,487–559.

Avila, C. (2006). Molluscan natural products as biologicalmodels: Chemical ecology, histology and laboratory culture.Pp 1–23 In G. Cimino and M. Gavagnin (Eds) Molluscs:

Progress in Molecular and Subcellular Biology Subseries Marine Molecular

Biochemistry, Springer-Verlag Berlin Heidelburg.Badiu, D.L., Balu, A. M., Barbes, L., Luque, R., Nita, R.,

Radu, M., Tanase, E. & Rosoiu, N. (2008). Physico-chemicalcharacterization of lipids from Mytilus galloprovincialis (L.) andRapana venosa and their healing properties on skin burns. Lipids

43, 829–841.Bailey, K. (1929). The Elder Pliny’s Chapters on Chemical Subjects,

Part 1. Edward Arnold and Co., London.Baker, J. and Duke, C. (1976). Isolation of choline ester

salts of tyrindoxyl sulphate from the marine molluscs Dicathais

orbita and Mancinella keineri. Tetrahedron Letters 15, 1233–1234.Baker, J. & Sutherland, M. (1968). Pigments of marine

animals VIII. Precursors of 6,6’-dibromoindigotin (tyrian purple)from the mollusc Dicathais orbita (Gmelin). Tetrahedron Letters, 1,43–46.

Baker, J. T. & Murphy, V. (1976). Handbook of Marine Science:

Compounds from Marine Organisms. Vol. I . CRC Press, Ohio.Baker, J. T. & Murphy, V. (1981). Handbook of Marine Science:

Compounds from Marine Organisms. Vol. II . CRC Press, Boca Raton,Florida.

Beesley, P. L., Ross, G.J.B. & Wells, A., (Eds) (1998). Mollusca

the Southern Synthesis Part B. CSIRO Publishing, Melbourne.Benkendorff, K. (2002). Potential conservation benefits and

problems associated with bioprospecting in the marineenvironment. Pp 90–100 in D. Lunney and C. Dickman, Eds.A Zoological Revolution: Using native fauna to assist in its own survival.Royal Zoological Society of New South Wales and AustralianMuseum, Sydney.

Benkendorff, K. (2009). Aquaculture and the production ofpharmaceuticals and nutraceuticals. Chapter 28 Pp 866–891 inG. Burnell and G. Allen (Eds) New technologies in aquaculture:

Improving production efficiency, quality and environmental management.

Woodhead Publishing, Cambridge.Benkendorff, K., Bremner, J. B. & Davis, A. R. (2000). Tyrian

purple precursors in the egg masses of the Australian muricid,Dicathais orbita: A possible defense role. Journal of Chemical Ecology

26, 1037–1050.Benkendorff, K., Bremner, J. B. & Davis, A. R. (2001). Indole

Derivatives from the Egg Masses of Muricid Molluscs. Molecules

6, 70–78.Benkendorff, K., Pillai, R. & Bremner, J. B. (2004). 2,4,5-

Tribromo-1H -imidazole in the egg masses of three muricidmolluscs. Natural Products Research 18, 427–431.

Benkendorff, K. McIver, C. M. & Abbott, C.A, (2009).Bioactivity of the Murex homeopathic remedy and ofextracts from an Australian muricid mollusc against humancancer cells. Evidence-based Complementary and Alternative Medicine.doi:10.1093/ecam/nep04223.

Bernay, B., Floc’h, M. B., Gagnon, J. & Henry, J. (2006).Ovarian jelly-peptides (OPJs), a new family of regulatorypeptides identified in the cephalopod Sepia officinalis. Peptides 27,1256–1268.

Bichurina, M. A., Taros, L.J.U., Nikitina, L. E., Bojkov,J.U.A., Kubar, O. I. & Zachek, L. G. (2001). Pharmaceuticalcomposition for herpes treatment. Patent No. RU2165264.Accessed online esp@cenet database 20/2/2001.

BIOSKINCARE (2009). Skin treatment benefits of Helix aspersa

Muller glycoconjugates. http://www.abateit.com/skin-benefits/Accessed online 15/08/2009.

Blunt, J. W., Copp, B. R., Hu, W-P., Munro, M.H.G.,Northcote, P. T. & Prinsep, M. R. (2008). Marine naturalproducts. Natural Product Reports 25, 35–94.

Blunt, J. W., Copp, B. R., Hu, W-P., Munro, M.H.G.,Northcote, P. T. & Prinsep, M. R. (2009). Marine naturalproducts. Natural Product Reports 26, 170–244.

Blunt, J. W., Copp, B. R., Munro, M.H.G., Northcote, P. T.& Prinsep, M. R. (2003). Marine natural products. Natural

Product Reports 20, 1–48.Blunt, J. W., Copp, B. R., Munro, M.H.G., Northcote, P. T.

& Prinsep, M. R. (2004). Marine natural products. Natural







Product Reports 24, 31–86.Boericke, W. (1999). Homeopathic Materia Medica, 9th Edition, pre-

sented by Medi-T, Winhomeo Books. Available online Http://homepage.ntlworl.com/homeopathy advice/Remedies/MATERA MEDICA

Bonnemain, B. (2005). Helix and drugs: Snails for Western healthcare from antiquity to the present. Evidence-based Complementary

and Alternative Medicine. 2, 25–28.Bouchet, P. (2006). The magnitude of marine biodiversity. Pp

33–64 in C. M. Duarte (Ed.) The Exploration of Marine Biodiveristy,

Scientific and Technological Challenges. Fundacion BBVA, France.www.fbbva.es

Boyle, P. R. (1977). The physiology and behaviour of chitons(Mollusca: Polyplacophora). Oceanography and Marine Biology. An

Annual Review 15, 461–509.Bricelj, V. M. & Shumway, S. E. (1998). Paralytic shellfish

toxins in bivalve molluscs: occurrence, transfer kinetics andbiotransformation. Review of Fisheries Science 6, 315–383.

