AD ________

Anti-Cyanite Drugs

Annual Report

Peter Hambright

may 1, 1986

0") Supported by

*U. S. ARMY MIED ICAL RESEARCH AND DEVELOPMENT COMMAND

o Fort Detrick, Frederick, Maryland 21701-S012* Contract No. DAMD7-85-C-5OS6

Department of ChemistryHoward University

Washington, D. C. 20059 ED TICELECTE

distribution unlimited

* The findings In this report are not to be construedas an official Department of the Army position unlessso designated by other authorized documents

89 1100o58

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4. PERFORMING ORGANIZATION REPORT NUMBER(S) S MONITORING ORGANIZATION REPORT NUMBER(S)

68. NAME OF PERFORMING ORGANIZATION 6b. OFFICE SYMBOL 7a. NAME OF MONITORING ORGANIZATIONHoward University (If appicabie)Department of Chemistry

6c. ADDRESS (City, State, and ZIP Code) 7b ADDRESS (City. State, and ZIP Code)

Washington, D.C. 20059

S.. NAME OF FUNDING/SPONSORING 8b OFFICE SYMBOL 9 PROCUREMENT INSTRUMENT IDENTIFICATION NUMBERORGANIZATIQN U . S . Army (If apokabie)

Medical Research & Develop ent Command

.ADDRESS (City, State, and ZIP Code) 10 SOURCE OF FUNDING NUMBERS

Fort Detrick PROGRAM PROJECT TASK WORK UNIT

Frederick, Maryland 21701-5012 ELEMENT NO No 3M1 NO CCESSION NO

61102A 61102BSII EG 05711. TITLE (Include Security Classification)

Anti-Cyanide Drugs

12. PERSONAL AUTHOR(S) Peter Hambright

13a. TYPE OF REPORT 13b. TIME COVERED 14 DATE F (EP r, (YeAtonth Day) 1S. PAG& COUNTAnnual Report IFROM 4/1/87 4/31/88 198 May I

16. SUPPLEMENTARY NOTATION

17. COSATI CODES 18. SUBJECT TERMS (Continue on reverse if necessary and identify by block number)

FIELD GROUP SUB-GROUP Cyanide, Cyanide Scaveqers. Porphyrins

Q ,Aetallopo r2 ~ia ob~alt,2tyanohydrinsjis & 1 Aldehydes. letones, Metal ComplexesArA4*( CI,, .\ -

I BSTRACT (Continue on reverse if neceswae'y __ bybl uni0m-

The extent of cyanide uptake by various molecules at pH 7.4 was monitoredwith a cyanide specific electrode. Low molecular weight aliphatic aldehydesscavenged cyanide best, followed by aromatic aldehydes with electronwithdrawing functions. Palladium(ll) complexes rapidly bound four molesof cyanide, gold(III) species bound three, while platinum(ll, IV) andtrivalent rhodium and ruthenium complexes were less reactive. A rutheniumporphyrin complexed two cyanides in both the +2 and +3 oxidation states.

A nickel(II) Schiff-base adduct took up four 0oles of cyanide througha dissociative process. Nickel(1l) cyclams ra~idly bound one cyanide,

and three more at later times. -# * < U-'/ C

20. DISTRIBUTION/AVAILABILITY OF ABSTRACT 21 ABSTRACT SECURiTy CASS,'ICATION

o UNCLASSIFIEDAJNLIMITED e SAME AS RPT 3 3Tii usR .n c 1 ass i f i ed22s. NAME OF RESPONSIBLE INDIVIDUAL Coe)Mrs Virginia Miller

DD Form 1473, JUN 86 Peoqu0uovmuoa,eoe o6ete SECURITY CLASSIFICATION OF THIS PAGE

