核苷酸还原酶抑制剂抗癌活性与电子结构的关系

用CNDO/2量化方法计算了32个异羟肟酸化合物、6个酰胺化合物和9个羧甲酯类化合物的电子结构,对其中的44个化合物的量化指数与其抑制核苷酸还原酶的活性参数PC进行逐步回归计算,得到关于异羟肟酸化合物、酰胺类化合物和羧甲酯类化合物的二个QSAR,由QSAR表明化合物抑制核苷酸还原酶的机制是络合机制。同时,用模式识别方法研究了其中35个化合物的结构对治疗患L₁₂₁₀肿瘤小鼠药效的影响,得到满意的分类图,结果表明化合物的抗癌活性是通过抑制核苷酸还原酶所致,但化合物在体内到达受体的过程和难易程度对药效的影响较大。

STUDIES ON THE RELATIONSHIP OF ANTITUMOR ACTIVITY AND THE ELECTRONIC STRUCTURE OF RIBONUCLEOTIDE REDUCTASE INHIBITORS

By using the CNDO/2 quantum chemistry method,32 substituted hydroxamicacids,6 substituted benzamides and 9 substituted methyl benzoates have been calculated.Among them44 compounds were studied by step regression method. Two quantitative structure-(ribonucleotidereductase inhibitory) activity relationships of two groups(hydroxamic acids and benzamides ,methylbenzoates)were obtained. They were(1) PC=3.00—2.74 CQS—0.15 E_HOMO+0.22 SHEP forsubetituted hydroxamic acids and(2) PC=10.06—0.96 CQS+1.07 E_LUMO+0.66 SHEP forsubetituted benzamides and methyl benzoates. The results show that the quantum chemical indexes inthe two QSAR affected the inhibitory activity to similar degree and the mechanism of inhibition ofribonucleotide reductase by inhibitors involves metal chelation. Furthermore ,the effects of thestructure of 35 compounds on the life span of L₁₂₁₀ leukemia-bearing mice were studied by patternrecognition method. The antitumor activity classification figure obtained by four parameters π,CQS,ELUMO and SHEP, is satisfactory. This indicates that the antitumor activities of these compounds arethe result of inhibiting ribonucleotide reductase which is governed by the speed and extent of thesecompounds to reach the acceptor.