Brieva, A., Phillips, N., Tejedor, P., Guerroa, A., Pivel,J. P., Alonso-Lebrero, J. & Gonzalez, S. (2008). Molecularbasis for the regenerative properties of a secretion of the molluskCryptomphalus aspersa. Skin Pharmacology and Physiology 21, 15–22.

Buczek, O., Bulaj, G. & Olivera, B. M. (2005). Conotoxinsand the posttranslational modification of secreted gene products.Cellular and Molecular Life Sciences 62, 3067–3079.

Camprasse, G & Camprasse, S. (1998). Cutaneous rejuvenatingand healing product, method for its manufacture and uses thereof.Patent No. US5773034 Accessed online esp@cenet database20/2/2001.

Carballeira, N. M., Cruz, H., Hill, C. A., De Voss, J. J. &Garson, M. (2001). Identification and total synthesis of novel



fatty acids from the siphonarid limpet Siphonaria denticulata. Journal

of Natural Products 64, 1426–1429.Cazalet, S. (2007). Materia Medica: Repertorium Homepathicum

(Reversed Kent’s Repertory) Homeopathe International. http://www.homeoint.org/hidb/kent/index.htm. Accessed online 2007.

Cellura, C., Toubiana, M., Parrinello, N. & Roch, P. (2007).Specific expression of antimicrobial peptide and HSP70 genesin response to heat-shock and several bacterial challenges inmussels. Fish & Shellfish Immunology 22, 340–350.

Ciminiello, P. & Fattorusso, E. (2006). Bivalve molluscsas vectors of marine biotixins involved in seafood poisoning.Pp 53–77 In G. Cimino and M. Gavagnin (Eds) Molluscs


Biochemistry, Springer-Verlag Berlin Heidelburg.Cimino, G., Ciavatta, M. L., Fontana, A. & Gavagnin, M.

(2001). Metabolites of marine opisthobranchs: chemistry andbiological activity. Pp 578–637 in C. Tringali, Ed. Bioactive

Compounds from Natural Sources. Taylor & Francis, London.Cimino, G., Fontana, A., Cutignano, A. & Gavagnin, M.

(2004). Biosynthesis in opisthobranch molluscs: general outlinein the light of recent use of stable isotopes. Phytochemistry Reviews,3, 285–307.

Cimino, G. & Gavagnin, M. (2006). Molluscs: Progress in Molecular

and Subcellular Biology Subseries Marine Molecular Biochemistry,Springer-Verlag Berlin Heidelburg. Pp 387.

Cimino, G. & Ghiselin, M. T. (2001). Marine natural productschemistry as an evolutionary narrative. Pp 115–154 in JBMcKlintock and BJ Baker, (Eds). Marine Chemical Ecology

CRC Press, Boca Raton.Cimino, G., Passeggio, A., Sodano, G., Spinella, A. &

Villani, G. (1991). Alarm pheromones from the Mediterraneanopithobranch Haminoea navicula. Experientia 47, 61–63.

Cimino, G. & Sodano, G. (1989). The chemical ecology ofMediterranean opisthobranchs. Chemica Scripta 29, 389–394.

Colgan, D. J., Ponder, W. F. & Eggler, P. E. (2000). Gastropodevolutionary rates and phylogenetic relationships assessed usingpartial 28S rDNA and histone sequences. Zoologica Scripta 29,29–63.

Cooksey, C. J. (2001). Tyrian Purple: 6,6’-dibromoindigo andrelated compounds. Molecules 6, 736–769.

Craig, A. G. (2000). The characterization of conotoxins. Journal of

Toxicology—Toxin Reviews 19, 53–93.Cummins, S. F., Nicholas, A. E., Schein, C. H. & Nagle,

G. T. (2006). Newly identified water-borne protein pheromonesinteract with attractin to stimulate mate attraction in Aplysia.Peptides 27, 597–606.

Darias, J., Cueto, M. & Diaz-MARRERO, A. R. (2006). Thechemistry of marine pulmonates. Pp 105–132 In G. Cimino andM. Gavagnin (Eds) Molluscs: Progress in Molecular and Subcellular

Biology Subseries Marine Molecular Biochemistry, Springer-VerlagBerlin Heidelburg.

Davies-Coleman, M. T. (2006). Secondary metabolites from themarine gastropod molluscs of Antarctica, Southern Africa andSouth America. Pp 133–150 In G. Cimino and M. Gavagnin(Eds) Molluscs: Progress in Molecular and Subcellular Biology Subseries

Marine Molecular Biochemistry, Springer-Verlag Berlin Heidelburg.Davis, A. R., Targett, N. M., McConnell, O. J. & Young, C.

M. (1989). Epibiosis of marine algae and benthic invertebrates:Natural products chemistry and other mechanisms inhibitingsettlement and overgrowth. Pp 85–114 In P. J. Scheuer (Ed.)Bioorganic Marine Chemistry, Vol. 3. Springer-Verlag, Heidelberg..

