抗艾滋病药物。42. 二取代(3'R,4'R)-3',4'-二-O-(S)-樟脑酰基-(+)-顺式凯刺内酯类似物的合成及抗HIV活性
Anti-AIDS agents. 42. Synthesis and anti-HIV activity of disubstituted (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone analogues.
作者信息
Xie L, Takeuchi Y, Cosentino L M, McPhail A T, Lee K H
机构信息
Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
出版信息
J Med Chem. 2001 Mar 1;44(5):664-71. doi: 10.1021/jm000070g.
A series of disubstituted 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogues (1-10) were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. 5-Methoxy-4-methyl DCK (8) was the most promising compound with an EC(50) value of 7.21 x 10(-6) microM and a therapeutic index of >2.08 x 10,(7) which were much better than those of lead compound DCK in the same assay. Another six disubstituted DCK analogues (1-5 and 7) were more potent than AZT but less active than DCK. Conformational analysis suggested that resonance of the coumarin system is an essential structural feature for potent anti-HIV activity. Steric compression of C(4) and C(5) substituents of the coumarin moiety can reduce the overall planarity and thus resonance of the coumarin nucleus, resulting in a decrease or lack of anti-HIV activity.
合成了一系列二取代的3'，4'-二-O-（S）-樟脑酰基-（+）-顺式凯拉内酯（DCK）类似物（1-10），并评估了它们对H9淋巴细胞中HIV-1复制的抑制作用。5-甲氧基-4-甲基DCK（8）是最有前景的化合物，其半数有效浓度（EC50）值为7.21×10^(-6) μM，治疗指数>2.08×10^7，在相同试验中比先导化合物DCK的这些指标要好得多。另外六个二取代的DCK类似物（1-5和7）比齐多夫定（AZT）更有效，但活性比DCK低。构象分析表明，香豆素系统的共振是强效抗HIV活性的关键结构特征。香豆素部分C(4)和C(5)取代基的空间压缩会降低整体平面性，从而减少香豆素核的共振，导致抗HIV活性降低或丧失。
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