Glatt H, Piée A, Pauly K, Steinbrecher T, Schrode R, Oesch F, Seidel A
Department of Toxicology, University of Mainz, Federal Republic of Germany.
Cancer Res. 1991 Mar 15;51(6):1659-67.
The fjord-region diol-epoxides of benzo(c)phenanthrene combine high mutagenic and carcinogenic activity with low chemical reactivity. To study whether this is a unique property of these compounds or a more general characteristic of fjord-region diol-epoxides, we have synthesized the anti- and syn-diastereomers of r-9,t-10-dihydroxy-11,12-oxy-9,10,11,12-tetrahydrobenzo(c)chrysene and r-11-t-12-dihydroxy-13,14-oxy-11,12,13,14-tetrahydrobenzo(g)chrysene. These compounds as well as the anti- and syn-diastereomers of the fjord-region diol-epoxides of benzo(c)phenanthrene and of the bay-region diol-epoxides of phenanthrene, chrysene, and benzo(a)pyrene were investigated for their half-lives in a physiological buffer, for their mutagenicity in Salmonella typhimurium (reversion of the his- strains TA97, TA98, TA100, and TA104), for induction of SOS response in Escherichia coli (SOS chromotest in strain PQ37) and for their mutagenicity in V79 Chinese hamster cells (acquisition of resistance to 6-thioguanine). All six of the investigated fjord-region diol-epoxides were more stable in physiological buffer at 37 degrees C (t1/2 greater than 2 h) than the six bay-region diol-epoxides (t1/2 = 0.011 to 1.2 h). The half-lives correlated negatively with the calculated delta Edeloc values for the formation of the benzylic carbocations, and were consistently shorter for the syn- than for the corresponding anti-diastereomer. All fjord-region diol-epoxides showed extraordinarily high activity in all six genotoxicity assays used. In mammalian cells, the anti-diol-epoxide of benzo(c)chrysene was 8.6 and 12 times more active than the anti-diol-epoxides of benzo(c)phenanthrene and benzo(a)pyrene, respectively, which were the most potent mutagens among the reference compounds. The other three newly available fjord-region diol-epoxides were also markedly more mutagenic in mammalian cells than the reference compounds. Whereas the syn-diastereomers of the simple bay-region diolepoxides were clearly less mutagenic in mammalian cells than the corresponding anti-diastereomers, the differences in potency between diastereomers were small for the fjord-region diol-epoxides. In conclusion, the diol-epoxides of benzo(c)phenanthrene are not unique in their high biological activities. The two newly available diastereomeric pairs of fjord-region diol-epoxides of benzo(g)- and benzo(c)chrysene proved to be even more active. For one of them, the diol-epoxides of benzo(g)chrysene, the delta Edeloc value for the formation of the benzylic carbocation is lower than for the benzo(c)phenanthrene diol-epoxides, for the other it is higher.
苯并(c)菲的峡湾区二醇环氧化物兼具高致突变性和致癌活性，且化学反应活性较低。为研究这是这些化合物的独特性质还是峡湾区二醇环氧化物的更普遍特征，我们合成了r-9,t-10-二羟基-11,12-氧-9,10,11,12-四氢苯并(c)屈的反式和顺式非对映异构体以及r-11-t-12-二羟基-13,14-氧-11,12,13,14-四氢苯并(g)屈。研究了这些化合物以及苯并(c)菲的峡湾区二醇环氧化物和菲、屈及苯并(a)芘的湾区二醇环氧化物的反式和顺式非对映异构体在生理缓冲液中的半衰期、在鼠伤寒沙门氏菌中的致突变性（his-菌株TA97、TA98、TA100和TA104的回复突变）、在大肠杆菌中的SOS应答诱导（菌株PQ37中的SOS显色试验）以及在V79中国仓鼠细胞中的致突变性（获得对6-硫鸟嘌呤的抗性）。所研究的六种峡湾区二醇环氧化物在37℃生理缓冲液中比六种湾区二醇环氧化物更稳定（半衰期大于2小时，而六种湾区二醇环氧化物的半衰期为0.011至1.2小时）。半衰期与苄基碳正离子形成的计算ΔEde loc值呈负相关，且顺式异构体的半衰期始终短于相应的反式非对映异构体。所有峡湾区二醇环氧化物在所有六种遗传毒性试验中均表现出极高的活性。在哺乳动物细胞中，苯并(c)屈的反式二醇环氧化物的活性分别比苯并(c)菲和苯并(a)芘的反式二醇环氧化物高8.6倍和12倍，而苯并(c)菲和苯并(a)芘的反式二醇环氧化物是参比化合物中最有效的诱变剂。另外三种新得到的峡湾区二醇环氧化物在哺乳动物细胞中的致突变性也明显高于参比化合物。虽然简单湾区二醇环氧化物的顺式非对映异构体在哺乳动物细胞中的致突变性明显低于相应的反式非对映异构体，但峡湾区二醇环氧化物的非对映异构体之间的活性差异较小。总之，苯并(c)菲的二醇环氧化物并非因其高生物活性而独具特性。新得到的两对苯并(g)-和苯并(c)屈的峡湾区二醇环氧化物非对映异构体的活性甚至更高。对于其中一种，即苯并(g)屈的二醇环氧化物，苄基碳正离子形成的ΔEde loc值低于苯并(c)菲二醇环氧化物；对于另一种则更高。