De Faire, J. (1999). Use of an antimicrobial composition. PatentNumber WO9909835. Accessed online esp@cenet database20/2/2001.

Den Brok, M. W., Nuijen, B., Meijer, D.M.,M Millan, E.,Manada, C. & Beijnen, J. H. (2005). Pharmaceuticaldevelopment of a parenteral lyophilized formulation of theinvestigational anticancer agent ES-285.HCL. Pda Journal of

Pharmaceutical Science & Technology 59, 246–257.Derby, C. D., Kicklighter, C. E., Johnson, P. M. & Zang, X.

(2007). Chemical composition of inks of diverse marine molluscssuggests convergent chemical defenses. Journal of Chemical Ecology

33, 1105–1113.Faircloth, G. & Cuevas, C. (2006). Kahalalide F and ES285:

Potent anticancer agents from marine molluscs. Pp 363–381In G. Cimino and M. Gavagnin (Eds) Molluscs: Progress

in Molecular and Subcellular Biology Subseries Marine Molecular

Biochemistry, Springer-Verlag Berlin Heidelburg.Faulkner, D. J. (1984a). Marine natural products: Metabolites of

marine algae and herbivorous marine molluscs. Natural Product

Reports 1, 251–280.Faulkner, D. J. (1984b). Marine natural products: Metabolites of

marine invertebrates. Natural Product Reports 1, 551–598.Faulkner, D. J. (1986). Marine natural products. Natural Product

Reports 3, 1–33.Faulkner, D. J. (1987). Marine natural products. Natural Product




Reports 8, 97–147.Faulkner, D. J. (1992a). Chemical defenses of marine molluscs.

Pp 119–163 in V. J. Paul, Ed. Ecological Roles of Marine Natural

Products. Comstock, Ithaca.Faulkner, D. J. (1992b). Marine natural products. Natural Product











Reports 19, 1–48.Fernandez, R., Rodriguez, J., Quinoa, E., Riguerra, R.,

Munoz, L., Fernandez-Suarez, M. & Debitus, C. (1996).Onchidin B: A new cyclodepsipeptide from the mollusc Onchidium

sp. Journal of the American Chemical Society 118, 11635–11643.Fontana, A. (2006). Biogenetical proposals and biosynthetic

studies on secondary metabolites of opisthobranch molluscs.



Pp 303–328 In G. Cimino and M. Gavagnin (Eds) Molluscs:


Biochemistry, Springer-Verlag Berlin Heidelburg.Fretter, V. & Graham, A. (1994). British Prosobranch Molluscs: their

Functional Anatomy and Ecology, Ray Society, London.Fujita, T., Fukase, M., Miyamoto, H., Matsumoto, T. &

Ohue, T. (1990). Increase of bone mineral density by calciumsupplement with oyster shell electrolysate. Journal of Bone &

Mineral Research 11, 85–91.Garson, M. J. (1993). The biosynthesis of marine natural products.

Chemical Reviews 93, 1699–1733.Garson, M. J. (2006). Marine mollusks from Australia and New

Zealand: Chemical and ecological studies. Pp 159–172 InG. Cimino and M. Gavagnin (Eds) Molluscs: Progress in Molecular

and Subcellular Biology Subseries Marine Molecular Biochemistry,Springer-Verlag Berlin Heidelburg.

Geiger, D. L., Nutzel, A. & Sasaki, T. (2008). Vetigastropoda.Pp 296–330 In Ponder, W. F. & Lindberg, D. R. (Ed)Phylogeny and Evolution of the Molluscs University of CaliforniaPress, Berkley.

Gibson, S. L. M (2000). The effect of a lipid extract of the NewZealand Green- lipped mussel in three cases of arthritis. Journal

of Alternative & Complementary Medicine 6, 351–354.Goetz, G., Nakao, Y. & Scheuer, P. J. (1997). Two acyclic

kahalides from the sacoglossan mollusk Elysia rufescens. Journal

of Natural Products 60, 562–567.Halpern, G. M. (2000). Anti-inflammatory effects of a stabilized

lipid extract of Perna canaliculus (Lyprinol). Allergie et Immunologie

32, 272–278.Hamann, M. T., Otto, C. S., Scheuer, P. J. & Dunbar, D. C.

(1996). Kahalalides: Bioactive peptides from a mollusk Elysia

rufescens and its algal diet Bryopsis sp. Journal of Organic Chemistry

61, 6594–6600.Haszprunar, G. (2000). Is the Aplacophora monophyletic?

A cladistic point of view. American Malacological Bulletin 15,115–130.

Haszprunar, G, Schander, C. & Halanych, K. M. (2008).Relationships of higher molluscan taxa. Pp 19–32. InPonder, W. F. & Lindberg, D. R. (Ed) Phylogeny and Evolution

of the Molluscs, University of California Press, Berkley.Hayashi, A., Matsukawa, M., Nishizawa, Y., Nakamura, M.,

Ogidoh, H., Suzuki, T. & Matsubara, T. (1991). Studies onsphingolipids of chiton Liolophura japonica. Kinki Daigaku Rikogakubu

Kenkyu Hokoku 27, 83–93.Herbert, D. G., Hamer, M. L., Mander, M., Mkhize, N. &

Prins, F. (2003). Invertebrate animals as a component of thetraditional medicine trade in KwaZulu-Natal, South Africa. African

Invertebrates 44, 327–344.Hesbacher, S., Baur, B, Baur, A. & Proksch, P. (1995).

