Anti-HIV-1 activity and structure-activity relationship of cepharanoline derivatives in chronically infected cells
Anti-HIV-1 activity and structure-activity relationship of cepharanoline derivatives in chronically infected cells
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DOI：
10.1177/095632020101200506
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发表时间：
2001-09-01
影响因子：
--
通讯作者：
Ono, M
中科院分区：
文献类型：
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作者：
Baba, M;Okamoto, M;Ono, M
三尖杉碱(12-O-甲基头孢氨酚)是一种植物生物碱，已被证明能抑制肿瘤坏死因子-α或佛波酯13-醋酸酯诱导的前单核细胞系U1中HIV-1的复制。其作用机制被认为是抑制核因子kappaB，核因子kappaB是HIV-1基因表达的有效诱导剂。在这项研究中，我们合成了96个头孢氨酚的衍生物，包括头孢嘌呤，并检测了它们对HIV-1在U1细胞中复制的抑制作用。在12-O-烷基衍生物中，头孢花碱的活性最强，且活性随着烷基链长的增加而降低。所有的12-O-酰基衍生物都是完全失活的，而少数12-O-氨基甲酰衍生物表现出一定的活性。由于12-O-乙基衍生物被发现与头孢嘌呤一样具有抗HIV-1复制的活性，我们进一步合成了不同的12-O-乙基头孢菌素衍生物。在这些衍生物中，有5个被证明是比头孢嘌呤活性更高的抑制剂，其中活性最高的化合物是12-O-乙基哌嗪基头孢氨酚。其半数有效浓度分别为0.0041和0.028微克/毫升(0.0060微米和0.046微米)。
Cepharanthine (12-O-methyl cepharanoline) is a plant alkaloid and has been shown to inhibit tumour necrosis factor-alpha- or phorbol 12-myristate 13-acetate-induced HIV-1 replication in the chronically infected promonocytic cell line, U1. Its mechanism of action is considered to be the inhibition of nuclear factor kappaB, a potent inducer of HIV-1 gene expression. In this study, we have synthesized 96 derivatives of cepharanoline, including cepharanthine, and examined their inhibitory effects on HIV-1 replication in U1 cells. Among the 12-O-alkyl derivatives, cepharanthine proved to be the most active, and the activity decreased as the length of the alkyl chain increased. All of the 12-O-acyl derivatives were totally inactive, while a few 12-O-carbamoyl derivatives displayed modest activity. Since 12-O-ethyl derivatives were found to be as active as cepharanthine against HIV-1 replication, we further synthesized various 12-O-ethyl derivatives of cepharanoline. Among the derivatives, five proved to be more active inhibitors than cepharanthine, and the most active compound was 12-O-ethylpiperazinyl cepharanoline. The 50% effective concentrations of this compound and cepharanthine were 0.0041 and 0.028 mug/ml (0.0060 and 0.046 muM), respectively.