Chem. Res. Toxicol. 1992, 5, 5-7 and persistence of 7-(2’-oxoethyl)guanineand W,3-ethenoguanine in rat tissue DNA. Carcinogenesis 11,1287-1292. (10) Barbin, A., Laib, R. J., and Bartsch, H. (1985) Lack of miscoding properties of 7-(2-oxoethyl)guanine,the major vinyl chloride-DNA adduct. Cancer Res. 45, 2440-2444. (11) Singer, B., Abbott, L. G., and Spengler, S. J. (1984)Assessment of mutagenic efficiency of two carcinogen-modified nucleosides, 1,P-ethenodeoxyadenosineand 04-methyldeoxythymidine,using polymerases of varying fidelity. Carcinogenesis 5, 1165-1171. (12) Kusmierek, J. T., and Singer, B. (1982) Chloroacetaldehydetreated ribo- and deoxyribopolynucleotides. 2. Errors in transcription by different polymerases resulting from ethenocytosine and its hydrated intermediate. Biochemistry 21, 5723-5728. (13) Singer, B., Spengler, S. J., Chavez, F., and Kusmierek, J. T. (1987) The vinyl chloride-derived nucleoside, W,3-ethenoguanosine, is a highly eficient mutagen in transcription. Carcinogenesis 8, 745-747. (14) Singer, B., Kusmierek, J. T., Folkman, W., Chavez, F., and Dosanjh, M. K. (1991) Evidence for the mutagenic potential of the vinyl chloride induced adduct, W,3-etheno-deoxyguanosine, using a site-directed kinetic assay. Carcinogenesis 12, 745-747. (15) Leonard, N. J. (1984) Etheno-substituted nucleotides and coenzymes: fluorescence and biological activity. CRC Crit. Reu. Biochem. 15, 125-199. (16) Barbin, A., Friesen, M., O’Neill, I. K., Croisy, A., and Bartsch, H. (1986) New adducts of chloroethylene oxide and chloroacetaldehyde with pyrimidine nucleosides. Chem.-Bid. Interact. 59, 43-54. (17) Bedell, M. A., Dyroff, M. C., Doerjer, G., and Swenberg, J. A. (1986) Quantitation of etheno adducts by fluorescence detection. In The Role of Cyclic Nucleic Acid Adducts in Carcinogenesis and Mutagenesis (Singer, B., and Bartach, H., Eds.) pp 425-436, IARC Scientific Publications, Lyon. (18) Barbin, A., &r&iat, J. C., Croisy, A., ONeill, I. K., and Bartsch, H. (1990) Nucleophilic selectivity and reaction kinetics of chloroethylene oxide assessed by the 4-(p-nitrobenzyl)pyridineassay and proton nuclear magnetic resonance spectroscopy. Chem.-Biol. Interact. 73, 261-277. (19) Roe, J., Jr., Paul, J. S., and Montgomery, P. O., Jr. (1973) Synthesis and PMR spectra of 7-hydroxyalkylguanosiniumacetates. J. Heterocycl. Chem. 10, 849-857. (20) Piper, J. R., Laseter, A. G., and Montgomery, J. A. (1980) Synthesis of potential inhibitors of hypoxanthine-guanine phosphoribosyltransferase for testing as antiprotozoal agents. 1. 7Substituted 6-oxopurines. J. Med. Chem. 23, 357-364. (21) Sattsangi, P. D., Leonard, N. J., and Frihart, C. R. (1977) 1JP-Ethenoguanine and N2,3-ethenoguainine. Synthesis and comparison of the electronic spectral properties of these linear and angular triheterocycles related to the Y bases. J. Org. Chem. 42, 3292-3296. (22) Barrio, J. R., Secriot, J. A., 111, and Leonard, N. J. (1972) Fluorescent adenosine and cytidine derivatives. Biochem. Biophys. Res. Commmun. 46, 597-604. (23) Guengerich, F. P., Wang, P., Mitchell, M. B., and Mason, P. S. (1979) Rat and human liver microsomal epoxide hydratase. Purification and evidence for the existence of multiple forms. J. Biol. Chem. 254, 12248-12254.
