Genotoxicity of chryseno[4,5‐bcd]thiophene and its sulfone derivative

Abstract

Our recent syntheses of chryseno[4,5-bcd]thiophene together with its potential sulfone metabolite, chryseno[4,5-bcd]thiophene-4,4-dioxide, have made these compounds available for genotoxicity testing. Such toxicity testing is of interest as this thiophene is an isoster of the established carcinogen benzo[a]pyrene and is one of the thiaarenes which are potential environmental contaminants found in fossil fuels. Although the thiophene was less mutagenic than benzo[a]pyrene in Salmonella strains TA98 and TA100 after S9 activation, it exhibited in vivo chromosomal aberration activity equal to that of benzo[a]pyrene in the bone-marrow cells of mice. A reduced activity with Salmonella as well as in the bone-marrow cell assay for the sulfone does not support its role as the key active metabolic intermediate for the genotoxicity of the thiophene. Our molecular orbital calculations would be consistent with the concept of activation through a diol-epoxide mechanism and offers an explanation for the reduced genotoxicity of the sulfone via this mechanism. These genotoxicity studies support the concern that sulfur isosters of established carcinogenic polycyclic aromatic hydrocarbons could themselves be toxic.

Genotoxicity related to transfer of oil spill pollutants from mussels to mammals via food

“…Recently, Binet et al (2002), who reviewed bitumen fumes, wrote about the necessity of taking thiophenes into account in chemical analyses because of their suspected carcinogenic potential. The thiophene compounds present in our samples possessed mutagenic properties similar to benzo(a)pyrene (Sinsheimer, 1992). Histological abnormalities (peribiliary fibrosis and hyperplasia) were observed in rats receiving a diet contaminated with benzothiophene in the range of 0.5-500 ppm for 13 weeks (Poon et al, 1998).…”

Synthesis of trans-3,4-dihydroxy-3,4-dihydrophenanthro[3,2-b ][1]benzothiophene, a potentially carcinogenic metabolite of sulfur heterocycle phenanthro[3,2-b ][1]benzothiophene

“…Synthetic application of the Suzuki cross-coupling reaction has recently been developed in our laboratory for a concise, regiospecific synthesis of methoxy-substituted PAHs, 19 which are analogous to 6. One of the key starting materials, 2-(dihydroxyboryl)-5-methoxybenzaldehyde (12), has been synthesized in the literature 23 from the dimethyl acetal of 2-bromo-5-methoxybenzaldehyde (16) in less than 30% yield. A significant improvement in the yield (>90%) of 12 was achieved by replacing the dimethyl acetal of 16 with the ethylene acetal of 16.…”

“…A significant improvement in the yield (>90%) of 12 was achieved by replacing the dimethyl acetal of 16 with the ethylene acetal of 16. The coupling reaction of 3-bromodibenzothiophene (11) 24 with 2-(dihydroxyboryl)-5methoxybenzaldehyde (12), in the presence of anhydrous CsF and a catalytic amount of Pd(PPh 3 ) 4 , produced 3-(2-formyl-4methoxyphenyl)dibenzothiophene ( 13) in 87% yield. The aldehyde functionality of 13 was modified to ethylene epoxide by reacting it with trimethylsulfonium iodide and powdered KOH in acetonitrile at 65 ЊC for 12 h to produce the relatively unstable ethylene epoxide derivative 14 as an oil.…”

“…6,7 These observations are consistent with the speculation that the bay-region concept of metabolic activation of PAHs 10,11 may be extended to thia-PAHs because Hückel MO calculations have predicted bay-region diol epoxides of thia-PAHs to be more electrophilic than their carbocyclic analogues. 12 Recently, synthesis and subsequent biological studies of dihydrodiols of a weak carcinogen, naphtho [1,2-b] [1]benzothiophene (NBT, a thia-analogue of chrysene) have demonstrated that, among two major dihydrodiol metabolites of NBT, 8 trans-3,4-dihydroxy-3,4-dihydronaphtho [1,2-b][1]benzothiophene (NBT 3,4-diol), a metabolic precursor to the bay-region diol epoxide of NBT, is significantly more mutagenic than the isomeric trans-1,2dihydroxy-1,2-dihydronaphtho [1,2-b][1]benzothiophene (NBT 1,2-diol). 13 However, in contrast to a significant difference noted between the mutagenicity of chrysene and its 1,2-diol, 14 no significant difference was noted between the mutagenicity of NBT and NBT 3,4-diol.…”

Determination of Thiaarenes and Polycyclic Aromatic Hydrocarbons in Workplace Air of an Aluminum Reduction Plant

“…Thiaarenes have been found to be generally more acute toxic than their analogous polycyclic aromatic hydrocarbons (PAH) (). Some thiaarene compounds are potent mutagens and carcinogens ( − ). In different studies indications were found that thiaarenes increase the carcinogenic potential of environmental matter ( , ).…”