Jerina D M, Chadha A, Cheh A M, Schurdak M E, Wood A W, Sayer J M
Laboratory of Bioorganic Chemistry, National Institutes of Health NIDDK, Bethesda 20892.
Adv Exp Med Biol. 1991;283:533-53. doi: 10.1007/978-1-4684-5877-0_70.
Although the solution chemistry of diol epoxides is now fairly well understood, a great deal remains to be elucidated regarding their reaction in the presence of DNA. Not only DNA but also small molecules are capable of sequestering diol epoxides in aqueous solutions with equilibrium constants on the order of 10(2)-10(4) M-1. In the case of DNA, at least two major families of complexes are presently recognized, possibly the result of groove binding vs. intercalation. As is the case for diol epoxides free in solution, the complexed diol epoxides undergo solvolysis to tetraols and in some cases possibly to keto diols as well. Fractionation between covalent bonding and solvolysis from within the complex(s) is determined more by the nature of the parent hydrocarbon from which the diol epoxide is derived than any other factor. Studies of a wide variety of alkylating and arylating agents have show that practically every potentially nucleophilic site on DNA can serve as a target for modification. In the case of the diol epoxides, practically all of the modification occurs at the exocyclic amino groups of the purine bases. In contrast to the diol epoxides, other epoxides such as those derived from aflatoxin B1, vinyl chloride, propylene, 9-vinylanthracene, and styrene preferentially bind to the aromatic ring nitrogens N-7 in guanine and N-3 in adenine (cf. Chadha et al., 1989). Molecular modeling as well as the spectroscopic evidence suggests that the hydrocarbon portion of the diol epoxides lies in the minor groove of DNA when bound to the exocyclic 2-amino group of guanine and in the major groove when bound to the exocyclic 6-amino group of adenine. Detailed conformational analysis of adducted DNA should prove to be extremely valuable in developing mechanistic models for the enzymatic processing of chemically altered DNA. At present, the critical lesion or lesions responsible for induction of neoplasia remains obscured by the large number of apparently noncritical adducts which form when polycyclic hydrocarbon diol epoxides bond to DNA.
尽管二醇环氧化物的溶液化学目前已相当清楚，但关于它们在DNA存在下的反应仍有许多有待阐明之处。不仅DNA，小分子也能够在水溶液中螯合二醇环氧化物，其平衡常数约为10(2)-10(4) M-1。就DNA而言，目前至少已识别出两个主要的复合物家族，这可能是沟槽结合与嵌入的结果。与溶液中游离的二醇环氧化物情况一样，络合的二醇环氧化物会发生溶剂解形成四醇，在某些情况下也可能形成酮二醇。复合物内部共价键合与溶剂解之间的分馏更多地取决于二醇环氧化物所衍生的母体烃的性质，而非其他任何因素。对多种烷基化和芳基化剂的研究表明，DNA上几乎每个潜在的亲核位点都可作为修饰靶点。就二醇环氧化物而言，几乎所有修饰都发生在嘌呤碱基的环外氨基上。与二醇环氧化物不同，其他环氧化物，如源自黄曲霉毒素B1、氯乙烯、丙烯、9-乙烯基蒽和苯乙烯的环氧化物，优先与鸟嘌呤中的芳香环氮N-7和腺嘌呤中的N-3结合（参见Chadha等人，1989）。分子建模以及光谱证据表明，二醇环氧化物的烃部分在与鸟嘌呤的环外2-氨基结合时位于DNA的小沟中，而在与腺嘌呤的环外6-氨基结合时位于大沟中。加合DNA的详细构象分析在开发化学改变DNA的酶促加工机制模型方面应具有极高价值。目前，当多环烃二醇环氧化物与DNA结合时形成的大量明显非关键加合物掩盖了导致肿瘤形成的关键损伤。