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(24) Thomas, P. E., Bandiera, S., Maines, S. L., Ryan, D. E., and Levin, W. (1987)Regulation of cytochrome P-450j, a high-affinity N-nitrosodimethylamine demethylase, in rat hepatic microsomes. Biochemistry 26, 2280-2289. (25) Ciroussel, F., Barbin, A., Eberle, G., and Bartach, H. (1990) Investigations on the relationship between DNA ethenobase adduct levels in several organs of vinyl chloride-exposed rats and cancer susceptibility. Biochem. Pharmacol. 39, 1109-1113. (26) Kadlubar, F. F., Miller, J. A., and Miller, E. C. (1976) Microsomal N-oxidation of the hepatocarcinogen N-methyl-4-aminoazobenzene and the reactivity of N-hydroxy-N-methyl-4-aminoazobenzene. Cancer Res. 36, 1196-1206. (27) Fedtke, N., Walker, V. E., and Swenberg, J. A. (1989) Determination of 7-(2’-oxoethyl)guanine and W,3-ethenoguanine in DNA hydrolysates by HPLC. Arch. Toxicol. Suppl. 13,214-218. (28) Leithauser, M. T., Liem, A., Stewart, B. C., Miller, E. C., and Miller, J. A. (1990) 1,WEthenoadenosine formation, mutagenicity and murine tumor induction as indicators of the generation of an electrophilic epoxide metabolite of the closely related carcinogens ethyl carbamate (urethane) and vinyl carbamate. Carcinogenesis 11,463-473. (29) Guengerich, F. P., Kim, D.-H., and Iwasaki, M. (1991) Role of human cytochrome P-450 IIEl in the oxidation of several low molecular weight cancer suspects. Chem. Res. Toxicol. 4,168-179. (30) Kim, D.-H., and Guengerich, F. P. (1990) Formation of the DNA adduct S-[2- (N-guanyl)ethyl]glutathione from ethylene dibromide: effects of modulation of glutathione and glutathione S-transferase levels and the lack of a role for sulfation. Carcinogenesis 11,419-424. (31) Malaveille, C., Bartach, H., Barbin, A., Camus, A. M., and Montesano, R. (1975) Mutagenicity of vinyl chloride, chloroethyleneoxide, chloroacetaldehyde and chloroethanol. Biochem. Biophys. Res. Commun. 63, 363-370. (32) Guengerich, F. P., and h e y , V. M. (1991) Formation of etheno adducts of adenosine and cytidine from l-Mooxiranee. Evidence for a mechanism involving initial reaction with the endocyclic nitrogen atoms. J. Am. Chem. SOC. (in press). (33) Wong, L. C. K., Winston, J. M., Hong, C. B., and Plotnick, H. (1982) Carcinogenicityand toxicity of l,2-dibromomethane in the rat. Toxicol. Appl. Pharmacol. 63, 155-165. (34) Guengerich, F. P., and Kim, D.-H. (1991) Enzymatic oxidation of ethyl carbamate to vinyl carbamate and its role as an intermediate in the formation of 1$P-ethenoadenosine. Chem. Res. Toxicol. 4, 413-421. (35) Brady, J. F., Lee, M. J., Li, M., Ishizaki, H., and Yang, C. S. (1988)Diethyl ether as a substrate for acetone/ethanol-inducible cytochrome P-450 and as an inducer for cytochrome(s) P-450. Mol. Pharmacol. 33, 148-154. (36) Eberle, G., Barbin, A., Laib, R. J., Ciroussel, F., Thomale, J., Bartsch, H., and Rajewsky, M. F. (1989) l$P-ethen0-2’-deoxyadenosine and 3,N4-etheno-2’-deoxycytidinedetected by monoclonal antibodies in lung and liver DNA of rats exposed to vinyl chloride. Carcinogenesis 10, 209-212. (37) Wiseman, R, W., Stowers, S. J., Miller, E. C., Anderson, M. W., and Miller, J. A. (1986) Activating mutations of the c-Hams protooncogene in chemically induced hepatomas of the male B6C3 F1 mouse. Proc. Natl. Acad. Sci. U.S.A. 83, 5825-5829.
