Comparison of DNA lesions produced by tumor-inhibitory 1,2-bis(sulfonyl)hydrazines and chloroethylnitrosoureas
Comparison of DNA lesions produced by tumor-inhibitory 1,2-bis(sulfonyl)hydrazines and chloroethylnitrosoureas
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DOI：
10.1016/s0006-2952(99)00328-7
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发表时间：
2000-02-01
影响因子：
5.8
通讯作者：
Sartorelli, AC
中科院分区：
文献类型：
--
作者：
Penketh, PG;Shyam, K;Sartorelli, AC
1,2-双（磺酰基）肼衍生物，旨在产生几种传统上认为负责氯乙基亚硝基脲（CNU）烷基化（氯乙基化）和/或氨基甲酰化活性的亲电子物质，将T7 DNA的交联和切口与1,3-双（2-氯乙基）-1-亚硝基脲（BCNU）引起的交联和切口进行比较， 1-(2-氯乙基)3-环己基-1-亚硝基(CCNU)和1-(2-氯乙基)-3-(4-反式-甲基环己基)-1-亚硝基脲(MeCCNU)。就 BCNU 而言，发现很大一部分 T7 DNA 链切口是由于 2-氯乙胺的产生所致，2-氯乙胺是由 2-氯乙基异氰酸酯水解产生的，在母体亚硝基脲分解过程中形成的朗姆酒中。 1,2-双（甲基磺酰基）-1-（2-氯乙基）肼（化合物 1）比 CNU 产生更高的 DNA 交联产量。化合物I及其不能产生2-氯乙基异氰酸酯的衍生物没有产生可检测水平的链切口，表明这些试剂没有在显着程度上发生鸟嘌呤的N-7-烷基化。由于化合物 1 及其衍生物被认为会产生氯离子和氯乙基重氮离子，因此这些物质似乎不会显着参与由 CNU 引起的鸟嘌呤的 N-7-烷基化。鸟嘌呤残基的 N-7-烷基化水平相对较低，并且一些 1,2-双(磺酰基)-1-(2 氯乙基)肼衍生物产生的交联产率相对较高，这意味着它们是比 CNU 更独特的 O-6-鸟嘌呤氯乙基化剂。 O-6-鸟嘌呤氯乙基化被认为是治疗相关事件：由 CNU 产生；因此，化合物 1 衍生物代表了有前途的新型 Canter 化疗药物，因为与 CNU 相比，它们似乎产生较少量的治疗上不重要的、致癌性病变以及更多的治疗相关的 O-6-鸟嘌呤氯乙基化。
1,2-Bis(sulfonyl)hydrazine derivatives, designed to generate several of the electrophilic species classically believed to be responsible for the alkylating (chloroethylating) and/or carbamoylating activities of the chloroethylnitrosoureas (CNUs), were compared with respect to the cross-linking and nicking of T7 DNA to that caused by 1,3-bis(2-chloraethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl) 3-cyclohexyl-1-nitroso (CCNU), and 1-(2-chloroethyl)-3-(4-trans-methylcyclohexyl)-1-nitrosourea (MeCCNU). In the case of BCNU, a large proportion of T7 DNA strand nicking was found to be due to the generation of 2-chloroethylamine, produced from the hydrolysis of 2-chloroethylisocyanate, in rum formed during the decomposition of the parental nitrosourea. 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (compound 1) gave a greater yield of DNA cross-links than the CNUs. Compound I, as well as its derivatives that were incapable of generating 2-chloroethylisocyanate, did not produce detectable Levels of strand nicking, indicating that N-7-alkylation of guanine did not occur to a significant extent with these agents. Since compound 1 and its derivatives are believed to generate chloronium and chloroethyldiazonium ions, it would appear that these species could not be significantly involved in the N-7-alkylation of guanine caused by the CNUs. The relatively low level of N-7-alkylation of guanine residues and the relatively high yield of cross-links generated by some of the 1,2-bis(sulfonyl)-1-(2 chloroethyl)hydrazine derivatives implies that they are more exclusive O-6-guanine chloroethylating agents than the CNUs. O-6-Guanine chloroethylation is believed to be the therapeutically relevant event: produced by the CNUs; therefore, compound 1 derivatives represent promising new canter chemotherapeutic agents, since they appear to generate lower quantities of therapeutically unimportant, get carcinogenic lesions, and more of the therapeutically relevant O-6-guanine chloroethylation than the CNUs.