Sequestration of lichen compounds by the three species ofterrestrial snails. Journal of Chemical Ecology 21, 233–246.

Hooper, C., Day, R., Slocombe, R., Handlinger, J. &Benkendorff, K. (2007). Stress and immune responses inabalone: Limitations in current knowledge and investigativemethods based on other models. Fish & Shellfish Immunology 22,363–379.

Horgen, F. D., Delos Santos, D. B., Goetz, G.,Sakamoto, B., Kan, Y., Nagi, H. & Scheuer, P. J. (2000).A new depsipeptide from the sacoglossan mollusk Elysia ornate

and the green alga Bryopsis species. Journal of Natural Products 63,152–154.

Hu, S. Y. (1980). An Enumeration of Chinese Materia Medica. TheChinese University Press, Hong Kong.

Idler, D. R., Khalil, M. W., Brooks, C. J., Edmonds, C. G. &Glibert, J. D. (1978). Studies of sterols from marine mollusksby gas chromatography and mass spectrometry. Comparative

Biochemistry & Physiology B 59B, 163–167.Iijima, R., Kisugi, J. & Yamazaki, M. (2003). A novel peptide

from the sea hare Dolabella auriculata. Developmental & Comparative

Immunology 27, 305–311.Ireland, C. M., Biskupiak, J. E., Hite, G. J., Rapposch, M.,

Scheuer, P. J. & Ruble, J. R. (1984). Ilikonapyrone esters,likely defense allomones of the mollusc Onchidium verruculatum.Journal of Organic Chemistry 49, 559–561.

Ireland, C & Faulkner, D. J. (1978). The defensive secretion ofthe opisthobranch mollusc Onchidella binneyi. Bioorganic Chemistry

7, 125–131.Jannun, R. & Coe, E. L. (1987). Bromoperoxidase from the

marine snail Murex trunculus. Comparative Biochemistry & Physiology

88B, 917–922.Kamiya, H, Sakai, R. & Jimbo, M. (2006). Bioactive molecules

from seahares. Pp 25–52 In G. Cimino and M. Gavagnin(Eds) Molluscs: Progress in Molecular and Subcellular Biology Subseries

Marine Molecular Biochemistry, Springer-Verlag Berlin Heidelburg.Kamm, R. (1997). Mussels as therapy in ancient Crete. Sudhoffs Arch

Z Wissenschaftsgesch 81, 235–237.Kanda, A., Iwakoshi-Ukena, E., Takuwa-Kuroda, K. &

Minakata, H. (2003). Isolation and characterization of noveltachykinins from the prosterior salivary gland of the commonoctopus Octopus vulgaris. Peptides 24, 35–43.

Kanda, A. & Minakata, H. (2006). Isolation and characterizationof a novel small cardioactive peptide-related peptide from thebrain of Octopus vulgaris. Peptides 27, 1755–1761.

Kandaswarmy, C. K. & Rajulu, G. S. (1978). Sterols and lipidsof some scaphopods (Mollusca). National Academy of Science Letters

(India) 1, 119–120.Karuso, P. (1987). Chemical ecology of nudibranchs. Pp 31–60

in PJ Scheuer, Ed. Bioorganic Marine Chemistry, Vol 1. Springer,Berlin Heildelburg.

Kawashima, H. (2005). Unusual minor nonmethylene-interupteddi-, tri-, and tetraenoic fatty acids in limpet gonads. Lipids 40,627–630.

Kawashima, H. & Ohnishi, M. (2006). Occurrence of novelnonmethylene-interupted C sub(24) polyenoic fatty acids infemale gonads of the limpet Cellana grata. Bioscience, Biotechnology

& Biochemistry 70, 2575–2578.Kelley, W. P., Wolters, A. M., Sacks, J. T., Jockusch,

R. A., Jurchen, J. C., Williams, E. R., Sweedler, J. V. &Gilly, W. F. (2003). Characterization of a novel gastropod toxin(6-bromo-2-mercaptotryptamine) that inhibits shaker K channelactivity. Journal of Biological Chemistry 278, 32934–34942.

Kigoshi, H., Imamura, Y., Yoshikawa, K. & Yamada, K.(1990). Three new cyctotoxic alkaloids, aplaminone, neoapla-minone and neoaplaminone sulfate from the marine molluscsAplysia kurodai. Tetrahedron Letters 31, 4911–4914.

Kigoshi, H., Kanematsu, K., Yokota, K. & Uemura, D.(2000). Turbotoxins A and B, novel diiodotyramine derivativesfrom the Japanese gastropod Turbo marmorata. Tetrahedron 56,9063–9070.

Kimura, Y., Ohminami, H & Okuda, H. (1998). Effects of extractof oyster on lipid metabolism in rats. Journal of Ethnopharmacology

59, 117–123.Kind, C. A. & Meigs, R. A. (1955). Sterols of marine mollusks. IV.

7-cholestenol. The principle sterol of Chiton tuberculatus L. Journal

of Organic Chemistry 20, 1116–1118.



Kita, M & Uemura, D. (2006). Shellfish poisions. Pp 25–46 InG. Cimino and M. Gavagnin (Eds) Molluscs: Progress in Molecular


Kvitek, R. & Bretz, C. (2005). Shorebird foraging behaviour, dietand abundance vary with harmful algal bloom concentrations ininvertebrate prey. Marine Ecology Progress Series 293, 303–309.

