Lee S H, Goldberg I H
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Mol Pharmacol. 1988 Apr;33(4):396-401.
To determine the role of the epoxide moiety of the nonprotein chromophore of the antitumor antibiotic neocarzinostatin in its ability to damage DNA, the diol monomethyl ether derivative was prepared, and its stability and biological properties were studied. This analogue was found to be more stable than the epoxide (about 9-fold), but to be much less active in nicking supercoiled DNA and in forming covalent adducts with poly(dA-dT). However it is able to bind noncovalently to DNA and to the neocarzinostatin apoprotein. Another analogue, the chlorohydrin derivative, is about half as active as the epoxide in the DNA scission reaction and appears to produce the same covalent adducts with poly(dA-dT) as does the epoxide, suggesting that both compounds undergo similar types of activation by thiol. These results indicate that the epoxide moiety of the neocarzinostatin chromophore is an important part of the highly unsaturated, strained bicyclo[7.3.0]dodecadiendiyne in the thiol-dependent, DNA-damaging reaction. It may be involved in the activation of the drug to its active species and/or may be the site of new bond formation in its reaction with DNA.
为了确定抗肿瘤抗生素新制癌菌素非蛋白质发色团的环氧化物部分在其损伤DNA能力中的作用，制备了二醇单甲醚衍生物，并研究了其稳定性和生物学特性。发现该类似物比环氧化物更稳定（约9倍），但在切割超螺旋DNA和与聚（dA-dT）形成共价加合物方面活性要低得多。然而，它能够与DNA和新制癌菌素脱辅基蛋白非共价结合。另一种类似物氯醇衍生物在DNA断裂反应中的活性约为环氧化物的一半，并且似乎与环氧化物一样与聚（dA-dT）产生相同的共价加合物，这表明这两种化合物通过硫醇经历相似类型的活化。这些结果表明，新制癌菌素发色团的环氧化物部分是高度不饱和、张力双环[7.3.0]十二碳二烯二炔在硫醇依赖性DNA损伤反应中的重要组成部分。它可能参与药物向其活性物种的活化过程，和/或可能是其与DNA反应中新键形成的位点。
