Flazinamide, a novel beta-carboline compound with anti-HIV actions.
A beta-carboline compound, flazin isolated from Suillus granulatus has been shown weak anti-HIV-1 activity. Based on the structure of flazin, flazinamide [1-(5'- hydromethyl-2'-furyl)-beta-carboline-3-carboxamide] was synthesized and its anti-HIV activities were evaluated in the present study. The cytotoxicity of flazinamide was about 4.1-fold lower than that of flazin. Flazinamide potently reduced syncytium formation induced by HIV-1IIIB with EC50 value of 0.38muM, the EC50 of flazinamide was about 6.2-fold lower than that of flazin. Flazinamide also inhibited HIV-2ROD and HIV-2CBL-20 infection with EC50 values of 0.57 and 0.89microM, respectively. Flazinamide reduced p24 antigen expression in HIV-1IIIB acute infected C8166 and in clinical isolated strain HIV-1KM018 infected PBMC, with EC50 values of 1.45 and 0.77microM, respectively. Flazinamide did not suppress HIV-1 replication in chronically infected H9 cells. Flazinamide blocked the fusion between normal cells and HIV-1 or HIV-2 chronically infected cells. It weakly inhibited activities of recombinant HIV-1 reverse transcriptase, protease or integrase at higher concentrations. In conclusion, the conversion of the carboxyl group in 3 position of flazin markedly enhanced the anti-viral activity (TI value increased from 12.1 to 312.2) and flazinamide might interfere in the early stage of HIV life cycle.
Wang
Yun-Hua
YH
Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
Tang
Jian-Guo
JG
Wang
Rui-Rui
RR
Yang
Liu-Meng
LM
Dong
Ze-Jun
ZJ
Du
Li
L
Shen
Xu
X
Liu
Ji-Kai
JK
Zheng
Yong-Tang
YT
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005663:Furans / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D019427:HIV Integrase / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D015394:Molecular Structure; D011485:Protein Binding; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D002243:Carbolines; D005663:Furans; C518828:flazinamide; D019427:HIV Integrase