Anti-HIV-1 activity and structure-activity relationship of cepharanoline derivatives in chronically infected cells.
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 microg/ml (0.0060 and 0.046 microM), respectively.
Baba
M
M
Division of Human Retroviruses, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, Japan. baba@m.kufm.kagoshima-u.ac.jp
Okamoto
M
M
Kashiwaba
N
N
Ono
M
M
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D044182:Benzylisoquinolines; D002460:Cell Line; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009000:Monocytes / Q000821:virology; D010946:Plants, Medicinal / Q000737:chemistry; D013234:Stem Cells / Q000821:virology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D052117:Benzodioxoles
D000470:Alkaloids; D019380:Anti-HIV Agents; D044182:Benzylisoquinolines; D014409:Tumor Necrosis Factor-alpha; C006947:cepharanthine; D052117:Benzodioxoles