L

AD _ _ _ _ _ _ _ _ _

Anti-Cyanide Drugs

Annual Report

Peter Hambright

May 1, 1988

Supported by

U. S. ARMY MEDICAL RESEARCH AND DEVELOPMENT COMMAND

Fort Detrick, Frederick, Maryland 21701-5012

NIS G;pr&iContract No. DAMD17-85-C-5086

D TAB

J'utificat Ion -Department of Chemistry

Howard UniversityWashington, D. C. 20059 By.Dlstribution/_ _

Availviiity Codes

Approved for public release: Dist Specialdistribution unlimited i2

The findings in this report are not to be construedas an official Department of the Army position unlessso designated by other authorized documents

SUMMARY

This Is the third year of a project to identify and develop

compounds that might act in a prophylactic fashion against therapid acting poison, cyanide. Such compounds Include metal ions

and metal complexes, aldehydes, ketones, porphyrins,

phthalocyanines, and alkylidenes. Although many compounds bind

cyanide at high pH, the limitations here are that the moleculesmust be water soluble and react with cyanide at reasonable ratesat the physiologic pH of 7.4. Several such derivatives will besupplied to WRAIR for further testing. The two earlier reports(1,2) give the extensive background and literature for thisproject.

In earlier work, we studied the kinetics and mechanisms ofcobalt(IIl) and rhodium(lll) porphyrins reacting with cyanide.Such compounds have structures similar to the Vitamin B-12derivative hydroxocobalamin, a known cyanide scavenger. TheRh(lll) adduct reacts with cyanide too slowly to be of interest,while the Co(Ill) porphyrins have high equilibrium constants andshow rapid complexation with cyanide at the physiologic pH. Themolecular weights of such species are about halt that of B-12,and since such porphyrins bind two moles of cyanide (B-12 bindsone in-vivo), they are perhaps four times more effective on aper-gram basis. The Co(Ill) porphyrins and B-12 derivative aswell as the Rh(lll) system have a high affinity for ligands otherthan cyanide, such as hydroxide and other nitrogenous bases. Thisyear we studied ruthenium(ll) porphyrins, that have no affinityfor hydroxide in aqueous solution, due to their low oxidationstate, and are specific binders for cyanide. Upon complexationwith cyanide, the ruthenium(ll) monocyano porphyrins are rapidlyoxidized to the ruthenium( II) state, at which time they add onemore cyanide to their coordination sphere. Equilibrium andkinetic data are presented for one such ruthenium porphyrinsystem.

Low molecular weight aldehydes and ketones react withcyanide to form cyanohydrins. We previously demonstrated thataldehydes are more reactive than the corresponding ketones, andsuch reactions were easily followed using a cyanide selectiveelectrode. Thus 2,6-pyridinedicarboxaldehyde bound two moles ofcyanide per mole of ligand, whereas glyoxylic acid (CHO-COOH)reacts with one mole of cyanide per mole of ligand. All otherderivatives studied showed lesser cyanide uptake abilities. Witharomatic aldehydes, this year we demonstrated that electronwithdrawing groups on the ring facilitate cyanohydrin formation.Thus 2,6-difluorobenzaldehyde has a cyanide/ligand ratio of0.97/1 whereas the 4-hydroxybenzaldehyde shows 0.08/1. The bestscavengers were aliphatic aldehydes. For example acetaldehyde(Me-CHO) showed a cyanide to ligand ratio of i/1.

In terms of simple metal complexes, we found that therelatively non-toxic palladium derivatives rapidly bind fourmoles of cyanide, whereas gold(Ill) species bind three moles ofcyanide at pH 7.4. Various Pt(IV), Rh(l1i), and Ru(lll) complexeshave rather less affinity for cyanide.

....... i--=i'l ii i lll~ l l m Ii II l ml I °o.

