[Studies in Natural Products Chemistry] Volume 42 || Plant Secondary Metabolites

Chapter 9

Plant Secondary Metabolites:Structure–Activity Relationshipsin Human Health Preventionand Treatment of CommonDiseases

Silvia R. Leicach and Hugo D. ChludilChemistry of Biomolecules, Department of Applied Biology and Food, School of Agronomy,

University of Buenos Aires (UBA). Avda. San Martın 4453, Ciudad Autonoma de Buenos Aires,

C1417DSE, Argentina

Chapter OutlineIntroduction 267

Nutraceuticals 268

Plant Chemical Defenses 272

Natural Products in Medicine 273

Phenolic Compounds 275

Ellagic Acid 276

Phenolic Acids 276

Coumarins 277

Flavonoids 278

Isoflavonoids 282

Catechins 283

Anthocyanins 284

Less Distributed Phenolics 286

Quinones 287

Xanthones 288

a,b-Unsaturated d-Lactones 289

Terpenoids 289

Triterpenoids 291

Nitrogen Compounds 292

Alkaloids 292

Sulfur Compounds 295

Concluding Remarks 295

Acknowledgments 296

References 297

INTRODUCTION

Intuitive knowledge about interactions with other living organisms has

accompanied mankind since its very beginning, particularly those related to

toxic, allergenic, and/or healing properties of plants. Plants have been thera-

peutically used to prevent and/or to cure diseases for millenniums;

Studies in Natural Products Chemistry, Vol. 42. http://dx.doi.org/10.1016/B978-0-444-63281-4.00009-4

© 2014 Elsevier B.V. All rights reserved. 267

http://dx.doi.org/10.1016/B978-0-444-63281-4.00009-4

archeological findings have demonstrated early breeding of species with

strong effects on human mind such as coca (Erythroxylum coca), hemp (Can-nabis sativa), and poppy (Papaver somniferum) by different civilizations.

Plant extracts have been used over three millennia in China to control dis-

eases; their earliest written document being Yellow Emperor’s Canon of Med-

icine, a compilation of their knowledge from 500 BC to 300 BC [1].

Egyptians have also described the use of medicinal plants in Ebers papyrus

more than a millennium ago, and Indian civilization has documented botani-

cal’s medicinal properties in Ayurveda, around 900 BC [2].

Greek physician Hippocrates (fifth century BC), the first European to

explore plants with medicinal purposes, was followed by Romans Dioscorides

(first century AD) and Galen (second century AD). Pharmacological knowl-

edge was further enriched by Arab scholars (Avicenna, Ibn al-Baitar) between

tenth and twelfth centuries AD. The first physician to suggest the existence of

active principles in medicinal plants that would exert their biological effects

in a dose-dependent manner was Paracelsus (1493–1541). Isolation of mor-

phine from Opium latex by Serturner at the beginning of nineteenth century

represented the first research work leading to a pure active principle that

demonstrated to have higher therapeutic potential than the parent extract.

Other bioactive pure structures such as alkaloids, emetine (1817), atropine

(1819), quinine (1820), caffeine (1820), and cardiac glycoside digitoxin

(1841), were obtained in the following decades [3].

Ancient American people have also developed knowledge about medi-

cines and poisons from native plants, being able to diagnose and treat physical

and spiritual illnesses in their own way. Infusions of bark of cinchona tree

(Cinchona officinalis) cultivated in South American Incas royal households

were early used against fevers. This species was known in Europe when

Jesuits carried plant samples in their way back. Aymaras used the word coca

meaning tree, to name E. coca; its leaves were chewed for centuries by differ-

ent cultures from the Andean plateau as a stimulant to treat altitude-derived

symptoms and against appetite, thirst, and fatigue [2].

Natural resources have been early used by primitive people to enhance

physical and mental abilities, to treat common ailments (fever, poisoning, ani-

mal biting, or parasitic infection), and later when agricultural practices were

developed, to protect their crops.

NUTRACEUTICALS

Increase in population lifespan has been accompanied in the last decades by a

higher incidence of age-related diseases such as neurodegenerative and cardio-

vascular disorders and cancer, most of which have been proved to result from

multifactorial processes in which different cellular pathways become abnor-

mal. Oxidative stress has been thoroughly demonstrated to play a major role

in their pathogenesis. Vegetable-derived foodstuff includes a variety of

Studies in Natural Products Chemistry268

bioactive compounds, antioxidants among them, which have been proved to

exert chemopreventive effects delaying such disorders. In combination with

one another, they may enhance their effectiveness to improve more than one

abnormal pathway, and/or display a broader activity range. Liu [4] has pointed

out that most antioxidant activity of fruit and vegetables comes mainly from

phenolics and flavonoids, suggesting that additive and/or synergistic effects

among them contribute to their antioxidant and anticancer properties.

Ancient Egyptian texts include reports on herbs and foods prescribed by

physicians centuries ago to treat various ailments. Hippocrates pointed out

the strong relationship between food and health, emphasizing that difference

in diseases depends on nutriment; he said “Let thy food be thy medicine

and thy medicine be thy food” reflecting the preventive and therapeutic roles

of bioactive components in dietary components with particular emphasis on

their high level of safeness and versatility [5,6].

Food beneficial effects on health have been scientifically confirmed in our

days by epidemiological studies, showing that countries such as India and

China, where vegetables, fruits, and spices represent an essential part of human

diet, have lower incidence of cancer and cardiovascular diseases. Valuable

properties of mushrooms, earlier mentioned by the Vedas, were also known

by Romans that considered them Foods of the Gods and Chinese people that

called them “Elixir of Life” [7].

The term nutraceutical, coined in 1989 by Stephen DeFelice, arises from

combination of two words, “nutrition” and “pharmaceutical,” and defines food

or food products that can provide medical and health benefits, including preven-

tion and treatment of disease. Whole grains, beans, and herbs are known to

include natural products with therapeutic potential, but fruits and vegetables

are their main natural source. Edible mushrooms have also been reported to have

medicinal properties [8,9]. Fortified foods, dietary supplements, herbal pro-

ducts, genetically engineered foods, and processed products such as cereals,

soups, and beverages are considered nutraceuticals, even when in most cases

bioactive components have not been scientifically standardized [10].

National Academy of Sciences (USA) [11] has recommended a daily intake

of at least five servings of fruit and vegetables, particularly citric fruits,

carotene-rich fruits and vegetables, and cruciferous vegetables to reduce the risk

of both cancer and heart disease; scientific research has demonstrated that the

presence of dietary fibers and polyphenols in fruits and vegetables reduces the

risk of cancer because of their antioxidant and anti-inflammatory properties.

Apple nutraceutical potential has been acknowledged for a long time;

some of its skin components have been associated with the prevention of

cancer, cardiovascular diseases, pulmonary function failures, and age-related

cognitive decline. Apple peel contains high concentrations of antioxidant

polyphenolics, apigenin among them that has been associated with anti-

inflammatory, antispasmodic, and antioxidant activities. It has been proved

to induce apoptosis and to inhibit breast and ovarian cancer [12,13]. Other

Chapter 9 Plant Secondary Metabolites and Human Health 269

abundant component of apple peel, the triterpenoid ursolic acid present in its

wax, has been long known for its medicinal applications as antifungal, anti-

bacterial, anti-inflammatory, and antitumor drug [14]. Oranges, cherries, red

grapes, most berries, purple corn, and red sorghum contain anthocyanins,

ionic polyphenolic pigments that are responsible for their colors; they are used

as food additives and have been reported to exhibit antioxidant, anti-

inflammatory, and antiallergic effects [15]. Antioxidant potential of blueber-

ries and red grapes has been also related to the stilbenic derivative resveratrol,

considered to play a preventive role against aging, diabetes, cancer, and heart

diseases [16]. Anthocyanins and other wine polyphenols such as resveratrol

and epigallocatechin gallate have been suggested to contribute to wine’s anti-

oxidant potential [17,18]; it has been suggested that moderate wine consump-

tion may contribute to prevent coronary diseases and to reduce relative risk

for clinical dementia caused by Alzheimer’s disease [19,20]. Dietary supple-

ments based on blueberry extracts containing the same polyphenols have been

reported to reduce neurological deficits in aged animal, probably playing a

protective role against neuronal apoptosis. Catechins, particularly abundant

in green tea, have been demonstrated to exhibit antioxidant, diuretic, and

stimulant properties. Several fruits and nuts produce ellagitannins, which are

easily hydrolyzed to ellagic acid, another chemopreventive polyphenol exhi-

biting antioxidant and anticancer potential.

