Dibenzo diol epoxide

Methods for the synthesis of the biologically active dihydrodiol and diol epoxide metabolites of both carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbons are reviewed. Four general synthetic routes to the trans-dihydrodiol precursors of the bay region anti and syn diol epoxide derivatives have been developed. Syntheses of the oxidized metabolites of the following hydrocarbons via these methods are described benzo(a)pyrene, benz(a)anthracene, benzo-(e)pyrene, dibenz(a,h)anthracene, triphenylene, phen-anthrene, anthracene, chrysene, benzo(c)phenanthrene, dibenzo(a,i)pyrene, dibenzo(a,h)pyrene, 7-methyl-benz(a)anthracene, 7,12-dimethylbenz(a)anthracene, 3-methylcholanthrene, 5-methylchrysene, fluoranthene, benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)-fluoranthene, and dibenzo(a,e)fluoranthene. 

These hexacyclic hydrocarbons are generally recognized as two of the most potent unsubstituted carcinogenic PAH (38). The 3,4-dihydro-diol of dibenzo(a,i)pyrene (17) and the 1,2-dihydrodiol of dibenzo-(a,h) pyrene (lg) have been synthesized from 4-oxo-l,2,3,4-tetra-hydrodibenzo(a,i)pyrene and 1-oxo-l,2,3,4-tetrahydrodibenzo(a,h)py-rene, respectively, by Method I. (69). Treatment of these dihydro-diols with m-chloroperbenzoic acid gave the corresponding anti diol epoxides (66). 

Figure 8. Epoxide ring opening reactions of bay-region diol epoxides and epoxides from dibenzo[a,h] acridine, and epoxides from benzo[a]acridine and benzo[c]acridine. Figure adaptedfrom reference 27. 

MelendezColon, V.J., Smith, C.A., Seidel, A., Luch, A., Platt, K.L., and Baird, W.M. (1997) Formation of stable adducts and absence of depurinating DNA adducts in cells and DNA treated with the potent carcinogen dibenzo[a,l] pyrene or its diol-epoxides. Proc. Natl. Acad. Sci. USA, 94, 13542-13547. 

Amin, S., Desai, D., Dai, W., Harvey, R.G., and Hecht, S.S. (1995) Tumori-genicity in newborn mice of fjord region and other sterically hindered diol epoxides of benzo[g]chrysene, dibenzo[a,l]pyrene (dibenzo[de/p] chrysene), 4H -cyclopenta[de/]chrysene and fluoranthene. Carcinogenesis, 16, 2813-2817. 

Amin, S., Krzeminski, J., Rivenson, A., Kurtzke, C., Hecht, S.S., and El-Bay-oumy, K. (1995) Mammary cardno-genidty in female CD rats of fjord region diol epoxides of benzo[c] phenanthrene, benzo[g]chrysene and dibenzo[a,l]pyrene. Carcinogenesis, 16, 1971-1974. 

Ruan, Q., Kolbanovskiy, A., Zhuang, P., Chen, J., Krzeminski,)., Amin, S., and Geacintov, N.E. (2002) Synthesis and characterization of site-specific and stereoisomeric fjord dibenzo[a,I]pyrene diol epoxide-JV6)-adenine adducts unusual thermal stabilization of modified DNA duplexes. Chem. Res. Toxicol, 15, 249-261. 

PAHs are ubiquitous environmental pollutants known to be mutagenic and carcinogenic in mammalian cells [131, 132]. PAHs require metabolic activation that results in diol epoxide formation via reactions that are catalyzed by epoxide hydrolase and the CYP450 family of enzymes [133], Diol epoxides are highly reactive, particularly toward purines in DNA, forming guanine and adenine adducts that exist as as and trans stereoisomers [134]. Transcription past adducts derived from diol epoxides of benzo[o]pyrene (benzo[a]pyrene diol expoxide (B[a]PDE)), benzo[c]phenanthrene (benzo[c]phenanthrene diol epoxide (B[c]PhDE)), and dibenzo[a,l]pyrene (dibenzo[o,l]pyrene diol epoxide (B[a,l]PDE)) has been studied. 

Dreij, K., Seidel, A., and Jemstrom, B. (2005) Differential removal of DNA adducts derived from anti-diol epoxides of dibenzo[a,l]pyrene and benzoja] pyrene in human cells. Chem. Res. Toxicol., 18, 655-664. 