We have been seeking agents that strongly complex metal ionsand allow release of this metal to form tightly bonded cyanideadducts only in the presence of a certain external tension ofcyanide. In this direction, a nickel(ii)-cyclam-14 will bind onecyanide ligand with a reasonably high formation constant oflog K = 4.4, and after standing for days, the very stabletetracyano-nickel(Il) is produced. This nickel ion is held in amacrocyclic ring of four nitrogen atoms in the cyclam. We havefound a Schiff base nickel derivative that has the metal attachedto nitrogen and oxygen atoms, in a ligand-metal-ligandconfiguration. Upon addition of cyanide, the nickel(ll) ionreacts rapidly with four moles of free cyanide and is releasedfrom the complex.

2.

TABLE OF CONTENTS

Page

Report Documentation Page-DD Form 1473 .................

Title Page ..............................................

Summary ................................................ I

Table of Contents ...................................... 3

Compounds Submitted to WRAIR, May, 1988 ................... 4

General Report ............................................. 5

Table 1. Cyanide/Ligand Ratios for Aromatic Aldehydesand Ketones, Aromatics ............................... 6

Alkylidenes ............................................ 8

Table 2. Aliphatic Aldehydes and Ketones, pH 7.4 ....... 9

Metal Complexes ........................................ 10

Ruthenium(Il) Porphyrins ................................. 11

Figure 1. Reactions of Ruthenium Porphyrinswith Cyanide ...................................... 12

Figure 2. Equilibrium and Kinetic Ruthenium Data ....... 13

Nickel(ll)-Cyclam-14 ................................... 14

Schiff Base Complexes .................................. 15

References ............................................. 17

Publications ........................................... 18

Project Personnel ...................................... 18

Binding Ratio Data ..................................... 19

Distribution List ...................................... 26

3.

COMPOUNDS SUBMITTED TO WRAIR, MAY 1988

COMPOUND NUMBER

A-88. Glyoxal sodium bisulfite addition

compound, monohydrate Bl. 53620

B-88. 4-Quinolinecarboxaldehyde BL 53639

C-88. 4-Pyridinecarboxaldehyde-N-oxide BL. 53648

D-88. Hydrogen tetrachloroaurate trihydrat. Bl. 53611

E-88. trans-Dichlorobis(dimethyl gui oxide) -

pal ladium( II) BL 53657

F-88. Bhu(1,3-dicyanomothylene)-2-keto-4-cyclopentene, 4, 5-diol, B L 53666dipotassium salt

G-88. Ammonium hexachlororuthenium(IV) BL. 53675

H-88. Tetraamminepalladium(II) nitrate SL 53684

1-88. Hexamminerhodium(ill) chloride BL. 53693

J-88. 2,5-Dlmethoxy-3-tetrahydrofuran- BL. 53700

carboxa Idehyde

4.

GENERAL REPORT

The aim of this project was to explore the chemistry ofspecies that have a high affinity for cyanide at the physiologicpH of 7.4, in order to develop drugs that could counteract therapid acting CW agent, cyanide. To this end, aldehydes, ketones,metal ions and metal complexes, alkylidenes, metalloporphyrins,and metallophthalocyanines were investigated for their cyanidebinding ability. The better compounds were submitted to WRAIR forfurther testing.

ALDEHYDES AND KETONES: The carbonyl group in aldehydes andketones has a high affinity for cyanide. The pKa value for the(HCN)/(H+)(CN-) reaction at an ionic strength of 1.0 is 9.1, andthus at pH 7.4, the bulk of the total cyanide Is in theundissociated HCN form. The mechanism of cyanide addition ispostulated () to be:

HCN + OH- = CN" * H20 (fast)

0 + CN- (slow)

CN CN

C + H'O u (fast)0-

OH

As a rapid method of determining the cyanide affinity of variouscarbonyl compounds, we used a Radiometer cyanide electrodesystem. Fifty ml of a 0.2 ionic strength solution (0.1 M inphosphate buffer at pH 7.4 containing 0.1 M NaN03) was placed Inthe reaction flask containing the cyanide electrode, a referenceelectrode and combination pH electrode and magnetic stirring bar.Four 0.25 ml portions of standardized aqueous KCN solution wereadded from a micropipet, and the potential was noted after eachaddition. The final cyanide concentration was about I x 1O(E-03)M, and a linear plot of potential vs log total cyanideconcentration was constructed. The compound to be investigatedwas dissolved in 10 ml of the buffer solution and added inportions to the solution of known cyanide concentration. The newcyanide level was noted two minutes after ligand addition. Plotsof cyanide vs ligand concentration were made, and the initialslopes of such plots were used as a measure of relative cyanide

5.