Dietary relevance of soy has been increased in the last decades and nutraceu-

tical potential of its chemical components has been thoroughly investigated. Soy

isoflavones known to exert phytostrogenic effects, plus its saponines and trypsin

inhibitors have been associated to its chemopreventive properties [21]. Genis-

tein, main isoflavone in soybean, has been demonstrated to affect multiple bio-

chemical functions in living cells; its activity as tyrosine kinase inhibitor

affecting cell growth and proliferation signal cascades is one of them. It has been

suggested that consumption of genistein through soy-derived foods during

childhood and adolescence may protect women at risk of breast cancer, with

similar effects on colon, prostate, and thyroid cancers [22]. Epidemiologic stud-

ies suggest that soy phytoestrogens may play an important preventive role

against hormone-dependent cancers. Cross and coworkers [23] have related

their protective effect to a lower incidence of colorectal cancer in women than

in men, suggesting that soy phytoestrogens may help prevent colorectal cancer

in both sexes. They have demonstrated that soy and genistein can enhance the

synthesis of antimitotic vitamin D metabolite 1,25-dihydroxycholecalciferol,

slowing tumor growth and progression. However, concerns have emerged on

the potential of soy isoflavones to stimulate growth of estrogen-sensitive breast

tumors in postmenopausal women at high risk for breast cancer, where estrogen

therapy is known to be used. It has been reported that genistein can behave as

estrogen agonist in vivo and in vitro enhancing proliferation of cultured human

breast (MCF-7) cancer cells [24]. Epidemiologic evidence suggests something

different showing about one-third less breast cancer risk in Asian women,


known to have higher soy intake, compared to Western women. Moreover,

Japanese breast cancer patients have also shown higher survival rates. Until

now, there is no enough clinical evidence to support that soy isoflavones can

increase breast cancer risk in healthy women or worsen prognosis of breast can-

cer patients when ingested at the usual amounts in Asian soy food. American

Cancer Society has concluded in 2006 that breast cancer patients can daily con-

sume three servings of traditional soyfoods without deleterious effects; never-

theless, they have also warned against powders and supplements containing

high concentrations of isoflavones [25].

Besides polyphenols, some terpenic derivatives such as phytosterols and

carotenoids are ubiquitous components in most plant species considered to

exhibit nutraceutical potential. Because of its wide distribution in plant king-

dom, b-sitosterol represents more than half the phytosterols in human diet,

which also includes campesterol and stigmasterol; the last one particulary

abundant in soybean, calabar, and rape seed has been claimed to play a che-

mopreventive role against osteoporosis and ovarian, prostate, breast, and

colon cancers, and also to exhibit hypolipidemic effect. Plant sterols and their

saturated stanol derivatives have been marketed as dietary supplements based

on their hypocholesterolemic effect that has been related to their capacity to

compete with dietary and biliary cholesterol for intestinal absorption in mixed

micelles. Even when consumption of 2g phytosterols per day by healthy

human does not cause health risks since the major part of it is directly elimi-

nated via liver and biliary system; serious concerns have been developed

about their adverse cardiovascular effects on young subjects with homozygous

sitosterolaemia characterized by high phytosterol concentrations, xanthomato-

sis, and premature, frequently lethal atherosclerosis [26–28].

Several fruits and vegetables are known to produce tetraterpenic chromo-

phores called carotenes. Red fruits and vegetables such as tomato, red pepper,

red carrot, apricot, papaya, pink guava, and watermelon contain lycopene, a

powerful quencher of oxygen singlet at cellular levels, known for its antioxi-

dant potential and chemopreventive capacity against prostate cancer, athero-

sclerosis, and coronary heart disease [29,30].

Cruciferous vegetables, such as cabbage, cauliflower, broccoli, Brussels

sprouts, kale, collards, turnip, and radish, have long been recognized as nutra-

ceuticals because of the presence of glucosinolates and isothiocyanates in

their chemical composition, both sulfur compounds also containing nitrogen.

Epidemiological data have demonstrated positive health effects in people con-

summing high levels of these vegetables, showing an inverse correlation

between consumption of one or more Brassica species and risk of lung, stom-

ach, colon, and rectal cancer. Isothiocyanates, product of glucosinolates

hydrolysis, have been suggested to affect different processes related to chem-

ical carcinogenesis such as the DNA-binding, and mutagenic activity of pro-

mutagens [31]. Lund [32] has agreed on preventive effects of dietary

combinations of these species related to the ability of isothiocyanates and


nitriles to modify xenobiotic metabolizing enzymes and to induce cell cycle

arrest and apoptosis.

Spices have been also considered to be nutraceuticals. Curry powder, a

commercial spice blend from India used nowadays worldwide, includes tur-

meric, obtained from Curcuma longa. Beneficial effects of turmeric, known

in Europe as Indian saffron since medieval times, have been associated to

one of its components, curcumin with antihypertensive, anti-inflammatory,

antioxidant, and cancer preventive activities [33–35].

PLANT CHEMICAL DEFENSES

Plant secondary metabolites are fundamental to all aspects of plant–

environment interactions, their ecological role usually differing from their

potential in medicine. Chemical and physical defenses, essential for plants

to succeed in plant communities, have allowed their survival despite environ-

mental stressful conditions caused by biotic factors such as invasive patho-

gens, herbivores, and competitors. Chemical defenses vary among plant

species reflecting each evolutionary history and allowing their classification

through chemical taxonomy according to the particular array of secondary

metabolite families they produce. Benzoic and cinnamic acids, phenolic deri-

vatives, flavonoids, terpenoids, alkaloids, and long-chain hydrocarbon com-

pounds and derived alcohols, carbonylic and carboxylic compounds, are

among the most common defensive chemicals in plant kingdom. Glucosino-

lates, amines, tiophenes, cyanogenic glycosides, disulfures, and sulfoxides

are less distributed and restricted to particular genera.

Environmental factors have been proved to modulate chemical defenses

production, generally enhancing it under stressful conditions and also affect-

ing nutraceutical value of plant-derived foods [36–40]. We have reported

the data on abiotic and biotic environmental effects on secondary metabolites

production by several plant species [41–48]. Studies performed in the last

50 years have identified nutrients, light, and water deficits, and extreme tem-

peratures as common abiotic factors affecting production of phytochemicals,

soil quality playing a main role on it. Changes in pH, soil aggregates mean

weighted diameter, and extractable phosphorus are also critical abiotic para-

meters, deviations from their optimum values in Argentinean continuously

cultivated soil have been proved to increase phytotoxins production by Che-nopodium album. This edible weed causing economic losses in crop produc-

tion that exhibits cross and multiple resistances to synthetic herbicides is

consumed in American countries as alternative source for nutrients [42]. We

have also reported an increment in its flavonoid production under those con-

ditions, which increased its nutraceutical value justifying its consumption as a

source for free radical-scavenging phytochemicals [44].

Alkaloid production enhancement by environmental stress can be particu-

larly dangerous when related to an invasive weed species such as Senecio gri-sebachii. We have reported it to produce higher amounts of toxic pyrrolizidine


alkaloids when grown in overexploited cropping soils, representing an impor-

tant hazard because this weed grows in crops, pastures, and fields near bee-

hives, and pyrrolizidine alkaloids have been already detected as foodstuff

contaminant in cereals, offal, eggs, milk, and honey [47].

Environmental pollution in addition to resistance development by agricul-

tural pests has triggered scientific interest in more sustainable methods to con-

trol pests in agriculture and forestry, including the use of resistant plants or

integrated cropping strategies in which enhanced plant chemical defenses may

contribute to crop protection diminishing agrochemicals overuse. Contribution

of biotechnology and breeding techniques to the enhancement of defensive che-

micals and nutraceuticals production has allowed their use in sustainable pest

control and human health prevention and treatment. Controlled stress treatments

have been evaluated on fruit and vegetable species [49]. Metabolic engineering

strategies to obtain specific design products with higher nutraceutical amounts

and/or free of undesired byproducts have been also developed; an enhancement

in nutraceuticals production by lactic acid bacteria has been reported [50,51].

Nutraceutical value and seed vigor of light-germinated fava bean (Vicia faba)seedlings has been improved by priming with natural elicitors that stimulated

phenylpropanoid pathway enhancing production of total phenolics and seed

vigor; these seedlings are a rich source of levo-dihydroxyphenylalanine

(L-DOPA), precursor of neurotransmitter dopamine [52].

Resistance development to previously effective medicines by dangerous

pathogens that have trespassed boundaries between animal kingdom and

men causing a wide spectrum of zoonotic diseases represents a serious hazard

to both animals and human also encouraging research work on biologically

active phytochemicals. Emergence of new zoonotic diseases in agricultural

and clinical environments as much as existence of environmental reservoirs

of resistance represents a threat to human health [53]. Escherichia coli, Cam-pylobacter jejuni, Salmonella enterica, and Listeria monocytogenes infectionsare common examples of foodborne illnesses caused by pathogens that have

developed resistance to previously effective drugs [54,55,56]. Resistant bacte-

ria have been shown to adhere to damaged tissues or implants encasing them-

selves in a polysaccharide plus protein matrix to form a biofilm, very difficult

to treat. The same behavior has been observed in persistent Pseudomonas aer-uginosa lung infections that do not respond to long-term antibiotic therapy in

cystic fibrosis patients [57,58].