Semiempirical Self-Consistent Field (CNDO) Calculations of Arsenical-Antidote Adducts Dennis W. Bennett,+Lihua Huang,* and Kilian Dill*J Department of Chemistry, University of Wisconsin, Milwaukee, Wisconsin 53201, and Department of Chemistry, Clemson University, Clemson, South Carolina 29634 Received August 8, 1991 Introduction A requisite feature of antidotes for heavy metals such as arsenic is the ability of the antidote to sequester the
* Author to whom correspondence should be addressed. t University
of Wisconsin.
* Clemson University.
metal and eventually excrete the adduct. Thus, the pharmacokinetics of the antidote and the stability of the adduct fOrmed are of utmost importance 88 the first step in the detoxification process. In recent years, we have published extensively on the reactions of organic arsenicals with simple thiol-containing compounds in order to develop a strategy in the search for
0893-228x/92/2705-0005$03.00/00 1992 American Chemical Society
6 Chem. Res. Toxicol., Vol. 5, No. 1, 1992
1 50
I 65
1 80
1 95
2 10
2 25
AS-Si
2 40
2 55
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2 70
2 85
3 00
DISTANCE
Figure 1. Plots of energy versus the arsenicsulfur bond length. The plots have been stacked so that the minima can be observed. The absolute values of the energy minima are almost identical. (A) MDA-PDT; (B) MDA-BAL; (C) MDA-DTE; (D) MDADMPS; (E) MDA-DMSA. better arsenic antidotes (1-9). Most emphasis has been placed on gaining information about dithiol compounds which form five- and six-membered heteroatom rings upon reaction with the organic arsenicals (I-4,7-9). The results obtained so far indicate that several factors influence the strength of the adduct formed. These include the electronic nature of the substituents on the antidote, solvent, pH of the media, and the size of the arsenical-antidote adduct ring formed. In order to further our understanding dealing with the structures, stabilities, and physical parameters for various arsenical-antidote adducts, we investigated several adducts in the gas phase using CNDO calculations. This allowed us to obtain some basic information about these species without the interference of solvent effects and other solution perturbations. For our calculations, we used MDAl as our arsenical and several candidate antidotes which contain vicinal dithiol groups as depicted. CH~ASCI~ MDA
CHSCHCH,
CHZCHC H2
I I I
I I
SHSH
OH SHSH
PDT
BAL
CH2CHCHCH2
H02CCHCHC02H
CH2CHCHzSOsH
OH SHSHOH
SH SH
DTE
DMSA
I I l l
I I
I I
SH SH DMPS
Experimental Section The program used for these calculations was CND0/2-3R (IO), and the system was run on a Defiicon DS1-020 coprocessor board housed in a Gateway 386 P4AT compatible computer. The first approximation of bond angles and bond lengths for the arsenic and sulfur atoms was taken from the arsenical-antidote adduct crystal structure by Adams et al. (11). The calculations were performed as follows. The S-S midpoint was moved along the As-midpoint vector. Thus,the S-S distance was fixed, but the S-As-S angle as well as the As-S bond length were varied until the minimum energy was reached. The gas-phase enthalpies of reactions were determined by the equation: CH3AsC12 dithiol CH3As-dithiol 2HC1
+
-
+
and AEZreaction =
AEZf(CH3As-dithiol)+ 2AEZf(HC1) AHf(CH3AsC12) - AHf(dithiol)
Abbreviations: MDA, methyldichloroarsine; PDT, propanedithiol; BAL, British antilewisite; DTE, 2,3-dithioerythritol; DMSA, dimercaptosuccinic acid; DMPS, dimercaptopropanesulfonicacid.
