SYNTHESIS, SPECIFICITY, AND ANTIFUNGAL ACTIVITY OF INHIBITORS OF THE CANDIDA-ALBICANS DELTA-24-STEROL METHYLTRANSFERASE
SYNTHESIS, SPECIFICITY, AND ANTIFUNGAL ACTIVITY OF INHIBITORS OF THE CANDIDA-ALBICANS DELTA-24-STEROL METHYLTRANSFERASE
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DOI：
10.1021/jm00079a012
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发表时间：
1992-01-10
影响因子：
7.3
通讯作者：
BARONE, JM
中科院分区：
文献类型：
--
作者：
ATOR, MA;SCHMIDT, SJ;BARONE, JM
合成了一系列胆固醇和羊毛甾醇的侧链修饰类似物（1-10），并评价了其作为白色念珠菌DELTA-24-甾醇甲基转移酶抑制剂的作用。两种甾醇底物类似物1和2含有24-硫杂取代基，是相对温和的酶抑制剂（K（i）= 1.5-72 μ M）。模拟用于甲基转移酶反应的碳阳离子中间体的化合物，包括锍盐4-6、脒7和8以及咪唑9和10，是基本上更有效的抑制剂（K（i）= 5-500 nM）。所有的甾醇类似物检查显示小于10倍的选择性抑制甲基转移酶对大鼠肝脏DELTA-24-甾醇还原酶。对甾醇类似物进行了体外抗真菌活性测试。白色念珠菌、热带念珠菌和光滑球拟酵母。最低抑菌浓度与C.白色念珠菌的活性与甲基转移酶抑制的K（i）值相关良好，并且几种化合物的效力接近于白曲霉素B，尽管仅观察到适度的杀真菌活性。
A series of side chain modified analogues of cholesterol and lanosterol (1-10) have been synthesized and evaluated as inhibitors of the Candida albicans DELTA-24-sterol methyltransferase. Two sterol substrate analogues 1 and 2 which contained a 24-thia substituent were relatively modest inhibitors of the enzyme (K(i) = 1.5-72-mu-M). Compounds which mimic the carbocation intermediates proposed for the methyltransferase reaction, including sulfonium salts 4-6, amidines 7 and 8, and imidazoles 9 and 10 were substantially more potent inhibitors (K(i) = 5-500 nM). All of the sterol analogues examined displayed less than 10-fold selectivity for inhibition of the methyltransferase versus the rat liver DELTA-24-sterol reductase. The sterol analogues were tested for in vitro antifungal activity against C. albicans, Candida tropicalis, and Torulopsis glabrata. The minimum inhibitory concentrations versus C. albicans correlated well with the K(i) values for methyltransferase inhibition, and the potency of several compounds approached that of amphotericin B, although only modest fungicidal activity was observed.