Lawrence, J. M. (1970). Lipid composition of the organs of twotropical chitons. Caribbean Journal of Science 10, 1–3.

Lee, S. H. (1994). Burn remedial composition using natural mate-rials and its production method. Patent No. US4690816. Acc-essed online www.patentstorm.us/patents/5362499-descriptors.13/09/2007.

Levene, P. A. (1925). The mucoproteins of the snails Helix aspersa

and Helix pomatia. The Journal of Biological Chemistry LXV, 683–700.Li, C. P. (1960). Antimicrobial effect of abalone juice. Proceedings of

the Society for Experimental Biology & Medicine 103, 522–524.Li, C. P., Prescott, B. & Jahnes, W. G. (1962a). Antiviral

activity of a fraction of abalone juice. Proceedings of the Society

for Experimental Biology & Medicine 109, 534–538.Li, C. P., Prescott, B., Jahnes, W. G. & Martino, E. C.

(1962b). Antimicrobial agents form molluscks. Transactions of the

New York Academy of Science Series II 24, 504–509.Li, C-H., Zhao, J-M. & Song, L-S. (2009). A review of advances

in research on marine molluscan antimicrobial peptides andtheir potential application in aquaculture. Molluscan Research 29,17–26.

Lindberg & Ponder (1996)???Livett, B. G., Gayler, K. R. & Khalil, Z. (2004). Drugs from

the sea: Conopeptides as potential therepeutics. Current Medicinal

Chemistry 11, 1715–1723.Llewellyn, L., Negri, A. & Robertsin, A. (2006). Paralytic

shellfish toxins in tropical oceans. Toxin Reviews 25, 159–196.Lopez-Macia, A., Jimenez, J. C., Royo, M., Giralt, E. &

Albericio, F. (2001). Synthesis and structure determinationof kahalalide F (1,2). Journal of the American Chemical Society 123,11398–11491.

Madden, T., Tran, H. T., Beck, D., Huie, R., Newman, R. A.,Pusztal, L., Wright, J. J. & Abbruzzese, J.L (2000).Novel marine-derived anticancer agents: a phase I clinical,pharmacological and pharmacodynamic study of dolastatin 10(NSC 376128) in patients with advanced solid tumors. Clinical

Cancer Research 6, 1293–1301.Magiatis, P. & Skaltsounis, A. L. (2006). From Hexaplex

trunculus to new kinase inhibitory indirubins. Pp. 147–156, inL. Meijer, N. Guyard, A. L. Skaltsounis, G. Eisenbrand(Eds.) Indirubin, the Red Shade of Indigo. Life in Progress Editions,Roscoff, France.

Manker, D. C. & Faulkner, D. J. (1996). Investigation of therole of diterpenes produced by marine pulmonates Trimusculus

reticulates and T. conica. Journal of Chemical Ecology 22, 23–36.Marin, A., Alvarez, L. A., Cimino, G. & Spinella, A. (1999).

Chemical defence in cephalaspidean gastropods: origin,anatomical location and ecological roles. Journal of Molluscan

Studies 65, 121–131.McFarlane, S.J & Croft, J. E. (1984). Pharmaceutical prepa-

rations with gastro-protective action. Patent No. US4455298.Accessed online esp@cenet database 20/02/2001.

Meijer, L., Skaltsounis, A. L., Magiatis, P., Poly-chronopoulos, P., Knockaert, M., Leost, M., Ryan, X.,Vonica, C., Brivanlou, A., Dajani, R., Crovace, C.,Tarricone, C., Musacchio, A., Roe, S. M., Pearl, L. &

Greengard, P. (2003). GSK-3-Selective inhibitors derived fromTyrian purple indirubins. Chemistry & Biology 10, 1255–1266.

Mitta, G., Vandenbulcke, F., Hubert, F., Salzet, M. &Roch, P (2000a). Involvement of mytilins in mussel antimicrobialdefense. Journal of Biological Chemistry 275, 12954–12962.

Mitta, G., Vandenbulcke, F. & Roch, P. (2000b). Originalinvolvement of antimicrobial peptides in mussel innate immunity.FEBS Letters 486, 185–190.

Miyamoto, T. (2006). Selected bioactive compounds fromJapanese anaspideans and nudibranchs. Pp 199–212. InG. Cimino and M. Gavagnin (Eds) Molluscs: Progress in Molecular


Miyamoto, T., Honda, M., Sugiyama, S., Higuchi, R. &Komori, T. (1988). Isolation and structure of two 5,8α-Epidioxysterols and a cholesteryl ester mixture from the albumenglands of Aplysia juliana. Liebigs Annals of Chemistry 1988, 589–592.

Moore, B. S. (2006). Biosynthesis of marine natural products:macroorganisms (Part B). Natural Product Reports 23, 615–629.

Mordan, P. & Wade, C (2008). Heterobranchia II: Thepulmonata. Pp 385–408. In Ponder, W. F. & Lindberg, D. R.(Ed) Phylogeny and Evolution of the Molluscs. University of CaliforniaPress, Berkley.

Morton, J. E. (1979). Molluscs. 5th Ed. Hutchinson & Co., London.Myers, R. A., Cruz, L. J., Rivier, J. E. & Olivera, B. M. (1993).

Conus peptides as chemical probes for receptors and ion channels.Chemical Reviews 93, 1923–1936.