b
Figure 2. Structure of MDA-BAL obtained from the calculations. Table I. Dipole Moments" for the Various MDA-Antidote Adducts dipole dipole adduct moment adduct moment MDA-PDT 4.81 MDA-DMSA 1.21 MDA-B AL 3.10 MDA-DMPS 5.05 MDA-DTE 3.58 Given in units of debye.
Table 11. Enthalpies of Reaction for the Reaction of the Various Dithiols with MDA dithiol PDT BAL DTE
AHrMdo$ 61.61
-41.76
dithiol DMSA DMPS
AHre,,,$ 64.46 59.02
65.25
Given in kJ/mol.
Results and Discussion The reaction of the dithiols with the arsenical yields HC1 and the adduct. The adduct can be formed as two geometric isomers (2,2,8)which readily interconvert in acidic media (8).The trans isomer is favored over the cis isomer by -4/1. In this paper we will focus only on the more stable trans isomer. For simplicity, the antidotes DMSA and DMPS were calculated in their protonated forms, whereas in neutral aqueous media they exist as charged species. Figure 1 shows the optimal As-S bond distances that we obtained for the various MDA-antidote adducts. For all the adducts studied, the As-S bond distances ranged from 2.14 to 2.24 A. Hence, it would appear that the antidote functional group does not influence the As-S bond length in the gas phase. Furthermore, the Aa-S bond lengths and the S-As-S bond angle from our calculations do not differ appreciably from those obtained from the crystal structure; the bond distances differed by 10.1 A. Thus, the crystal structure and gas-phase results are comparable. Figure 2 shows the structure of the MDA-BAL adduct obtained from the calculations. The ring is in a puckered configuration with the methyl (on the arsenic) and hydroxymethyl groups in the trans/anti position. In the solution state, it is known that the trans/anti and trans/syn structures interconvert very quickly (12). Tables I and I1 give information about the structure and stability of the various MDA-antidote adducts. The dipole moments show the polarization of the adduct and thus may
Communications
influence the solubility. It is noteworthy that the MDABAL has the lowest dipole moment whereas the aliphatic MDA-PDT adduct has a larger dipole moment. This results from the fact that the dipole moments are influenced by the lone pair of electrons on the arsenic atom. The aqueous solubilities are more likely to be determined by the nature of the substituent on the antidote. For instance, although the arsenical-PDT adduct has a large dipole moment, it is not soluble in water (9). On the other hand, the arsenical-BAL adduct (with the low dipole moment) is sparingly soluble in water (7). Table I1 gives the enthalpies for the reaction of MDA with the various dithiols. The reaction enthalpies are all endothermic except for the reaction of MDA with BAL which was found to be exothermic. A comparison of our gas-phase results with those of solution binding constant data for various arsenicalantidote adducts can only be qualitative because of the various solvent conditions used and because the substituents on the arsenical are different and the fact that the DMSA and DMPS were calculated in their nonionized forms. However, a general trend can be observed. The arsenical-BAL adduct is known to have a greater binding constant compared to all other adducts studied in this paper, with the exception of the arsenical-PDT adduct. For instance, we found that the relative binding constant for the arsenical-BAL adduct was 10 times greater than the arsenical-DMSA adduct (7) and -2 times greater than the arsenical-DTE adduct.2 The arsenical-PDT adduct binding studies were performed in nonaqueous conditions, and the increase in the relative binding constant for the PDT-arsenical adduct was attributed to small substituent effects (9). Our present gas-phase results suggest that there should not be significant differences in the stability of the adducts formed nor should the functional groups on the antidotes play a substantial role in influencing the formation of the adduct. Thus,the differences we do observe in the relative binding constants for these antidotes (7) and effects of substituents (9) on the relative binding constants must then be influenced by solvent and the charge on the adduct. Our calculations allowed us to view these adducts in a very simple form and limit the parameters that influence K. Dill, E. L. McGown, and V. L. Boyd, unpublished results.
