Anti-AIDS agents.: 37.: Synthesis and structure-activity relationships of (3′R,4′R)-(+)-cis-khellactone derivatives as novel potent anti-HIV agents
Anti-AIDS agents.: 37.: Synthesis and structure-activity relationships of (3′R,4′R)-(+)-cis-khellactone derivatives as novel potent anti-HIV agents
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DOI：
10.1021/jm9900624
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发表时间：
1999-07-15
影响因子：
7.3
通讯作者：
Lee, KH
中科院分区：
文献类型：
--
作者：
Xie, L;Takeuchi, Y;Lee, KH
为探索新型抗HIV药物（+）-cis-khellactone（DCK）的结构要求，采用不对称合成方法，合成了24个单取代的3 '，4'-二-O-（S）-胆酰基-（+）-cis-khellactone（DCK）衍生物。这些化合物包括4个异构的单甲氧基类似物（3-6）、4个异构的单甲基类似物（7-10）、4个4-烷基/芳基取代的类似物（11-14）和12个具有不同3 '，4'-取代基的4-甲基-（+）-顺式-凯内酯衍生物（15-26）。在急性感染的H9淋巴细胞中筛选这些（+）-顺式-凯内酯衍生物抗HIV-1复制。结果表明，（3 'R，4' R）-（+）-cis-khellactone骨架，3 '-和4'-位上的两个（S）-（-）-乙酰基，以及香豆素环上除6-位外的一个甲基是抗HIV活性的最佳结构部分。3-甲基-（7）、4-甲基-（8）和5-甲基-（9）3 '，4'-二-O（S）-乙酰基-（3 'R，4' R）-（+）-顺式-凯内酯在H9淋巴细胞中的EC 50和治疗指数值分别为2.15 × 10（6），在同一试验中，这比DCK和AZT的EC 50和治疗指数值好得多。此外，8和9还显示出对CEM-SS细胞系中HIV-1复制的有效抑制活性，并且在两种测定中，大多数单取代的DCK类似物的毒性低于DCK。
To explore the structural requirements of (+)-cis-khellactone derivatives as novel anti-HIV agents, 24 monosubstituted 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives were synthesized asymmetrically. These compounds included 4 isomeric monomethoxy analogues (3-6), 4 isomeric monomethyl analogues (7-10), 4 4-alkyl/aryl-substituted analogues (11-14), and 12 4-methyl-(+)-cis-khellactone derivatives (15-26) with varying 3',4'-substituents. These (+)-cis-khellactone derivatives were screened against HIV-1 replication in acutely infected H9 lymphocytes. The results demonstrated that the (3'R,4'R)-(+)-cis-khellactone skeleton, two (S)-(-)-camphanoyl groups at the 3'- and 4'-positions, and a methyl group on the coumarin ring, except at the 6-position, were optimal structural moieties for anti-HIV activity. 3-Methyl- (7), 4-methyl- (8), and 5-methyl- (9) 3',4'-di-O(S)-camphanoyl-(3'R,4'R)-(+)-cis-khellactone showed EC50 and therapeutic index values of 2.15 x 10(6), respectively, in H9 lymphocytes, which are much better than those of DCK and AZT in the same assay. Furthermore, 8 and 9 also showed potent inhibitory activity against HIV-1 replication in the CEM-SS cell line, and most monosubstituted DCK analogues were less toxic than DCK in both assays.