ANTI-AIDS AGENTS .15. SYNTHESIS AND ANTI-HIV ACTIVITY OF DIHYDROSESELINS AND RELATED ANALOGS
ANTI-AIDS AGENTS .15. SYNTHESIS AND ANTI-HIV ACTIVITY OF DIHYDROSESELINS AND RELATED ANALOGS
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DOI：
10.1021/jm00049a014
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发表时间：
1994-11-11
影响因子：
7.3
通讯作者：
LEE, KH
中科院分区：
文献类型：
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作者：
HUANG, L;KASHIWADA, Y;LEE, KH
合成了42个基于Suksdorfin(1)结构的二氢芝麻素，以评价它们的抗HIV活性。这些合成的衍生物包括3‘，4’-二-O-酰基和3‘或4’-O-酰基-顺式二氢芝麻素(8-21)和3‘，4’-反式-二氢芝麻素，在3‘和4’位带有O-酰基和/或O-烷基(6，22-43)。合成了两个4‘-叠氮基(44，45)和三个4’-烷基酰胺(46，48，49)衍生物。用光学纯试剂合成了三对非对映异构体，并将其分离为光学纯化合物(14，15；16，17；38，39)。此外，还研究了芝麻素(3)和(+/-)-顺式(4)、(+)-顺式-(5)和(+/-)-反式二氢芝麻素-3‘，4’-二醇(7)的体外抗HIV活性。光学纯的化合物3‘，4’-二-O-(-)-樟酰基-(+)-顺式-海带内酯(16)对HIV复制有很强的抑制活性和显著的选择性。16的EC(50)值和体外治疗指数(TI)分别为4×10(-4)mU M和136719，均优于AZT。此外，化合物16在单核细胞系和外周血单核细胞(PBMC)中也具有抗HIV复制的活性。我们的体外实验表明，与化合物1一样，化合物16不是HIV-1逆转录酶的抑制剂。此外，16的抗HIV活性是立体选择性的，因为它的三个非对映异构体(17，38，39)的活性至少低10000倍。由于其他合成的具有不同取代基或没有任何取代基的二氢芝麻素衍生物在更高的浓度下是无效的或具有活性的，因此16的抗病毒活性可能与其结构中的樟脑酰基有关。因此，化合物16代表了一种独特的香豆素结构，具有良好的抗HIV活性。
Forty-two dihydroseselins based on the structure of suksdorfin (1) were synthesized in order to evaluate their anti-HIV activity. These synthetic derivatives include 3',4'-di-O-acyl- and 3'- or 4'-O-acyl-cis-dihydroseselins (8-21) and 3',4'-trans-dihydroseselins with O-acyl and/or O-alkyl groups at the 3' and 4' positions (6, 22-43). Two 4'-azido (44, 45) and three 4'-alkylamido (46, 48, 49) derivatives were also prepared. By using optically pure reagents, three pairs of diastereoisomers were synthesized and separated as optically pure compounds (14, 15; 16, 17; 38, 39). Together with the above synthetic derivatives, seselin (3) and (+/-)-cis(4), (+)-cis- (5), and (+/-)-trans-dihydroseselin-3',4'-diol (7) were also tested for their in vitro anti-HIV activity. An optically pure compound, 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (16), showed potent inhibitory activity and remarkable selectivity against HIV replication. The EC(50) value and in vitro therapeutic index (TI) of 16 are 4 x 10(-4) mu M and 136 719, respectively, which are better than those shown by AZT in the same assay. In addition, compound 16 is also active against HIV replication in a monocytic cell line and in peripheral blood mononuclear cells (PBMCs). Our in vitro assay indicated that, like compound 1, compound 16 is not an inhibitor of HIV-1 reverse transcriptase. Moreover, the anti-HIV activity of 16 is stereoselective as its three diastereoisomers (17, 38, 39) are at least 10 000 times less active. Since other synthetic dihydroseselin derivatives with different substituents or without any substituents are inactive or are active only at much higher concentrations, the antiviral potency of 16 could be associated with the camphanoyl moieties of its structure. Therefore, compound 16 represents a unique coumarin structure with promising anti-HIV activity.