(0*

0

zz(0 CDC

LLII

'a 0

0 0 0

0 Uo 0 V->

0 C z 00

U)U0 /= x0

00

o 0x 0

0 0

0

TL\ 00 ,\ 0-i z z x nca SOI-D

CC

C

0

C0

0 di

0

u 0

0-C;

xz

0 O*Z u

U r CDJ

0 0(

LU X U CCC

I-z

affinities of the test samples. This corresponds to the moles ofcyanide bound per mole of ligand, when a small amount of ligandis added to a large and constant cyanide concentration. Inseveral cases the compounds to be tested were of such lowsolubility in tdter that their stock solutions were prepared in40% by volume nethanol, and such compounds are denoted by a ( * )in the acc-mpanying work. Control experiments indicated that themethanol had little effect on the cyanide/ligand ratio measured.

The cyanide vs ligand concentration data obtained this yearare in the Data section. Table I is a summary of the results onvarious ring structures containing aldehyde or keto groups. Table2 is a list of compounds containing aliphatic aldehydes orketones. Several generalizations can be made.

(1). Aldehydes have higher tendencies for cyanohydrinformation than related ketones. Thus 2,6-diacetyl-pyridine gives a cyanide/ligand ratio of 0.45 whereasthe 2,6-pyridinedicarboxaldehyde is 2/1.

(2). In a series of substituted benzaldehydes, electronwithdrawing groups favor cyanohydrin production. Thusthe 4-N,N-dimethylaminobenzaldehyde shows 0.06/1,whereas the 2,6-difluorobenzaldehyde gives 0.97/1.

(3). In general, aliphatic aldehydes are better cyanohydrinformers than compounds containing aromatic groups.Glyoxylic acid (HOOC-CHO) and acetaldehyde (Me-CHO)both show 1/1 uptake of cyanide.

ALKYLIDENES: Alkylidenes are compounds containing double bonds inwhich one carbon atom in the bond has strongly electronwithdrawing substituents that should draw electrons from thedouble bond facilitating cyanide addition to the other carbon.Compound A below, alpha-cyano-4-carboxyethylcinnamate,is an example of an alkylidene and shows a cyanide/ligand ratioof 0.1/1. Compound B is the dipotassium salt of 1,3-bis(dicyanomethylene)croconate (1). While formally similar tocompound A, the electron delocalization is such that no true ketoor double bond character is present, and a ratio of 0.15/1 isobtained. Compound C is croconic acid, and the anion is ratherfully delocalized so no real keto groups exist. Again thecyanide/ligand ratio was 0.15/1. Replacing two oxygen groups bysulfur atoms would break up such conjugation, perhaps making formore useful derivatives. For compound B. it has been speculatedthat (f) the nitrile (-CN) group might saturate biologicalcyanide binding sites, and thus provide a measure of protection.

0 0.1CN IfCN

"0 O0A B C

- --- = k i l l l l.

Table 2. Aliphatic aldehydes and ketones, pH 7.4

C20pound Structure CN /Ligand

HO 0 0 OHGlyoxal trimeric OH1.9/1

dihydrate HO XA 0

Glyoxylic acid HCO-COOH 1.0/1

Acetaldehyde CH3-CHO 1.0/1

Glyoxal sodium bisuititeaddition compound [03S-CH(OH)-CH(OH)-SO3]Na2 0.7/1

Juobutyraldehyde (CH3)2-CH-CHO 0.4/1.

