Iyengar B S, Dorr R T, Shipp N G, Remers W A
Department of Pharmaceutical Sciences, University of Arizona, Tucson 85721.
J Med Chem. 1990 Jan;33(1):253-7. doi: 10.1021/jm00163a042.
Mitomycin C and certain analogues alkylate DNA with their C-1 position and cross-link it by a second alkylation involving C-10. We now show that monoalkylation by C-10 (carbamate group) can occur for mitosene analogues that have no reactive C-1 functionality. Sodium dithionite reduction of 2,7-diaminomitosene or 2,7-diamino-1-hydroxymitosene in the presence of calf thymus DNA resulted in alkylation of the DNA to the extent of one molecule per 14 and 11 bases, respectively, although no covalent binding was observed on catalytic reduction. Reduction of each of these mitosenes by sodium dithionite in the presence of 2'-deoxyguanosine gave monoalkylation on the 2-amino group of this nucleotide. The 2,7-diaminomitosenes inhibited L-1210 leukemia cell colony formation in vitro at concentrations 3-4-fold greater (less potent) than mitomycin C. DNA single-strand breaks were also produced by each mitosene, but these lesions did not correlate with cytotoxicity and were less prominent than breaks produced by another monofunctional alkylating agent, methyl methanesulfonate. Mitosene-induced DNA strand breaks are probably due to excission-repair endonuclease activity and not from oxygen free radicals produced by redox cycling of the quinone moiety. There was no evidence of DNA-DNA cross-links by either 2,7-diaminomitosene.
丝裂霉素C及其某些类似物通过其C-1位使DNA烷基化，并通过涉及C-10的第二次烷基化使其交联。我们现在表明，对于没有反应性C-1官能团的丝裂霉素类似物，C-10（氨基甲酸酯基团）可以发生单烷基化。在小牛胸腺DNA存在下，连二亚硫酸钠还原2,7-二氨基丝裂霉素或2,7-二氨基-1-羟基丝裂霉素，导致DNA烷基化程度分别为每14和11个碱基一个分子，尽管在催化还原时未观察到共价结合。在2'-脱氧鸟苷存在下，连二亚硫酸钠还原这些丝裂霉素中的每一种，在该核苷酸的2-氨基上产生单烷基化。2,7-二氨基丝裂霉素在体外抑制L-1210白血病细胞集落形成的浓度比丝裂霉素C高3-4倍（效力较低）。每种丝裂霉素也会产生DNA单链断裂，但这些损伤与细胞毒性无关，并且比另一种单功能烷基化剂甲磺酸甲酯产生的断裂不那么明显。丝裂霉素诱导的DNA链断裂可能是由于切除修复内切核酸酶活性，而不是由于醌部分的氧化还原循环产生的氧自由基。没有证据表明2,7-二氨基丝裂霉素会产生DNA-DNA交联。