Studies on genetic and biochemical diversitymay not only result in alternative

answers to diminish deleterious agriculture and forestry impacts on environment

but also contribute to finding new potentially useful chemical scaffolds formedic-

inal purposes, within a sustainable utilization of natural resources.

NATURAL PRODUCTS IN MEDICINE

Sedentary modern lifestyle, wrong diets, and multiple stress conditions have

contributed to development of ubiquitous diseases such as diabetes,


atherosclerosis, coronary heart disease, and cancer, most of them involving

chronic inflammation processes mediated by proinflammatory cytokines,

whose secretion can be regulated by nuclear factor-kappaB (NF-kB). Inflamma-

tion is triggered by long-term oxidative stress produced by reactive oxygen spe-

cies (ROS) and reactive nitrogen species (RNS) that can decrease cellular

antioxidant capacity and damage primary metabolites such as DNA, proteins,

and lipids consequently affecting numerous metabolic paths. Complex lipids,

ubiquitous components of nervous tissues, can be affected by oxidative stress

triggering neurodegenerative disorders such as Alzheimer and Parkinson’s dis-

eases [59]. Human diseases have been treated using a large number of bioactive

natural products with stereochemical and functional characteristics that have

been defined by their biological role and determined by the enzymes involved

in each biosynthesis pathway. Phytochemicals unique shape allows them to

complement enzymes active sites according to a space-filling model, and their

strategically distributed functional groups to interact with biological surfaces

by noncovalent interactions such as hydrogen-bonding, p-stacking, hydropho-bic, and dipolar interactions. Easy biological transformation and possible cyto-

toxic effects are other natural products features to be considered in their

medicinal use. Chemical characteristics of most representative families of sec-

ondary metabolites involved in the prevention and/or treatment of diseases will

be discussed and associated to their bioactivity later in this chapter.

Chemoprotective phytochemicals have been used for a long time to pre-

vent undesired cellular functions caused by abnormal proinflammatory signal

transmission. Many of them can reduce chronic inflammation by specifically

interfering with NF-kB action [60–62]. Natural antioxidants, mainly polyphe-

nolic derivatives, interfere with different targets in oxidative sequence;

decreasing localized oxygen concentrations, preventing chain initiation by

scavenging ROS and RNS, binding metal ions associated to their generation

and/or to lipid peroxides transformation to peroxyl and alkoxyl radicals, and

also chain-breaking by scavenging intermediate radicals hence preventing

continued hydrogen abstraction [63].

Extensive research in the last decades has proved that phenolic derivatives are

the most effective enhancing cellular antioxidant capacity and/or interfering with

carcinogenesis, as blockers (affecting initiation stage) or suppressors (impeding

promotion and/or progression stages). They may also prevent lipids oxidative

damage by interfering with a particular stage of the process such as scavenging

free radicals, arresting chain reactions, and/or chelating divalent cations known

to initiate oxidative events [64]. In vitro and in vivo trials have proved them to

affect multiple cell targets associated to chronic inflammation by interfering with

receptors for signal transduction or interacting with transcription complexes [62].

Isoflavones genistein and dihydrodaidzein have been proved to increase endothe-

lial function by eliciting vasorelaxation via enhanced bioactivity of nitric oxide

(NO); resveratrol has been also proved to enhance vasodilation by promoting

NO production [65,66]. Polyphenols from Pterocarpus santalinus extracts have


been shown to inhibit pathogenic microbial strains, including Enterobacter aero-genes and Staphylococcus aureus [67]. Kaempferol and epicatechin have been

proved to prevent neuronal apoptosis, exhibiting selective actions on protein

kinase signaling cascades [68]. Other flavonoids, such as isoflavones biochanin

A and daidzein, and catechins have been proved to inhibit breast cancer resis-

tance protein that lowers the action of chemotherapeutic drugs [69].

Besides the wide spectrum of diseases affecting mankind described above,

it has been estimated that parasitic diseases affect over one billion people

worldwide, with more than 80% infected population in tropical areas known

to have higher poverty levels. Medicinal plants have been used for centuries

to treat them; phytochemicals like the alkaloid quinine represent a milestone

in the treatment of parasitic diseases caused by Plasmodium, Leishmania,and Trypanosoma species. Resistance development and/or long treatments

do not always completed contribute to the dramatic impact of these illnesses.

Research on natural products in this area still represents a good prospect to find

novel bioactive structures based on which new less expensive drugs can be

developed; use of additive and/or synergistic combinations of synthetic drugs

and phytochemicals has been increasingly encouraged in the last decades.

PHENOLIC COMPOUNDS

Benzoic and cinnamic acid derivatives and flavonoids are the two most

distributed phenolics within plants. Polyphenolic units are biosynthesized

via shikimate pathway, resulting in cinnamic acids C6–C3 phenylpropanoid

building block that also contributes to other plant phenolics backbones such

as those from flavonoids (C6–C3–C6), anthocyanidins (C6–C3–C6), and

coumarins (C6–C3). Stilbeneoids (C6–C2–C6) and benzoic acid derivatives

(C6–C1) such as gallic and ellagic acids are also synthesized through this met-

abolic pathway (Fig. 1).

O

O

O

O

HO

HO OH

OH

COOH

HOOH

OH

O O

COOHCOOH

O+

O

O

Anthocyanidin Stilbene Coumarin Flavonoid

trans-Cinnamic acid Ellagic acid Benzoic acid Gallic acid

FIGURE 1 Polyphenolic backbones.


Polyphenolic antioxidant activity, a fundamental feature for their activity

on multiple biological targets, has been early correlated to their chemical

structures. Number and position of hydrogen-donating hydroxyl groups

(OH) in polyphenolic backbone has been proved to determine their free radi-

cal scavenging and antioxidant activities. Glycosylation generally reduces

antioxidant capacity, which is also modulated by conjugated double bonds,

and other hydrogen-donating groups such as amino and tiol. Electron delocal-

ization capacity of polyphenols turns them into stable radicals explaining their

action as hydrogen-donating and radical-scavenging compounds.

Several polyphenols can inhibit free radical production by interfering

enzymes action; they have been proved to inhibit topoisomerases or phospha-

tidylinositol kinases. Their ability to chelate metal ions involved in free radi-

cals generation has been also described; however, they may chelate metal ions

in the opposite way enhancing their catalytic potential in free radical produc-

tion [70]. Beneficial effects of exogenous antioxidants have been proved to

turn into deleterious when administered at high doses. Polyphenol cytotoxicity

is related to the fact that some of them can play antioxidant or prooxidant

roles depending on the concentration, the target molecule, and the free radical

source. Under particular conditions, they can induce significant oxidative

damage on primary metabolites [71,72]. At adequate doses, they can maintain

and/or reestablish redox homeostasis ensuring biological systems health

[73,74].

Ellagic Acid

Ellagitannins, natural polymers that cannot be absorbed in vivo, are easily

hydrolyzed in colon to give ellagic acid that can be metabolized by human

microflora (Fig. 1). Larrosa and coworkers [75] have reported that the antic-

arcinogenic effect of dietary ellagitannins is due to their hydrolysis product,

ellagic acid, which has been proved to induce apoptosis of colon cancer

Caco-2 cells without affecting normal colon cells.

Phenolic Acids

Multiple-drug-resistant tuberculosis requires nowadays long course treatments

with combination of antibiotics, usually exhibiting negative side effects. Cur-

rent concerns about the fact that many patients from developing countries give

up their treatments enhancing Mycobacterium tuberculosis multidrug resis-

tance have encouraged the search for new low toxic antimycobacterials or

synergistic agents to control these pathogens. Two isomers of cinnamic acid,

trans- and cis-, are naturally produced by plants as antimicrobials, predomi-

nating the first one because of its much higher stability. trans-Cinnamic acid

(Fig. 1) has been proved to be effective as antibiotic, antioxidant, anti-

inflamatory, anticancer, and antimalarial, also enhancing activity of various


antibiotics against Mycobacterium avium and exerting synergistic activity on

several drugs against M. tuberculosis. Chen and coworkers [76] have evalu-

ated cinnamic acids synergism levels on two first-line antituberculosis anti-

biotics, isoniazid and rifampicin, proving cis-isomer to be almost 120-fold

more effective than trans-one, and suggesting it should be considered a poten-

tial mycobactericide and/or a synergistic agent against tuberculosis.

Anticancer activity and cytotoxicity of natural and synthetic derivatives of

caffeic (3,4-dihydroxycinnamic) and gallic acids (Fig. 1) have been investi-

gated in terms of the number of phenolic hydroxyl groups and the carboxylate

carbon chain length and/or insaturation degree. A double bond in the side

chain was found to increase both activities, while trihydroxylated derivatives

produced higher antiproliferative effects and cytotoxicity than dihydroxylated

ones [77].

Coumarins

Chinese medicine has used different plant species containing coumarins to

treat several health disorders. Coumarin (1,2-benzopyrone) (Fig. 1) resulting

from ortho-hydroxycinnamic acid cyclization has been reported to help in

slow-onset long-term reduction of lymphoedema, probably by macrophage-

induced proteolysis of edema protein [78]; however, it exhibits low bioavail-

ability due to its readily hydroxylation and glucuronidation by human liver.