Nakao, Y., Yoshida, W. Y., Takada, Y., Kimura, J., Yang, L.,Mooberry, S. L. & Scheuer, P. J. (2004). Kulokekahilide-2, acytotixic depsipeptide from a Cephalaspidean Mollusk Philinopsis

speciosa. Journal of Natural Products 67, 1332–1340.NATURAL MEDICINES COMPREHENSIVE DATABASE.

Accessed online www.naturaldatabase.com 6/09/2007Nie, S. Q., Li, T. L., Jiang, A. H. & Li, G. Q. (1994).

A comparative study on anti-ulcer action of unprepared andcalcined oyster shell. Zhongguo Zhong Yao Za Zhi 19, 405–407.

Norman, M. (2008). Cephalopods. Museum Victoria. http://museumvictoria.com.au/Collections-Research/Our-Research/Sciences/Marine-Biology/Cephalopods/ accessed online 22/5/2008.

Olicard, C., Didier, Y., Marty, C., Bourgougnon, N. &Renault, T. (2005). In vitro research of anti-HSV-1 activityin different extracts from Pacific oysters Crassostrea gigas. Diseases

of Aquatic Organisms 67, 141–157.Olivera, B. M., Rivier, J., Clark, C., Ramilo, C. A., Corpuz,

G. P., Abogadie, F. C., Mena, E. E., Woodward, S. R.,Hillyard, D. R. & Cruz, L. J. (1990). Diversity of Conus

neuropeptides. Science 249, 257–263.Otaiza, R. D. & Santelices, B. (1985). Vertical distribution of

chitons (Mollusca: Polyplacophora) in the rocky intertidal zoneof central Chile. Journal of Experimental Marine Biology and Ecology

86, 229–240.Ouyang, M. A. (2006). A new adenosyl-alkaloid from Ostrea

rivularis. Natural Product Research 20, 79–83.Patil, A. D., Feyer, A. J., Eggleston, D. S., Haltiwanger,

R. C., Bean., M. F., Taylor, P. B., Caranfa, M. J., Breen,A. L., Bartus, H. R., Johnson, R. K., Hertzberg, PR.P.& Westley, J. W. (1993). The inophyllums, novel inhibitorsof HIV-1 reverse transcriptase isolated from Malaysian treeCalophyllum inophyllum Linn. Journal of Medicinal Chemistry 36,4131–4138.

Paul, V. J. & Van Alstyne, K. L. (1988). Use of ingestedalgal diterpenoids by Elysia halimedae Macnae (Opisthobranchia:



Ascoglossa) as antipredator defenses. Journal of Experimental Marine

Biology and Ecology 119, 15–29.Pawlik, J. R., Albizati, K. F & Faulkner, D. J. (1986).

Evidence of a defensive role for limatulone, a novel triterpenefrom the intertidal limpet Collisella limatula. Marine Ecology Progress

Series. 30, 251–260.Pechenik, J. A. (2000). Biology of the Invertebrates. 4th Edition

McGraw Hill, New York.Pettit, G. R., Tang, Y. & Knight, J. C. (2005). Antineoplastic

agents. 545. Isolation and structure of turbostatins 1-4 from theAsian marine mollusc Turbo stenogyrus. Journal of Natural Products

68, 974–978.Poncet, J, (1999). The dolastatins, a family of promising

antineoplastic agents. Current Pharmaceutical Design 5, 139–162.Ponder, W. F. & Lindberg, D. R. (1997). Towards a phylogeny

of gastropod molluscs—a preliminary analysis using morpho-logical characters. Zoological Journal of the Linnaean Society 119,83–265.

Ponder, W. F. & Lindberg, D. R. (2008). Phylogeny and Evolution

of the Molluscs. University of California Press, Berkley, 469 pp.Poon, P. A. (1987). The diet and feeding behavior of Cadulus tolmiei

Dall, 1897 (Scaphopoda: Siphonodentalioida). The Nautilus 101,88–92.

Prabhakar, A. K. & Roy, S. P. (2009). Ethno-medical uses ofsome shell fishes by people of Kosi River Basin of North-Bihar,India. Ethno-Medicine 3, 1–4.

Prescott, B., Li, C. P., Caldes, G. & Martino, E. C. (1966).Chemical studies of paolin. II. An antiviral substance fromoysters. Proceedings of the Society for Experimental Biology & Medicine.123, 460–464.

Prommer, E. (2006). Zinconotide: A new option for refractorypain. Drugs of Today 24, 369–378.

Roch, P., Hubert, F., Mitta, G. & Noel, T. (2001). Antimi-crobial peptide myticin from a bivalve mollusc. Patent NumberFR2796072. (Accessed online esp@cenet database 20/02/2001).

Rodriguez, J., Riguera, R. & Debitus, C. (1992). The naturalpolyproprionate-derived esters of the mollusc Onchidium sp. Journal

of Organic Chemistry 57, 4624–4632.Roller, R., Rickett, J. D. & Stickle, W. B. (1995). The

hypobranchial gland of the estuarine snail Stramonita haemastoma

canaliculata (Gray) (Prosobranchia: Muricidae): A light electronmicroscipal study. American Malacological Bulletin 11, 177–190.

Roseghini, M., Severini, C., Falconieri, E. & Erspamer, V.(1996). Choline esters and biogenic amines in the hypobranchialgland of 55 molluscan species of the neogastropod MuricidaeSuperfamily. Toxicon. 34, 33–55.