2-Ketobutyric acid C2H5-CO-COOH 0.4/1

Al pha-keto-glutaricacid HOOC-(CH2)2-CO-COOH 0.25/1

Ketomalonic acid HOOC-C(OH)2-COOH 0.17/1

Pyruvic acid CH3-CO-COOH 0.12/1

Acetone CH3-CO-CH3 0.08/1

Oxalacetic acid HOOC-CH2-CO-COOH 0.06/1

METAL COMPLEXES: The following data was observed for simple metal

complexes reacting with cyanide at pH 7.4. The ratio is moles of

cyanide bound per mole of metal ion added. In general, such

slopes are independent of the metal ion concentration.

COBALT

CCoCI 2 ( HO ).] . 2HO 5/1

(Co'' ( H1O ). Co''EDTA] . 2H,O(outdated sample of commercial Kelocyanor) 3/1

NICKEL

trans-[NiCl, ( HO ). . 2 H2 0 4/1

PALLADIUM

cis-PdCl (NH3 )2 4/1

trans-PdCI2 (NH,), 4/1

CPdCI4 Na2 3.8/1

PdCI2 ( DMSO )2 4/1-DMSO = ( CH 3 )2-SO -

[Pd(NH,)4 ] (NO,), 4/1

GOLD

H[AuC],] 3/1

AuBr, 3/1

PLAT I NUM

[Pt'v (en),] Cl, 0.15/1

cis-PtCl (NH,)2 2.6/1

trans-PtCl, (NH,)2 0.9/1

ZINC

Zn (N0 3 )2 . 6H2 0 1/1

RUTHEN I UM

[Ru-v CI,] (NH 4 ), 1/1

(Ru''' (NH 3 ),] C1 3 1/1

RHOD I UM[Rh- (NH,). ] C1, 0.09/1

10.

RVTHENIUM((lI)-PORPHYRINS: Since cobalt(ill) hydroxocobalamin, aVitamin B-12 derivative has been suggested to be useful incyanide therapy (6), we Investigated the kinetics and mechanismsof related rhodium(IlI) porphyrins (7) and cobalt(Ill) porphyrin(8% reactions with cyanide. The rhodium system had specific ratestoo slow to be of interest, whereas the cobalt(Ill) porphyrinshad rapid cyanide formation kinetics at physiologic pH and highstability constants for cyanide addition. On a per/gram basis,the cobalt(Ill) porphyrins might be four times more effectivethan the B-12 analogue, a rather small effect.

The cobalt(Ill) porphyrins and cobalamin and therhodium(IllI) porphyrin are in high oxidation states, and reactreadily with hard ligands such as hydroxide, amines,thiosulfate, etc. Thus the cobalt porphyrins (Co-P) form mono-hydroxy (HO-Co-P) and di-hydroxy species and perhaps oxo bridgeddimers (P-Co-O-Co-P) depending upon pH, and such groups need tobe removed before the uptake of cyanide. We decided to study thereactions of ruthenium(If) porphyrins, with the notion that thelow oxidation state would favor bonding to soft back bondingllgands such as cyanide, rather than the hard hydroxide anion.This proved to be the case.