Chem. Res. Toxicol., Vol. 5, No. 1, 1992 7
stabilities and structures. Aside from BAL, all the other dithiol compounds behave similarly. It is interesting that BAL has been widely used for the treatment of arsenic poisoning in the U.S.for the past 50 years (13, 14).
References (1) Dill, K., Adams, E. R., O’Connor, R. J., and McGown, E. L.
(1987) 2D NMR Studies of the phenyldichloroarsine-British anti-lewisite Adduct. Magn. Reson. Chem. 25, 1074-1077. (2) O’Connor, R. J., Dill, K., McGown, E. L., and Hallowell, S. F. (1989) 2D-NMR Studies of arsenical-sulfhydryl adducts. Magn. Reson. Chem. 27, 669-675. (3) Dill, K., Adams, E. R., O’Connor, R. J., and McGown, E. L. (1989) Structure and dynamics of a lipoic acid-arsenical adduct. Chem. Res. Toxicol. 2,181-185. (4) Boyd, V. L., Harbell, J. W., OConnor, R. J., and McGown, E. L. (1989) 2,3-Dithioerythritol, a possible new arsenic antidote. Chem. Res. Toxicol. 2, 301-306. (5) Dill, K., Hu, S., O’Connor, R. J., and McGown, E. L. (1990) Preparation, structure, and solution dynamics of phenyldichloroarsine-thio sugar adducts. Carbohydr. Res. 196, 141-146. (6) DilI, K., O’Connor, R. J., and McGown, E. L. (1990)Reaction of cysteine(s) with phenyldichloroarsine. Znorg. Chim. Acta 168, 11-14. (7) O’Connor, R. J., McGown, E. L., Dill, K., and Hallowell, S. F. (1990) Relative binding constants of arsenical-antidote adducts as determined by NMR spectroscopy. Res. Commun. Chem. Pathol. Pharmacol. 69,365-368. (8) Dill, K., Huang, L., Bearden, D. W., McGown, E. L., and O’Connor, R. J. (1991) Activation energies and formation rate constanta for organic arsenical-antidote adducts as determined by dynamic NMR spectroscopy. Chem. Res. Toxicol. 4, 295-299. (9) Dill, K., Huang, L., McGown, E. L., Youn, S. H., and OConnor, R. J. (1991) Substituent effects on the binding constanta of arsenical-dithiol adducts. Res. Commun. Chem. Pathol. PharmaC O ~ .72, 367-370. (10) Hase, H. L., and Schweig, A. (1991) CND0/2-3R, Quantum Chemistry Program Exchange. (11) Adams, E. R., Jeter, D., Cordes, A. W., and Kolis, J. W. (1990) Chemistry of organometalloid complexes with potential antidotes: structure of an organoarsenic (111) dithiolate ring. Znorg. Chem. 29, 1500-1503. (12) Aksnes, D. W., and Bjoroy, M. (1975) NMR Studies on Cyclic Arsenites. IH NMR Spectral analysis and conformational studies of 2-chloro-5-methyl-and 2-phenyl-5-methyl-l,3,2-oxathiarsolane and 2-chloro-5-methyl-l,3,2-dithiarsolane and -1,3,2-dioxarsolane. Acta Chem. Scand. A29,672-676. (13) Gilman, A. G., Goodman, L. S., and Gilman, A,, Eds. (1980) in Goodman and Gilman’s The pharmacological basis of therapeutics, 6th ed., Macmillan Publishing Co., New York. (14) Peters, R. A., Stocken, L. A., and Thompson, R. H. S. (1945) British anti-lewisite. Nature 156, 616-619.