Rothman, U.S.E. (1984). Polypeptide fraction isolated from thehaemolymph of the common mussel for use as an antiviralmedicine. Patent No. SE431215. Accessed online esp@cenetdatabase 20/2/2001.

Russo, G. L., De Nisco, E., Fiore, G., Di Donato, P.,D’ischia, M. & Palumbo, A. (2003). Toxicity of melanin-freeink of Sepia officinalis to transformed cell lines: identification ofthe active factors as tyrosinase. Biochemical & Biophysical Research

Communications 308, 293–299.Sanduja, R., Weinheimer, A. J., Euler, K. L. & Alam, M.

(1985). Unusual occurrence of fulvoplumierin, an antibacterialpigment, in the marine mollusk Nerita albicilla. Journal of Natural

Products 48, 335–336.San-Martin, A., Quezada, E., Soto, P., Palacios, Y. &

Rovirosa, L. (1996). Labdane diterpenes from the marinepulmonate gastropod Trimusculus peruvianus. Canadian Journal of

Chemistry 74, 2471–2475.

Scheumack, D. D., Howden, M.E.H., Spence, I. & Quinn,R. J. (1978). Maculotoxic: A neurotoxin from the venoms glandsof the octopus Hapalochlaena maculosa identified as tetrododoxin.Science 199, 188–189.

Simmons, T. L., Andrianasolo, E., McPhail, K., Flatt, P. &Gerwick, W. H. (2005). Marine natural products as anticancerdrugs. Molecular Cancer Therapeutics 4, 333–342.

Sleeper, H. L., Paul, V.J & Fenical, W. (1980). Alarmpheromones from the marine opisthobranch Navanax inermis.Journal of Chemical Ecology 6, 57–70.

Sminia, T. & Van Der Knaap, W.P.W. (1986). Immunorecogni-tion in invertebrates with special reference to molluscs. Chapter9, pp 112–124 in M. Brehelin, Ed. Immunity in Invertebrates.Springer-Verlag, Berlin.

Smith, K. A. & Otway, N. M. (1997). Spatial and temporalpatterns of abundance and the effects of disturbance on under-boulder chitons. Molluscan Research 18, 43–57.

Songdahl, J. H. & Shapiro, B. I. (1974). Purification andcomposition of a toxin from the prosterior salivary gland ofOctopus dolfleini. Toxicon 12, 109–115.

Spinella, A., Zubia, E., Martinez, E., Ortea, J. & Cimino, G.(1997). Structure and stereochemistry of aplyolides A-E,lactonized dihydroxy fatty acids from the skin of the marinemollusk Aplysia depilans. Journal of Organic Chemistry 62, 5471–5475.

Straus, S. E. (2000). Complementary and alternative medicine:Challenges and opportunities for pharmacology and therapeuticresearch. The Pharmacologist 42, 74–76.

Tenikoff, D., Murphy, K. J., Le, M., Howe, P. R. &Howarth, G. S. (2005). Lyprinol (stabilized lipid extract of NewZealand green-lipped mussel): a potential preventative treatmentmodality for inflammatory bowel disease. Journal of Gastroenterology

40, 361–365.Tensen, C. P., Cox, K.J.A., Smit, A. B., Van Der Schors, R. C.,

Meyerhof, W., Richter, D., Planta, R. J., Hermann,P. M., Van Minnen, J., Geraerts, W.P.M., Knol, J. C.,Burke, J. F., Vreugdenhil, E. & Heerikhuizen (1998).The lymnaea cardioexcitary peptide (LyCEP) receptor: A G-protein-coupled receptor for a novel member of the RFamideneuropeptide family. The Journal of Neuroscience 18, 9812–9821.

Terlau, H. & Olivera, B. M. (2004). Conus venoms: A richsource of novel ion channel-targeted peptides. Physiology Reviews

84, 41–68.Teshima, S. & Kanazawa, A. (1972). Comparative study on the

sterol composition of marine mollusks. Nippon Suisan Gakkaishi 38,1299–1304.

Teshima, S. & Kanazawa, A. (1973). Biosynthesis of 7-cholestenolin the chiton, Liolophura japonica. Comparative Biochemistry &

Physiology B 44B, 881–887.Teshima, S. & Kanazawa, A. (1978). Bioconversion of cholesterol

to 7-cholestenol in a chiton. Nippon Suisan Gakkaishi 44,1265–1268.

Teshima, S., Kanazawa, A., Yamada, I. & Kimura, S. (1982).Sterols of the chiton (Liolophura japonica): a new C30-sterol,(24Z)-24-propylidenecholest-7-enol, and other minor sterols.Comparative Biochemistry & Physiology B 71B, 373–378.

Tholleson, M. (1999). Phylogenetic analysis of Euthyneura(Gastropoda) by means of the 16S rRNA gene: use of a ‘fast’gene for ‘higher-level’ phylogenies. Proceedings of the Royal Society of

London B 266, 75–83.Treschow, A.P,, Hodges, L. D., Wright, PFA., Wynne, P. M.,

Kalafatis, N. & Macrides, T. A. (2007). Novel anti-inflammatory ω-3 PUFAs from the New Zealand green-lipped



mussel, Perna canaliculus. Comparative Biochemistry and Physiology, Part

B, 147, 645–656.Tripp, M. R. (1975). Humoral factors and molluscan immunity.