Anticoagulant dicoumarol and its synthetic derivative warfarin are bioactive

coumarin derivatives. Scoparone, a versatile 6,7-dimethoxycoumarin isolated

from Artemisia scoparia, has been proved to scavenge ROS, inhibit tyrosine

kinases and potentiate prostaglandin generation, reduce human peripheral

mononuclear cells proliferative responses, relaxe smooth muscle, and reduce

total cholesterol and triglycerides. Angelica pubescens, a Chinese herbal med-

icine, produces another active coumarin, osthole, which has been demon-

strated to cause hypotension in vivo, and platelet aggregation inhibition and

smooth muscle contraction in vitro (Fig. 2). It has been also suggested that

O O

H3CO

H3CO

O OH3CO

Scoparone

Osthole 5-

dimethoxy-3�-hydroxy-4-phenylcoumarin

O

OH

HOHO

OHO

H3CO O O

OHRO

R = H 5-O-b-D-Glucopyranosyl-7,4�-

R = CH3 O-b-D-Glucopyranosyl-7-methoxy-3�,4�-dihydroxy-4-phenylcoumarin

FIGURE 2 Bioactive coumarins.


this natural product can interfere with calcium influx and with cyclic nucleo-

tide phosphodiesterases [78].

Two natural antiparasitic coumarins, 5-O-b-D-glucopyranosyl-7,40-dimethoxy-30-hydroxy-4-phenylcoumarin and 5-O-b-D-glucopyranosyl-7-methoxy-30,40-dihydroxy-4-phenylcoumarin (Fig. 2) isolated from Hintonialatiflora stem bark, have been reported to exhibit antimalarial activity against

the development of Plasmodium berghei schizonts in vitro, the second one alsoshowing significant activity in vivo [79].

Flavonoids

Pharmacological potential of plant flavonoids and structure–activity relation-

ships has been reviewed by different authors [59,80–82]. Most ubiquitous fla-

vonoids are derived from a flavan skeleton (2-phenylbenzopyrane) exhibiting

a benzene ring (A) condensed with a heterocyclic six-membered ring (C) hav-

ing a g-pyrone, pyran, or pyrilium structure that is substituted by a phenyl ring

(B) at C-2 in flavonoids or C-3 in isoflavonoids (Fig. 3). Major flavonoids can

be further grouped as flavones, isoflavones, flavonols, flavanones, flavanols

(catechins), and anthocyanidins; flavones and catechins showing higher activ-

ities against ROS.

Antioxidant activity of flavonol derivatives kaempferol, quercetin, morin,

myricetin, and rutin has been suggested to explain their anti-inflammatory,

antiallergic, antiviral, as well as anticancer activities. It has been confirmed

that quercetin, kaempferol, and apigenin (Fig. 4) can induce cellular antioxi-

dant system by increasing intracellular glutathione levels [83].

O

O

O

A C

B

12

345

67

81�

2�3�

4�

5�6�

Flavonoid (g-pyrone) Isoflavonoid (pyran)

FIGURE 3 Major flavonoid backbones.

O

OH

OHOOH

HO

R

O

OH

OOH

HO

R

O

OH

OOH

HO

OH

R1

R2

R3

R1 = OH R2 = R3 = H MorinR1 = H R2 = R3 = OH Myricetin

R = H ApigeninR = OH Luteolin

R = H KaempferolR = OH Quercetin

FIGURE 4 Ubiquitous flavonols.


Flavonols have been proved to display cardioprotective effects on animals,

inhibiting low-density lipoprotein (LDL) oxidation and reducing myocardial

postischemic damage in rats. They can reduce ROS damages by chelating

redox-active metals, activating antioxidant enzymes, reducing alpha-tocopherol

radicals, and/or inhibiting oxidases, and also giving effective protection against

peroxynitrite toxicity [81]. Some flavonols can improve calcium homeostasis

balance by binding sarco/endoplasmic reticulum Ca2þ-ATPase, which changes

its conformation affecting its activity [84]. Others have been also described as

antimicrobials, apigenin, genkwanin, kaempferol, rhamnazin, quercetin-5,30-dimethylether, and rhamnocitrin (Figs. 4 and 5) isolated from Combretum ery-throphyllum have been proved to be active against Vibrio cholera and Entero-coccus faecalis. The last two were also effective against Micrococcus luteusand Shigella sonei [85].

Flavonol free radical-scavenging activity depends on their substitution

pattern; it has been reported to be strongly enhanced by B ring O-dihydroxy

substitution (catechol arrangement) that gives a higher stability to ortho-semiquinone radical. O-methylation of B ring hydroxyl groups has been

shown to strongly decrease antioxidant potential; methylation of kaempferol’s

(one hydroxyl group at B ring) results in 50% loss of its scavenging activity.

Rutin (Fig. 5), most abundant glycoside in C. album showing a catechol

moiety, has been demonstrated to exhibit significantly higher scavenging

potential than corresponding kaempferol glycoside lacking it [44]. Luteolin

(Fig. 4) with a catechol arrangement at B ring has been also reported to be

a stronger peroxyl radical scavenger than kaempferol exhibiting a 3-OH group

at C ring, suggesting that catechol arrangement at B ring has stronger effect

than the C-3 hydroxyl group. Quercetin exhibiting both structural features

behaves as a much stronger free radical scavenger than luteolin, confirming

that C-3 hydroxyl group is also significant.

Both a�b unsaturated carbonyl structure and 3-OH group at C ring have been

reported to increase it [44]. Polymerization leading to more stable flavonoid radi-

cals through conjugation and electron delocalization also does the same.

Wang and Zheng [86] have earlier reported that flavonols rutin and morin

exhibiting a�b unsaturated carbonyl plus 3-OH group in C ring showed much

higher chain-breaking capacity over autoxidation of linoleic acid than flava-

nones naringin and hesperidin (Figs. 4 and 6) lacking both.

O

OH

OH

H3CO

O

Genkwanin

O

OH

OH

H3CO

O

OCH3

OH

Rhamnazin

O

OH

OH

H3CO

OOH

Rhamnocitrin

FIGURE 5 Antimicrobial flavonols.


Flavonols occur mainly as glycosides in plants, their absorption level after

ingestion depending in part on sugar group’s nature. It has been shown that

glucoside bioavailability is almost fivefold that of rutinoside, suggesting

that they can be actively absorbed from small intestine, whereas rutinosides

seem to be absorbed from colon after losing glycosidic moiety [87]. Glycosi-

lation has been also proved to modulate these compounds antioxidant po-

tencial. Natural benzo-g-pyrones often occur as O-glycosides with glucose

as the most common glycosidic unit; galactose, arabinose, and rhamnose,

and disaccharide glucorhamnose have been also identified in plant-derived

foodstuff. Glycosides have shown less scavenging potential than corres-

ponding aglycones; their activity decreases as glycosidic moieties number

increases, being also affected by position and identity of those groups. It

has been reported that luteolin and quercetin were much more effective as

free radical scavengers than corresponding 3-, 40- and 7-O-glucosides and that

glycosylation at 3- or 7- resulted in higher bioactivity losses than in 40- posi-tion [88,89].

Flavonols have been demonstrated to interfere with multiple targets in

angiogenesis, known as key step in solid tumors development and progres-

sion, and also associated with other pathological conditions such as psoriasis,

rheumatoid arthritis, and diabetic retinopathy. This complex process needs a

sequential occurrence of cellular events involving enzymes; flavonols have

been proved to interfere with tyrosine kinases and protein kinase

C activities [90,91]. Luteolin (Fig. 4) has been demonstrated to inhibit tumor

invasion and angiogenesis [92]; more recently, it has been suggested to be a

useful adjuvant to interferon-b in multiple sclerosis (MS) therapy; it has been

also proved to inhibit experimental allergic encephalomyelitis, a model of MS

in rodents, and to have antioxidant and anti-inflammatory effects, including

inhibition of activated peripheral blood leukocytes from MS patients [93].

OHO

H3C

OH OH

O

OH

OOH

O

OH

HOHO

O

OH3C

OHOH

HOO

O

OHHO

HO

O

OH

O

OH O

OCH3

O

OH3CHO

HOOH

O

OH

OOH

HO

OH

OO

OHOHHO

O

NaringinHesperidin

Rutin

FIGURE 6 Flavonol glycosides.


Nobiletin and tangeritin (Fig. 7), polymethoxylated flavones found in citrus

fruits peel, have been proved to play a cytostatic role, inducing cell cycle

arrest in breast cancer, gastric adenocarcinoma, and human melanoma cells

significantly blocking proliferation without apoptosis [94]. They have been

also demonstrated to prevent cardiovascular disease reducing hepatic produc-

tion of cholesterol-containing lipoproteins. Whitman and coworkers [95] have

reported that in addition to reducing plasma cholesterol concentrations,

nobiletin may prevent atherosclerosis at vascular wall level by inhibiting mac-

rophage foam-cell formation.