The reactions of a carbonyl-ruthenium(ll) porphyrin withcyanide are shown in Figure 1. The porphyrin studied wasuroporphyrin-l, a compound containing eight carboxylic acidgroups, making it fully water soluble. The absorption spectrawere Independent of pH from pH 3 to 13, indicating that thespecies did not react with hydroxide or hydrolyze in the pH rangeconsidered. Upon adding cyanide, the 393.5 no CO-Ru-P bandshifted to 403 no, indicating the uptake of one mole of cyanide,forming CO-Ru-P-CN. The equilibrium constant for cyanide uptakewas found to be Log K = 4. The reaction was found to be firstorder in porphyrin and cyanide concentration, with a specificrate constant at 25 degrees C of 2.2 M(-i)sec(-1). These data areshown in Figure 2. In the presence of oxygen and excess cyanide,the CO-Ru(Il)-P was oxidized to the Ru(ill)-dicyano form(400 nm), where the carbon monoxide is lost to the solution uponoxidation. In the absence of cyanide, oxidation into what appearsto be a ruthenium(IV) state takes place in days. thus the cyanidefacilitates oxidation to the (iI) state. If the air-unstable CO-Ru(II)-CN is allowed to stand under nitrogen at room temperature,the carbon monoxide ligand is slowly lost, with the production ofdicyano-Ru(Il)-P (414 no). The kinetics of this reaction werefirst order in porphyrin, and independent of cyanide from 1.3 mmto 16 mm cyanide concentration. The half-life of the reaction is4.3 hours, giving a specific rate constant of the order of4.4(E-05) sec(-1). The porphyrin apparently features two modes ofcyanide uptake, an associative mechanism when the carbonyl ispresent, and a dissociative mechanism, wherein the slow step iscarbon monoxide loss, followed by the rapid uptake of a secondcyanide Into the unstable (CN-Ru(iI)J form. The dicyano-Ru(Il)porphyrin is rapidly air oxidized Into the dlcyano-Ru(lli) statepresumably by an outer sphere mechanism in which electron

IiI

I

0cu

~0

- 0U~

00U z

ctl ) -L

0-

FIGURE 2.(Top)Equilibriu and (bottom) Kinetic Ruthenium Data

x

0

Cuo

I CO

5 15

104 (CN-)

15-

0

0

6

1 2 1 0 3 (CN-) 5 6 7

transfer occurs through the intact dicyano-Rut IJ) coordinationshell. Adding dithionite to the Ru(lIl) form allows reductionback Into the dicyano-Ru(ll) state. Addition of acid ( pH 2 ) tothe dicyano-Ru(ll) porphyrin produces cyanide loss to anuncharacterized [Ru(II)] state, and the passage of CO throughthis solution reforms the CO-Ru(I1)-P.

If the dicyano cobalt(Ill) porphyrins or corrins arereduced, the cyanide is lost from the coordination sphere, as theCo(ll) forms have little cyanide affinity. This was one of themain reasons for investigating the rhodium(lll) porphyrins; theyare reduced much less readily than the cobalt(IIl) states. Theadvantage of the ruthenium porphyrins is that both the reducedand oxidized forms have an affinity for cyanide. In fact, thereduced state is very specific for cyanide and should notinteract with any other anionic or nitrogen base biologicalligands, or water. The complexation of one cyanide to a Ru(Il)porphyrin makes the compound more oxidizable, and the resultingoxidation both retains the coordinated cyanide and adds another

S"due to the oxidation process. The trivalent Ru(Ill) should have ahigher affinity for the negative cyanide than does the reduceddivalent state. The equilibrium constant for cyanide uptake isseveral orders of magnitude less than is desirable for ascavenger at pH 7, and no doubt other differently substitutedpositively charged porphyrins might raise the equilibriumquotient to reasonable values. The cobalt(Ill) porphyrins have ahuge affinity for cyanide, with log K > 13 for first cyanideaddition. This is probably the reason that Co(HII)-B12 is activein its dlaquo rather than its monocyano form in vivo.