Pp 201–223 in K. Maramorosch and R. E. Shope, Eds.Invertebrate immunity: Mechanisms of Invertebrate Vector-Parasite

Relations. Academic Press, New York.Tsushima, M., Maoka, T. & Matsuno, T. (1989). Comparative

biochemical studies of caroteniods in marine invertebrates—thefirst positive identification of ε,ε-carotene derivatives andisolation of two new carotenoids from chitons. Comparative

Biochemistry & Physiology B. 93B, 665–671.Vakalia, S. F. & Benkendorff, K. (2005). Antimicrobial activity

in the hemolymph of Haliotis laevigata and the effects of a dietaryimmunostimulant. Pp. 29–36 in A. E. Fleming (Ed) Proceedings

of the 12th Abalone Aquaculture Workshop, McLaren Vale, Adelaide,

Australia. Abalone Aqauculture Subprogram, Fisheries Researchand Development Corporation, Canberra, Australia.

Vine, K.L, Locke, J.M, Ranson, M., Benkendorff, K,Pyne, S. G. & Bremner, J. B. (2007). In vitro cytotoxicityevaluation of some substituted isatin derivatives. Bioorganic &

Medicinal Chemistry 15, 931–938.Voogt, P. A. & Van Rheenen, J.W.A. (1974). Capacity of

synthesizing 3β-sterols in Mollusca. XII. Composition andbiosynthesis of 3β-sterols in Lepidochitona cinerea. Comparative

Biochemistry & Physiology B 47B, 131–137.Wagele, H, Klussmann-Kolb, A., Vonnemann, V & Med-

ina, M. (2008). Heterobranchia 1: The opsithobranchia. Pp385–408 in In Ponder, W. F. & Lindberg, D. R. (Ed) Phy-

logeny and Evolution of the Molluscs, University of California Press,Berkley.

WaGELE, H., Ballesteros, M. & Avila, C. (2006). Defensiveglandular structures in opisthobranch molluscs—from histologyto ecology. Oceanography and Marine Biology: An Annual Review 44,197–276.

Wahidullah, S., Guo, YPW., Fakhr, I. & Mollo, E. (2006).Chemical diversity in opisthobranch molluscs from scarcelyinverstigated Indo-Pacific areas. Pp 175–192 In G. Cimino andM. Gavagnin (Eds) Molluscs: Progress in Molecular and Subcellular

Biology Subseries Marine Molecular Biochemistry, Springer-VerlagBerlin Heidelburg.

Weil, W. (1994). Filler forming hardenable paste with water used tofill tooth cavity- contains dry mixt. of flat or hollow bone material,gelatin and opt. mollusk shell flour. Patent No. DE4223754.Accessed online esp@cenet database 20/02/2001.

Westley, C. & Benkendorff, K. (2008). Sex-specific Tyrianpurple genesis: precursor and pigment distribution in thereproductive system of the marine mollusc, Dicathais orbita. Journal

of Chemical Ecology 34, 44–56.Westley, C. & Benkendorff, K. (2009). The distribution of

precursors and biosynthetic enzymes required for Tyrian purplegenesis in the hypobranchial gland, gonoduct and egg massesof Dicathais orbita (Neogastropoda: Muricidae). Nautilus 123,148–153.

Westley, C. B., Vine, K. L. & Benkendorff, K. (2006).A proposed functional role for indole derivatives in reproductionand defence of the Muricidae (Neogastropoda: Mollusca).Pp. 31–44 in L. Meijer, N. Guyard, L. Skaltsounis, andG. Eisenbrand, Eds. Indirubin, the Red Shade of Indigo. Life inProgress Editions, Roscoff, France.

Whitman, W. B., Coleman, D. C. & Wiebe, W. J. (1998).Prokaryotes: The unseen majority. Proceedings of the National

Academy of Science 95, 6578–6583.Whittaker, V. P. (1960). Pharmacologically active choline esters

in marine gastropods. Annals of the New York Academy of Science 90,695–705.

Xu, Z. (1997). Pharmacological effects of zhenzhu jingmu oralliquid. Zhongguo Zhong Yao Za Zhi 22, 434–436.

Yamaguchi, Y., Nakanishi, Y., Shimokawa, T., Hashiguchi,S. & Hayashi, A. (1992). Structure elucidation of oxygenatedsterols from the eggs of sea hare, Aplyisa juliana. Chemistry Letters

1992, 1713–1714.Yamazaki, M. (1993). Antitumor and antimicrobial glycoproteins

from seahares. Comparative Biochemistry & Physiology C 105,141–146.

Yasuda, S. & Fukamiya, N. (1977). Hydrocarbons of a chiton.Nippon Suisan Gakkaishi 43, 1249.

Yeung, H-C. (1983). Handbook of Chinese Herbal Formulas. Institute ofChinese Medicine, Rosemead, LA, USA.

Zatylny, C., Gagnon, J., Boucard-CAMOU, E. & Henry, J.(2002). ILME: a water-bourne pheromonal peptide releasedby the eggs of Sepia officinalis. Biochemistry & Biophysics Research

Communications 275, 217–222.Zhao, J. M., Song, L. S., Li, C. H., Ni, D. J., Wu, L. T., Zhu, L.

& Wang, H. (2007). Molecular cloning, expression of a bigdefensin gene from bay scallop Argopecten irradians and theantimicrobial activity of its recombinant protein. Molecular

Immunology 44, 360–368.


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