Preliminary studies have shown that tangeritin, used in plant-derived

menopausal medications, has hypolipidemic effects lowering cholesterol in ani-

mals [96], and chemoprotective effects against Parkinson’s disease on rats [97].

Tangeritin has been also demonstrated to be an effective tumor growth and

invasion inhibitor on human MCF 7/6 breast cancer cells in vitro; however,it has been shown to antagonize tamoxifen tumor-suppressing effect when

simultaneously used with it [98].

HIV has affected more than 40 million people in last three decades. Mul-

tiple steps in HIV-1 cycle have been reported to be interfered by flavones and

their derivatives (Fig. 8). Early reports have described inhibition of HIV-1

transcription by 5,7-dihydroxyflavone chrisin that stops casein kinase-II activ-

ity [99]. More recently, it has been reported that scutellarin inhibits viral

transmission on HIV-1 strains affecting its reverse transcriptase activity, par-

ticle attachment, and cell fusion [100]. Antitrypanosomal and antileishmanial

activities without cytotoxicity in vitro and in vivo have been reported for 7,8-

dihydroxyflavone and quercetin [101].

Malaria and fever have been treated for over two mileniums with Artemi-sia annua, called “green herb” by Chinise people. Besides artemisinin,

O

O

H3CO

OCH3

OCH3

OCH3OCH3

OCH3

OCH3

H3CO

OCH3O

O

H3CO

H3CO

Nobiletin Tangeritin

FIGURE 7 Citrus fruits peel flavones.

O

OOH

HO O

OHHO

HO

OHO

HO

OH

O

OH O

O

Chrysin Scutellarin

FIGURE 8 Anti-HIV flavones.


A. annua has been found to produce two antiparasitic methoxylated flavones,

artemetin and casticin (Fig. 9). Extracts from Artemisia absinthium have been

also reported to have antiprotozoal effects against Trypanosoma brucei,Trypanosoma cruzi, and Leishmania infantum [102].

Antiparasitic action of flavonoids is related to C-30 and C-40 hydroxylgroups, substitution of their hydrogen atoms for methyl group strongly dimin-

ishing it. Casticin has been reported to exhibit more than twice the activity of

artemetin against L. infantum and sixfold more active against T. cruzi [103].Some flavanones have been shown to have antimicrobial effects, A and

B rings substituents playing a fundamental role in this activity. Tsuchiya

and coworkers [104] have discussed the structure–activity relationships on

those inhibiting methicillin-resistant S. aureus, analyzing the role of B ring

(C-20,C-40 or C-20,C-60) and A ring (C-5,C-7) hydroxyl groups, and reporting

that aliphatic groups at C-6 or C-8 can increase this activity. Sakuranetin

(Fig. 9), a flavanone isolated from Baccharis retusa, has been reported to have

significant activity against Leishmaniasis and Chagas’ disease (Leishmaniaamazonensis, Leishmania braziliensis, Leishmania major, and Leishmaniachagasi) and also against T. cruzi trypomastigotes. Grecco Sdos and cowor-

kers [105] have reported its methylation at C-40 to give an inactive compound,

confirming that the presence of both C-40 hydroxyl group and methoxyl group

at C-7 is important to its antiparasitic activity.

Isoflavonoids

Isoflavones such as genistein and daidzein (Fig. 10) can bind to estrogen

receptors exhibiting weak estrogen-like effects under certain experimental

conditions; their degradation product by intestinal bacteria that occurs in

O

OH

O

H3CO

OH

Sakuranetin

O

OCH3

OOH

H3CO

OH

H3CO OCH3

O

OCH3

OOH

H3CO

OCH3

H3CO OCH3

Artemetin Casticin

FIGURE 9 Antiprotozoal flavonoids.

OHO

O OHR

OHO

OH O OCH3

OHO

OH

R = H Daidzein R = OH Geniestein Biochanin A S-equol

FIGURE 10 Bioactive isoflavonoids and degradation metabolite.


about one-third of healthy people, equol, has been demonstrated to show

similar behavior [25].

Genistein and related isoflavones have been proved to inhibit cell growth

and development of chemically induced cancer in stomach, bladder, lung,

and blood. At low concentrations, genistein seems to induce carcinogen detox-

ifying system providing a partial explanation for its anticancer effects. Though

daidzein, only differing from genistein by the lack of C-5 hydroxyl group,

behaves as a weak inhibitor of human prostate epithelial tumor cells growth,

its metabolite equol is a strong inhibitor at low concentrations, justifying daid-

zein’s role in dietary prostate cancer prevention (Fig. 10). Both genistein and

daidzein also seem to modulate cytokine production. Genistein has been proved

to interfere with angiogenesis particularly in rapidly proliferating cells such as

endothelial and tumor cells [106–108]. It has been proved to affect multiple tar-

gets in cancer development inhibiting leukemia, lymphoma, prostate, breast,

lung, and head and neck cancer cell lines by acting as a protein tyrosine kinases

inhibitor in some of them, which are critical enzymes in carcinogenesis, cell

growth, and apoptosis [109]. Combination of genistein and irradiation has been

reported to control prostate primary tumor and metastasis to lymph. Its C-30

methylated derivative, biochanin A, chickpeas major isoflavone has been also

found to produce cytotoxic effects on breast carcinoma cell growth [110].

Fotsis and coworkers [111] have reported three flavone derivatives, 30,40-dihydroxyflavone, luteolin, and 3-hydroxyflavone, as more effective inhibit-

ing angiogenesis than genistein. Apigenin, only differing from genistein in

B ring attachment position to g-pyrone, showed similar inhibitory level

against angiogenesis, suggesting this substitution place to be irrelevant to this

bioactivity. Neither eriodictyol, obtained by reduction of luteolin g-pyrone’sdouble bond, nor catechin exhibiting a pyrane heterocycle was effectively

inhibiting cells proliferation, demonstrating the fundamental role of g-pyroneC ring in angiogenesis inhibition.

Genistein has been proved to inhibit cancer progression, affecting nearly

every step of metastatic cascade. In vivo animal trials and early-phase human

clinical trials have demonstrated that it can inhibit metastasis and modulate

markers of metastatic potential in men being a promising therapeutic phyto-

chemical [112]. It has been recently reported to be effective against neuro-

blastoma, a fast growth tumor occurring in small children. Genistein has

been proved to inhibit DNA methyltransferase action playing an important

role against neuroblastoma growth in vivo [113]. Isoflavonoids have also been

considered to interfere at multiple target sites of HIV. Anticancer activity of

isoflavones has determined commercial development in last century of a pre-

nyl isoflavone derivative, ipriflavone, to treat resistant acute leukemias [114].

Catechins

Catechins are flavan-3-ol hydroxylated derivatives that exhibit two chiral cen-

ters at B ring (C-2 and C-3) giving rise to trans-isomers called catechins and


cis-isomers called epicatechins (Fig. 11). Catechins cardiovascular benefits

have been related to their ability to affect signal receptors and transduction

kinase activities.

Catechins are strong scavengers, B ring catechol moiety being its most

important feature to quench singlet oxygen and peroxynitrite [115]; the num-

ber and position of galloyl groups have been also proved to affect their bioac-

tivity levels [116]. Camellia sinensis, rich in catechins, is known by

antioxidative and anti-inflammatory effects, which have been mainly asso-

ciated to its major component (–)-epigallocatechin-3-gallate (EGCG). Cate-

chins have been demonstrated to inhibit DNA damage and LDL oxidation

also decreasing lipid peroxidation, production of NO radicals, and overpro-

duction of proinflammatory cytokines [117]. It has been reported that EGCG

creates a different oxidative environment in normal epithelial cells, favoring

their survival while promoting tumor cell death; it was suggested that EGCG

may contribute to enhance effectiveness of chemo/radiation therapy. EGCG

has been also reported to be useful for topical application in oral carcinoma

treatment [118].

Overexpression of P-glycoprotein associated with multidrug resistance

represents a serious problem in cancer treatment. Evaluation of catechins, fla-

vonoids, isoflavonoids, and anthocyanins effects on multidrug-resistant

human epidermal carcinoma cells has demonstrated that catechins and antho-

cyanidins are most effective inhibitors of P-gp overexpression. It was

observed that hydrophobicity enhances planar flavonoids inhibitory effects

without affecting nonplanar flavanols activity that significantly depended on

their chemical structure [119].

Catechins have been also proved to inhibit Streptococcus mutans strains;

they were suggested to be useful in oral infections, such as dental caries

and periodontal disease. Epigallocatechin-3-gallate, epicatechin, and

proanthocyanidins have been also described to interfere with HIV at multiple

target sites [120,121].