NICKEL(il)-CYCLAM-14: We would like to develop metal containingspecies that are strongly bonded to the ligand framework, andrelease the otherwise toxic (but multiple cyanide binding) metalion only upon demand by a certain tension of cyanide In solution.The high metal-cyanide formation constant might render both themetal and the cyanide itself non-toxic. The first effort in thisdirection was the synthesis of a nickel(ll)-cyclam-14 compound,the structure of which Is noted below. The equilibrium constantfor cyanide addition was measured spectrophotometrically at pH7.4, and the results are as follows:

% Ni-[cyclam-141 (Cyanide Log K

47.5 3.5 (E-05) 4.4

71.4 9.& (E-O5 4.A

90.2 1.4 (E-03) .. 5

l|

Thus, for the reaction:

Ni-[cyclam-14]J- + CN- NI-(cyclam-141-CN •

the equilibrium constant is K = 2.5 x IO(E O4), a sizeableeffect. It the mM cyanide solution of the complex is allowed to

stand for several days, the Ni(lI) is removed from the ligand,forming the very stable tetracyanonickelate di-anion:

NI-[cyclam-14]2 + 4 CN- Ni(CN),2 - + cyclam-14

It should be possible to vary the ring sizes of the cyclams andalter the central metal ion to favor immediate dissociation inthe presence of cyanide. We will try this approach, and look atthe cobalt(lll)-sulfite derivative of cyclam, in which thesulfite should labilize the ligand trans to itself, and lead tomono-cyano formation. Such cobalt(Ill) complexes are substitution

inert, and once complexed, the cyanide should be slow to beremoved. We attempted this with a [SOCo(lIl)(NH,),). complex,

but had difficulty obtaining the pure species in reasonable

amounts.

No

N N

HWe H

Nickel(I )-Cyclam-14

SCHIFF BASE COMPLEXES: The Schiff base complex below, bis(N,N-dimethylethane-i,2-diammine.2-hydroxy-4-methoxy-5-sulfonic acid

benzophenimine)nickel(ll) is water soluble. The cvanide electrodeindicated an immediate uptake of four moles of cyanide per moleof ligand. The cyclams and porphyrins above have the metal ion ina macrocyclic circle of ligands, and remcval of the metal isdifficult In that little ilgand deformation can occur during thedeligation process. In :ontrast. the present Schiff base isformally a (ligand-metal-ligani) combination. and twisting and

..... -- i°= imiimmlm IIKi ,.

removal of one ligand due to cyanide coordination can occur,

* followed by a stepwise dechelation of the second ligand. Some|i effort will be made to develop water soluble frameworks of this

sort, that protect the metal ion from reaction, until cyanide ispresent.

S03H

Nickel(II)-Schiff BaseComplex

NN

CH3 CH3

2

1l.

REFERENCES

1. Anti-Cyanide Drugs Annual Report to the U. S. Army MedicalResearch and Development Command, Peter Hambright, May,1986. Contract No. DAHD17-85-C-5086.

2. Anti-Cyanide Drugs Annual Report to the U. S. Army MedicalResearch and Development Command, Peter Hambright, May1987.. Contract No. DAHD17-85-C-5086.

3. W-H Ching and R. G. Kallen," Mechanism of Carbanion Additionto Carbolyl Compounds. Equilibrium and Kinetics ofSubstituted Cyanohydrin Clevage and Formation in AqueousSolution. Substituted Cyanohydrin Proton DissociationConstants", J. Am. Chem. Soc.. (1978), 1Q0, 6119

4. A.J. Fatiadi," Pseudooxocarbons. Synthesis of 1,2,3-Tris(dicyanomethylene)croconate Salts. A New Bond-Delocalized Dianion, Croconate Blue", J. Org. Chem., (1980)45, 1228

5. K. Alexander and S. 1. Baskin, "The Inhibition of CytochromeOxidas* by Dlaminomaleonitrile", Biochem. Blophys. Act&,(1987), 9=2, 41.

6. H. A. Posner,R. E. Tobey and H. McElroy," HydroxocobalaminTherapy of Cyanide Intoxication in Guinea Pigs",Anesthesiology, (1976),44, 157

7. P. Hambright and R. Langley,"Cyanide Scavengers: Kinetics ofthe Reaction of Rhodium(Ill)-Tetra(4-uulfonatophenyl)-porphyrin with Cyanide and Hydrogen Cyanide", Inorg. Chia.Acts, 1987, 137, 209

8. P. Hambright and R. Langley," Cyanide Scavengers: Kineticsof the Reaction of Cyanide with a Water Soluble Cobalt(Ill)Porphyrin", J. lnorg. Biochem., (1988), Ia, 197

17.