Abbreviations PAH, polycyclic aromatic hydrocarbon DE, diol epoxide PAHDE, polycyclic aromatic hydrocarbon diol epoxide PAHTC, polycyclic aromatic hydrocarbon triol carbocation TC, triol carbocation BaP, benzo[a]pyrene BeP, benzo[e]pyrene BA, benz[a]anthracene DBA, dibenz[a,h]anthracene BcPh, benzo[c)phenanthrene Ch, chrysene MCh, methylchrysene MBA, 7-methyl benz[a]anthracene DMBA, 7,12-dimethyl benz[a]anthracene EBA, 7-ethyl benz[a]anthracene DB(a,l)P, dibenzo[a,l]pyrene MSCR, mechanism-based structure-carcinogenicity relationship PMO, Perturbational molecular orbital method dA, deoxyadenosine dC, deoxycytosine dG, deoxyguanosine MOS, monoxygenase enzyme system EH, epoxide hydrolase enzyme system N2(G), exocyclic nitrogen of guanine C, electrophilic centre of PAHTC K, intercalation constant CD, circular dichroism LD, linear dichroism. 

GSTA2-2—Cumene hydroperoxide, fatty add hydroperoxides, dibenzo(a)-pyrene diol epoxide, CDNB-moderate, DCNB-moderate, 7-chloro-4-nitro-2-oxa-1,3-diazole, ethacrynic add (low moderate), PEITC, sulforophane. 

Studies carried out by Straif et al. (2005) showed that, in mice, B[a]P caused lung tumors, by the formation of diol-epoxide and skin tumors, triggered by diol-epoxide mechanisns and cations radicals. According to these same authors, few PAHs are considered carcinogens more potent than B[a]P. However, dibenzo(a,l)pyrene seems to be a carcinogenic 10 times more potent for rats than the own B[a]P (Okona-Mensah et al., 2005). Another PAH highly potent, according to Platt et al. (1990) is the dibenzo(a,h)anthracene. 

Lagerqvist A, Hakansson D, Prochazka G, Lundin C, Dreij K, Segerback D, Jemstrom B, Tomqvist M, Seidel A, Erixon K, Jenssen D Both replieation bypass fidelity and repair efficiency influence the yield of mutations per target dose in intact mammalian cells induced by benzo[a]pyrene-diol-epoxide and dibenzo[a4]pyrene-diol-epoxide. 

Dibenzo [a, l pyrene Dibenzo [a, l pyrene-11,12-diol-13,14-epoxide... 

Regtosdective reduction of an epoxide. A key step in a short synthesis of (+)-muscarine (6) from the dibenzoate of 2,5-anhydro-D-glucitol (1) involves reduction of the epoxide 2. Use of SMEAH gives a 12 1 mixture of 3 and 4 use or LiAlH4 gives the same diols in the ratio 3 1. ... 

Cholestane-2a,3 -diot dibenzoate, 1008 aiolestane-2/3,3a-diol dibenzoate, 1008 Cholestane-3/S,7,S-diol 3,7-dicathylate, 366 Cholestane-3/3,4(5-diol 5a,6a-epoxide, 796 Cholestane-3d,7a-diol 3-monocathylate, 366 Cholestane-4a,5a-diol-3-one, 476 Cholestane-4/3,5/3-diol-3-one, 476 Cholestane-4a,5ii-diol 4-tosylate, 103, 104 Cholestane-5a,6a-diol 6-tosylate, 103,104 Cholestane-2,3-dione, 304, 962 enols of, 747... 

C Pantarotto, L Cappellini, A De Pascale, A Frigerio. Epoxide-diol pathway in the metabolism of 5H-dibenzo[b,f -azepine (iminostilbene). 1 Chromatogr 134 307-314, 1977. 

An acyclic precursor devised by Bogndr and Herczegh, prepared via oxidative cleavage of the furane nucleus, has been applied in the synthesis of racemic pentoses. 2-(2-Furyl)-4,4,S,S-tetramethyl-l,3-dioxolane 257 obtained in reaction of furfural with 2,3-dimethylbutane-2,3-diol was chosen as a substrate, owing to its stability in acidic media (at pH > 3). Oxidation of 257 with bromine water gave the unstable endialone derivative 258, which was reduced with sodium borohydride to 259 (isolated as crystalline dibenzoate). Epoxidation of 259 gave... 

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