Anthocyanins

Anthocyanins, the largest group of water soluble pigments in nature, are

O-glycosides of flavilium cations called anthocyanidins, exhibiting one or

O

OH

HO

OH

OH

OH

(+)-Catechin (2R,3S)

O

OH

HO

OH

OH

OH

(-)-Epicatechin (2R,3R)

O

OH

HO

OH

OH

O

OH

C

O

OH

OH

OH

Epigallocatechin gallate EGCG

FIGURE 11 Bioactive catechins.


more glycosidic moieties at C-3, and/or C-5 and/or C-7 (Fig. 12) [122,123].

Glucose is the most common glycosidic units; rhamnose, xylose, galactose,

arabinose, and disaccharide rutinose (6-O-L-rhamnosyl-D-glucose) can be also

present [124].

Cyanidin, delphinidin, petunidin, peonidin, pelargonidin, and malvidin are

the most common anthocyanins in nature [125]. Their antioxidant, anti-

inflammatory, and detoxification activities justify their preventive roles

against cancer and cardiovascular diseases.

They have been proved to scavenge superoxide and lipid peroxyl radicals

much faster than flavonoids, and to enhance fatty acid stability by neutralizing

a-tocopherol radicals [90]. They have been reported to induce apoptosis, displayantiangiogenic and antiproliferative effects, and inhibit digestive enzymes

(a-glucosidase, b-amylase, protease, and lipase), which are therapeutic targets

in type II diabetes and obesity control. Anthocyanins have been also reported

to prevent aging process, reducing the risk of degenerative disorders such as

Alzheimer’s disease [124,126] and to exert inhibitory effects on HIV-1 [15].

Their antioxidant potential caused by the ability to turn into stable radicals

after scavenging deleterious ones is determined by the number and position of

free hydroxyl groups. Catechol arrangement at B ring also enhances their abil-

ity to chelate metal ions [127]. However, it depends on factors such as pH and

reactive species [128]; at moderate pH, they can chelate metal ions with

B ring ionized hydroxyl groups [129].

Some anthocyanin glycosides are absorbed from stomach entering sys-

temic circulation after passing through liver, where methylation and glucuro-

nidation reactions occur, leading to metabolites further transported to

intestine. Others move into small intestine, being transformed into a combina-

tion of chalcone and quinonoidal forms; further absorption has been suggested

to take place in jejunum, where microbiota may metabolize anthocyanins dis-

rupting C ring and leading to phenolic acids and aldehydes. Protocatechuic

acid (3,4-dihydroxybenzoic acid) has been reported as major metabolite after

transformation of cyanidin-3- glucoside and rutinoside [130,131]. It has been

suggested to be responsible of anthocyanins biological properties including

antioxidant, antiobesity, cardiovascular-protective, and anti-inflammatory

activities. Other phenolic derivatives such as 3-O-methylgallic acid, syringic

acid, and 2,4,6-trihydroxy-benzaldehyde are also products of human large

intestine microflora activities [126,132].

O+

1

2

345

6

78

1�

2�

3�

4�

5�

6�

Flavilium ion

O

R1

R2

OH

OH

HO

OH

+

Delphinidin R1 = R2 = OH

Cyanidin R1 = OH R2 = H

Petunidin R1 = OCH3 R2 = OH

Pelargonidin R1 = R2 = H

Peonidin R1 = OCH3 R2 = H

Malvidin R1 = R2 = OCH3

FIGURE 12 Natural anthocyanins.


Less Distributed Phenolics

Curcumin (Fig. 13) has been demonstrated to interrupt activation of transcrip-

tion factor NF-kB, a key step in most of the common diseases [133]. It has

been proved to be effective against colon and breast cancer and myeloid leu-

kemia [134,135], inhibiting cell growth and inducing apoptosis of chemoresis-

tant ovarian cancer cells, and also inhibiting human breast carcinoma cells

through modulation of insulin-like growth factor-1 system [136,137]. Pheno-

lic hydroxyl groups are fundamental for curcumin antioxidant activity; meth-

oxyl groups also playing an important role, since it has been proved to be a

stronger scavenger than desmethoxycurcumin and bis-desmethoxycurcumin,

lacking one and both of them, respectively [138]. Conjugation between curcu-

min b-diketone moiety and aromatic rings seems also important for its

biological activities [139].

Curcumin has been proved to inhibit accumulation of amyloid beta ligand

characterizing neurodegenerative processes such as Alzheimer’s disease; the

two terminal phenolic groups and the length and rigidity of linear chain linking

them have been suggested to play fundamental roles in it [140]. Curcumin is

poorly absorbed and readily transformed in glucuronide and sulfate; several

approaches have been developed to improve its bioavailability such as addition

of piperine to interfere with its glucuronidation, and use of liposomal curcumin,

curcumin nanoparticles, curcumin phospholipid complex, or structural analogs.

As other polyphenols, trans-resveratrol exhibits antioxidant and anti-

inflammatory activities (Fig. 13). It has been proved to reduce oxidant-

induced apoptosis and LDL oxidation. Its cardioprotective effect has been

associated to its ability to inhibit platelet aggregation and LDL oxidation

and to enhance artery vasorelaxation. It has been shown to exhibit antitumor

activities, inhibiting different stages of the process such as tumor cells growth

through apoptosis enhancement and/or cell cycle blockage. Resveratrol has

been shown to reduce inflammation inhibiting prostaglandin production, and

cyclooxygenase-2 and NF-kB activities. Modulation of cellular signal trans-

duction pathways such as mitogen-activated protein kinases may contribute

to explain bioactivity versatility of resveratrol, which has been also proved

to contribute to prostate tumor treatment enhancing radiation-induced cancer

cell death [141,142].

trans-Resveratrol is easily absorbed and transformed into sulfate and glu-

curonide; only around 25% of its intake is available to exert any biological

HO

OH

OHO O

HO OH

OCH3 OCH3

Curcumin trans-Resveratrol

FIGURE 13 Curcumin and trans-resveratrol.


action, the rest being excreted via feces and urine [142,143]. Its metabolic

degradation has been reported to be interfered by other dietary polyphenols,

resulting in an increased concentration of free form and suggesting that gas-

trointestinal cells may be possible targets in vivo.trans-Resveratrol has also shown synergistic effects on inhibitory activity

against HIV-1 infection of nucleoside analogs [144]; it has been also reported

to inhibit influenza A virus replication by blocking nuclear-cytoplasmic trans-

location of viral ribonucleoproteins and reducing expression of viral

proteins [145].

Quinones

Quinones act as dehydrogenating or oxidizing agents turning into a fully

aromatic system after reaction. Some of these natural products are phenolic

derivatives, while others lack phenolic hydroxyl groups; among the last ones,

thymoquinone (Fig. 14) from Nigella sativa volatile oil has been shown to

exert antineoplastic and anti-inflammatory effects. It has been reported to

induce apoptosis by p53-dependent and p53-independent pathways in cancer

cell lines and to act on the immune system by modulating inflammatory med-

iators levels. In combination with anticancer drugs, this bioactive benzoqui-

none has been shown to enhance therapeutic index and prevent nontumor

tissues from sustaining chemotherapy-induced damage [146].

Naphthoquinones (Fig. 14), which include phenolic hydroxyl groups, have

been reported to exert antiprotozoal activities; some of them have been iden-

tified as possible leads for drug development [147,148]. Plumbagin, a 1,4-

naphthoquinone, can induce oxidative stress on Trypanosoma congolenseand T. cruzi, being reduced to semi-quinone radicals by enzymes from trypa-

nosomes mitochondrial electron transport chain and trypanothione reductase,

a key enzyme of trypanosomal antioxidant thiol metabolism.

O

OOH

O

O

OH

OH O

O

Plumbagin Diospyrin Monomethylated derivative

O

OOCH3

OH O

O

O

O Thymoquinone Mansonone FO

O

O

2

3

FIGURE 14 Natural quinones.


Diospyrin and some semisynthetic derivatives (Fig. 14) have been reported

to exhibit proapoptotic and/or anticancer activities [149,150]. It has been also

shown to exert in vitro antitrypanosomal activity on T. brucei bloodstreamforms; semisynthetic monomethylated derivatives have been proved more

active than the parent compound [151]. Diospyrin has also been shown to

inhibit growth of Leishmania donovani promastigotes, probably inhibiting cat-

alytic activity of parasite DNA topoisomerase I [152].

Suh and coworkers [153] have reported antibacterial and antiproliferative

effects of mansonone F, a nonphenolic sesquiterpene o-quinone produced by

Mansonia altissima and Ulmus pumila. The quinone moiety and the tricyclic

system of mansonone F have been proved to be responsible for its activity

against antimethicillin-resistant S. aureus, the 2,3-olefin being slightly benefi-

cial for it. SAR studies on several synthetic analogs showing different substi-

tuents have suggested that lipophylicity is an important factor to enhance its

actin against this resistant bacterium [154].

Xanthones

Hay and coworkers [155] have evaluated antimalarial activity of natural

xanthones and synthetic derivatives against chloroquino-resistant strains of

Plasmodium falciparum, reporting that substitution of C-2 and/or C-4 hydro-

gen atoms by isopentenyl groups increased antimalarial activity, showing

more than 12-fold increment when two isopentenyl groups were present.