PUBLICATIONS

Cyanide Scavengers: Kinetics of the Reaction of Rhodium(IlI)-Tetrakis(4-sulfonatophenyl)porphyrln with Cyanide and Hydrogen

Cyanide. Peter Hambright and Robert Langley, lnorg. Chim. Acta,

1987, 17, 209.(Contribution No. 1809 to the U.S. Army Drug Development

Program].

Cyanide Scavengers: Kinetics of the Reactions of Cyanide with a

Water Soluble Cobalt(Ill) Porphyrin. Peter Hambright and Robert

Langley, J. Inorg. Biochem., 1988, Uj, 197.

[Contribution No. 1827 to the U.S. Army Drug Development

Program].

Reactions of a Water Soluble Ruthenium Porphyrin with Cyanide.Peter Hambright, in press, Inorg. Chim. Acta Letters, 1989.

(Contribution No. xxxx to the U.S. Army Drug Development

Program].

PROJECT PERSONNEL

Dr. Hambright worked part time the academic year 1987-1988

and full time summer, 1987. Ms. Shirleyanne Haye worked full time

on this project, summer, 1987.

l8.

BINDING RATIO DATA

I-I

-dg ( a nd)

10

6 CI43CH0

2- 1/1

0.5 1.0 mm

19.

10 (S 03(CHOH) 2 S 0 )Na 2 .

6 0. 7/1(NH)Rul

I1/I2

0.2 6 1.0 mM 1 2 3

10 [Pd(N H3)4] (N 03)2

4/1 86 -[R u(N H3)6] Cl3

4- 1/1

2-

I I I.1 .2 .3 1 2 3

H[Au C14] 8- cciOHC '4C6- 3/1 II

N4 )

II tI.1.2 .3 12 3

10.

8. [Pt(en),]C 4 8 CHO

OCH

0.8/1

I ' _-- ---- -. ----+0.2 .6 1.0 MM 1 28- 8

4 - [ R h(NH,) 6 CI3 4 - "CHO 0.07/1

0.0 9/1

I i I I i I I I

0.2 .6 1.0 1 2

H

8 PdC12 (DMSO) 8 CH 3 - - CHO

4/1 0-4/14 4

. I I I I0.1 .2 .3 I2

21.

8 8

HO H

o O0. 34/114 C 4 Q3 W 0. 1 2/1

1 2 MM 1 2

8CH

CH3 N CHO

0.666/14 0.66/i/8

1 2

8

4 CHi-Co-CH 3 0.08/1

2 4

H

12 3 mM 123

CHO

O4g/i 6FCHO

I 4

1 2

OHO

CO8 CHO

1 2

4 00.3611

12 3

rA

I00

6 H3 ,CH 3 .1/

CHO I.6/1 29

CHO

I00

'if eI ':0-8211

6

0.o57.22

8

CH CII

I 2. 3CHO

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DISTRIBUTION LIST

I copy CommanderUS Army Medical Research and Development CommandATTN: SGRD-RMI-SFort Detrick, Frederick, MD 21701-5012

5 copies CommanderUS Army Medical Research and Development CommandATTN: SGRD-PLEFort Detrick, Frederick, MD 21701-5012

2 copies Defense Technical Information Center (DTIC)ATTN: DTIC-DDACCameron StationAlexandria, VA 22304-6145

1 copy DeanSchool of MedicineUniformed Services University of the HealthSciences4301 Jones Bridge RoadBethesda, MD 20814-4799

1 copy CommandantAcademy of Health Sciences, US ArmyATTN: AHS-CDMFort Sam Houston, TX 78234-6100