In vitro studies with other natural xanthones revealed that hydroxyl groups’

position plays a fundamental role in their activity against P. falciparum, andthose exhibiting a C-2 hydroxyl group (1,2-dihydroxy-6,8-dimethoxy-x-

anthone) (Fig. 15) have shown higher activities than those with hydroxyl

groups at C-1, C-4, or C-8 [156].

Xanthones produced by Cratoxylum species (Fig. 15) have been reported

to have antibacterial, anti-HIV, and antimalarial activities. One of them, for-

moxanthone C, isolated from Cratoxylum maingayi stem bark also showing

higher cytotoxicity against NCI-H187 cell-line than standard antitumoral drug

elliptecine. Hydroxyl groups at C-5 and C-6 seem to play a determinant role

in xanthones antimalarial activity [157].

O

O

OHHO

OH

O

O

O OH

H3CO

OHOCH3

1,2-Dihydroxy-6,8-dimethoxy-xanthone Formoxanthone C

FIGURE 15 Bioactive xanthones.


a,b-UNSATURATED d-LACTONES

5,6-Dihydro-a-pyrones substituted at C-6, also called a,b-unsaturatedd-lactones (Fig. 16), are bioactive phytochemicals produced by some plant

species; their versatile therapeutic effects have been associated with the pres-

ence of the a,b-unsaturated d-lactone moiety.

Pironetin, isolated from Streptomyces sphas, has been found to be effec-

tive against resistant cells to microtubule-targeted drugs vindesine and pacli-

taxel and has been also shown to inhibit growth of human leukemic K562

multidrug-resistant cells. It has been proved to be a potent inhibitor of micro-

tubule assembly by covalently binding to alpha-tubulin at Lys352 [158].

Larvicidal, antiprotozoal, and antifungal effects have been described for

goniothalamin produced by Goniothalamus species, which has been also

proved to induce tumor cells apoptosis [159,160]. Another analog, rugulac-

tone produced by Cryptocarya rugulosa, has been proved to inhibit NF-kBactivation pathway [161] and, passifloricin A isolated from Passiflora foetida,has antifungal activity [162]. Argentilactone, first isolated from Aristolochiaargentina, has been shown to be active in vitro against Leishmania panamen-sis and L. amazonensis [163].

TERPENOIDS

Monoterpenoids and sesquiterpenoids are the main components of plants

essential oils known to be effective antimicrobials (Fig. 17). Bactericidal

activity of essential oils and some of their constituents on foodborne bacteria

have been reported a decade ago [164]. Among essential oil constituents,

terpinen-4-ol has been shown to significantly affect T. brucei bloodstreamforms viability [165]. Sesquiterpenes were found less active against trypano-

somes, allo-aromadendrene 10-fold more effective than its diastereoisomer

aromadendrene. Another sesquiterpene artemisinin, isolated from A. annua,is the antiparasitic drug most widely used in the world [166]. However,

O

O

O

Regulactone

O

O

Argentilactone(+)-Passifloricin A

OH OH O

O

OH

( )11

OCH3 OH O

O

C2H5

1 23

4

56O O

OAcOAc

OAcOAc

O

O

R E

GoniothalaminPironetin Spicigerolide

FIGURE 16 Bioactive a,b-unsaturated d-lactones.


resistance development to artemisinin by malarial parasites was reported in

the last decade and World Health Organization has discouraged its use as

monotherapy since 2006.

Moreover, artemisinin has limited bioavailability, short plasma half-life, and

poor solubility, and dihydroartemisinin, a semisynthetic derivative, exhibits six-

fold its activity in vitro [167,168,169,170] (Fig. 18). Other oil soluble deriva-

tives (artemether, arteether) are well absorbed on intramuscular

administration, whereas water soluble ionic artesunate is usually given intrave-

nously. Antiparasitic activity of artemisinin derivatives has been associated to

ring system polarity and to C-10 oxidation degree [167].

Douglas and coworkers [171] have strongly recommended artemisinin-

based combination therapies to eliminate malaria, which is used to treat

P. falciparum malaria; even when most blood-stage infections caused by Plas-modium vivax still respond to chloroquine treatment, a chloroquine-resistant

P. vivax strain has been already detected, suggesting that artemisinin-based

combination therapies should be used to treat both parasite strains.

Other monoterpenes such as espintanol [172] and piquerol A [173] have

been early described as antiparasites. More recently, it has been reported that

amino and methoxy goups significantly enhance citotoxic and antileishmanial

potentials in thymol synthetic derivatives, suggesting these natural com-

pounds should be considered lead structures for novel antileishmanial drugs

to be used in oral therapy [174] (Fig. 19).

Sesquiterpene peroxides, such as yingzhaosu A and C (isolated from roots

of Artabotrys uncinatus), have been also shown to have antiparasitic activity

against P. berghei [175] (Fig. 20).

OH HH

H H

H

HH

H

123

4 56

7

8

9

10

11

12

15

14

16

O

OH

O

OO

H

H

a-Terpineol aromadendrene allo-Aromadendrene Artemisinin

FIGURE 17 Bioactive terpenic derivatives.

O

OH

OH

OO

H

H

O

OH

O

OO

H

H

O

OH

O

OO

H

H

O

OH

O

OO

H

H

CO2-Na

+

O

Dihydroartemisinin Artemether Arteether Sodium artesunate

FIGURE 18 Artemisinin derivatives.


Antimalarial activity of Neurolaena lobata sesquiterpene lactones has

been tested in vitro against P. falciparum, demonstrating the fundamental role

of a/b-unsaturated keto function in antiparasitic activity; neurolenin

B exhibiting it was significantly more effective than lobatin A lacking it. Sev-

eral analogs have been also shown to exert cytotoxic effects on human carci-

noma cell lines [176] (Fig. 21).

Triterpenoids

Among triterpenoid derivatives, ursolic, oleanolic, betulinic, and moronic

acids have been proved to exhibit pharmaceutical potential (Fig. 22).

Ursolic acid has been proved to display anti-inflammatory effects by inhi-

biting NF-kB activation. It has also been reported to induce tumor cell apo-

ptosis and to increase muscle mass [177–182].

Ursolic and oleanolic acids have been early described to exert anti-

inflammatory and antihyperlipidemic activities. Betulinic acid has been

reported to exhibit antiretroviral, antimalarial, and anti-inflammatory proper-

ties. Thurnher and coworkers [183] have demonstrated its cytotoxic activity

against a variety of tumor cells originating from the neural crest. It has also

H3CO

OH

OCH3

OH

HO

OHOH

Espintanol Piquerol A Thymol Menthol

FIGURE 19 Bioactive monoterpenes.

OO

HO

OH

O OOH

Yingzhaosu A Yingzhaosu C

FIGURE 20 Bioactive sesquiterpenes.

O

O

O

O OCOCH3

OH O

O

O

O

O OCOCH3

OH O

2

34

89

Neurolenin B Lobatin A

FIGURE 21 Bioactive lactones.


been reported to exhibit anti-HIV potential; another triterpenic derivative

related to moronic acid scafold (3-oxoolean-18-en-28-oic acid) has also been

reported as anti-HIV agent [184].

Antitumor activity of ginseng, Panax ginseng, has been attributed mainly

to the presence of steroidal saponins, known as ginsenosides that have been

shown to modulate signaling pathways including regulation of cell prolifera-

tion mediator growth factors, tumor suppressors, oncogenes, cell death media-

tors, inflammatory response molecules, and protein kinases. Signal

transduction pathways targeted by selected ginsenosides have been thoroughly

described [185].

More than 60 ginsenosides have been isolated from different parts of

American ginseng, Panax quinquefolius, most of them also exhibiting a

four-trans-ring rigid steroid skeleton. Antioxidant, anti-inflammatory, and

immunostimulatory activities of ginseng seem to explain their neuroprotective,

cardioprotective, antidiabetic, antioxidant, and anticancer properties [186].

NITROGEN COMPOUNDS

Among nitrogen compounds, alkaloids are the most important family of sec-

ondary metabolites associated with pharmacological activities.

Alkaloids

Even when most alkaloids are toxic to men, some of them have been deriva-

tized in order to obtain novel less toxic drugs to treat different diseases, tuber-

culosis among them. There is an increasing incidence of deaths due to

tuberculosis in developing countries within Asia and Africa. This disease

caused by Mycobacteria species requires long treatments that many patients

give up increasing the chance of drug resistant strains. Moreover, HIV infec-

tion, compromising host defense, allows latent infections to reactivate in indi-

viduals more susceptible to Mycobacteria.

HO

R1

H COOH

H

R2

R1 = CH3, R2 = H Ursolic acidR1 = H, R2 = CH3 Oleanolic acid

HO

H COOH

H

H

H O

COOH

H

H

H

Betulinic acid Moronic acid

FIGURE 22 Triterpenoid acids.


Alkaloids have been tested to find analogs with potential to reduce therapy

time as an answer to the expanding problem of multidrug-resistant

M. tuberculosis strains [187]. Solsodomine B, a pyrrole derivative isolated

from Solanum sodomaeum, has been shown to significantly affect Mycobacte-rium intracellulare growth. More recently, banegasine, an indol alkaloid pro-

duced by Aristabacter necator, has been demonstrated to inhibit

M. smegmatis development [188] (Fig. 23).

Quinoline alkaloids such as graveolinine and kokusagine (Fig. 24) exhibit-

ing a fully aromatic quinoline ring and a 4-methoxyl group have been also

proved to be highly effective against M. tuberculosis, and the presence of

the aryl group at quinoline C-2 position in the first two alkaloids has been

demonstrated to enhance inhibition [187].

Quinine isolated from Cinchona succirubra represents the oldest example of

quinoline alkaloids antiparasitic effects, particularly antiplasmodial activity; it

has been used to treat malaria for more than three centuries. Other quinoline

alkaloids such as 2-n-propylquinoline, chimanine B, 2-n-pentylquinoline, and4-methoxy-2-phenylquinoline have been also shown to be effective against

strains of parasites causing cutaneous leishmaniasis [189,190] (Fig. 25).

NH2

N

H

COOH

N

NH

N

N

H

CHO

Solsodomine BBanegasine

FIGURE 23 Antituberculosis alkaloids.

N

OCH3

NO

O

OCH3

O

O

N O

OCH3

4-Methoxy-2-phenylquinoline Graveolinine Kokusagine

FIGURE 24 Bioactive quinoline alkaloids.

N

CH3O

HO N

N R1

R2

2-n-Propyl quinoline Chimanine B2-n-Pentylquinoline4-Methoxy-2-phenylquinoline

R1 = C3H7 R2 = H

R1 = CH=CHCH3 R2 = H

R1 = C5H11 R2 = H

R1 = phenyl R2 = OCH3Quinine

FIGURE 25 Bioactive antiparasitic alkaloids.


Among natural alkaloids, berberine produced by Chinese herb Rhizoma cop-tidis has been reported to exhibit a wide spectrum of pharmacological activities

such as anti-inflammatory, antibacterial, myocardial ischemia–reperfusion

injury prevention, blood vessels expansion, platelet aggregation inhibition,

sedation, hepatoprotective, and neuroprotective effects. It has also been used

to treat ulcer, diarrhea, neurasthenia, arrhythmia, and diabetes. Several studies

have shown that it can also inhibit tumor development by interfering with differ-

ent stages of carcinogenesis and tumor progression in both in vitro and in vivoexperiments [191]. Berberine has been also proved to inhibit acetylcholinester-

ase, butyrylcholinesterase, and two monoamine oxidase isoforms, four patho-

genic enzymes in Alzheimer’s disease, hydrophobic interactions playing a

major role in its activity [192,193] (Fig. 26).

It has been shown to inhibit Toxoplasma gondii, also being toxic to host

cell. Its partially reduced derivative, dihydroberberine, exhibited similar activ-

ity with significant less cytotoxicity. Further reduction led to the tetrahydro

derivative canidine, 15-fold less active suggesting that planarity plays a fun-

damental role in this kind of activity [194].

Piperine, responsible for black pepper pungency, has been found to inhibit

human CYP3A4 and P-glycoprotein enzymes involved in metabolism and

transport of xenobiotics and metabolites (Fig. 27). This alkaloid has been

reported that it can enhance curcumin and resveratrol bioavailabilities, proba-

bly inhibiting glucuronidation, hence slowing their elimination [195–197]. It

has been also reported to enhance bioavailability of co-administered drugs.

Natural compounds within other chemical families, such as quercetin, genis-

tein, naringin, sinomenine, glycyrrhizin, and nitrile glycoside, have proved

to play similar roles by inhibiting efflux pumps or oxidative metabolism,

and perturbing the intestinal brush border membrane [198].

N

O

ON

O

O

Dihydroberberine Canidine

N

OCH3

OCH3

OCH3

OCH3OCH3

OCH3

O

O +

Berberine

FIGURE 26 Berberine and analogs.

O

N

O

OPiperine

FIGURE 27 Piperine.


SULFUR COMPOUNDS

Glucosinolates are natural organic anions containing b-thioglucoside-N-hydroxysulfates with different side chains depending on the plant species,

and a sulfur-linked b-D-glucopyranose moiety. Their hydrolysis produces vol-

atile isothiocyanates, thiocyanates, and nitriles that have been reported to

exhibit antifungal, antibacterial, antioxidant, antimutagenic, and anticarcino-

genic activities [199].

Glucoraphanin, the main glucosinolate in broccoli and cauliflower young

sprouts, can be readily converted in their derived isothiocyanates (sulforaph-

ane, raphanin) (Fig. 28).

Beneficial properties of isotiocyanates, including increase in cell detoxifi-

cation potential and antioxidant capacity, inhibition of cell cycle progression

and angiogenesis, and induction of apoptosis have been reported by Traka

and Mithen [200]. It has been suggested that they may induce cytoprotective

genes by altering gene expression through modification of critical thiols in

regulatory proteins resulting in the inactivation of NF-kB, known to be

induced by carcinogenic agents. Sulforaphane has been shown to exhibit

strong activity against Helicobacter pylori, whose infections are known to

be associated with gastric cancer [201].

CONCLUDING REMARKS

Drug discovery based on natural products research is still a very complex and

expensive process. Increasing pressure to obtain less expensive novel drugs

has determined the decision by pharmaceutical companies to diminish and even

replace natural product research by novel technologies in drug discovery

screening. Development of molecular biology and computational chemistry

during the last three decades has allowed the generation of large screening

libraries, which are used by combinatorial chemistry and high throughput

screening technologies to evaluate affinity levels between target molecules

and library compounds [202,203]. This novel technology was supposed to pro-

vide massive numbers of new chemical entities to be useful as drug lead skele-

tons; however, results have been poor compared to the number lead drugs

derived from research on natural products in the same period [204,205]. This

fact has been attributed to the limited chemical space covered by combinatorial

chemistry products compared to commercial drugs derived from natural

Glucoraphanin Sulforaphane Raphanin

OOH

OHHO

HO

N

O

SS

OSO3-K

+

SN

O

CS

SN

O

CS

FIGURE 28 Sulfur derivatives.


products that exhibited much greater chemical diversity, also being more evenly

distributed into the chemical space.

Combinatorial chemistry libraries have been demonstrated to lack two

important drug-like features, chirality and structure rigidity, both known to

enhance drug specificity and efficacy, and common characteristics in natural

derived lead drugs [206]. Other differences between natural products and

compounds in combinatorial chemistry libraries are related to a higher num-

ber of aromatic moieties in the latter, along with the presence of sulfr and hal-

ogen atoms, while natural product-derived drugs mostly include O and N as

heteroatoms and a higher number of nonaromatic unsaturations. Around

10,000 natural products with high structural diversity are actually discovered

every year, covering a virtual chemical space larger than any collection of

synthetic compounds. Living organisms, particularly plants and microorgan-

isms, are responsible for a continuous development of novel bioactive chemi-

cal structures to obtain evolutionary advantages as coevolution takes place;

high-performance separative techniques associated with hyphenated technolo-

gies are currently available to pharmaceutical research for the isolation and

identification of these new natural products, which can be later associated

with combinatorial chemistry developments.

Based on the increasing acceptance that chemical diversity of natural pro-

ducts is fundamental to provide starting scaffolds for future drugs and the fact

that combinatorial chemistry techniques have demonstrated significant advan-

tages to drug discovery process, it seems that any further development need to

have a multidisciplinary approach including molecular diversity from natural

product sources plus combinatorial synthetic methodologies and combinato-

rial biosynthesis as the most effective answer to drug discovery and develop-

ment optimization.

ACKNOWLEDGMENTS

The authors gratefully acknowledge grants UBACYT (2011-2014) 20020100100229 and

UBACYT (2012-2015) 20020110200266 from University of Buenos Aires. Authors want to

thank MSc Margarita Yaber Grass for her contribution to bibliographic data recompilation.

ABBREVIATIONS

E. coca Erythroxylum cocaL-DOPA levo-dihydroxyphenylalanine

NF-κB nuclear factor kappa B

ROS reactive oxygen species

RNS reactive nitrogen species

DNA Deoxyribonucleic acid

NO nitric oxide

OH hydroxyl group

M. tuberculosis Mycobacterium tuberculosis


P. falciparum Plasmodium falciparumT. congolense Trypanosoma congolenseT. cruzi Trypanosoma cruziLDL low density lipoprotein

Ca2þ-ATPase calcium ATPase

MS multiple sclerosis

HIV Human immunodeficiency virus

S. aureus Staphylococcus aureusEGCGv(�) epigallocatechin-3-gallate

P-gp permeability glycoprotein

CYP3A4 Cytochrome P450 3A4

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[Studies in Natural Products Chemistry] Volume 42 || Plant Secondary Metabolites

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