2H-1, 4-苯并二氮卓-2-酮类HIV-1转录抑制剂的设计、合成及活性研究
Design, synthesis and evaluation of novel 2H-1, 4-benzodiazepine-2-ones as inhibitors of HIV-1 transcription
-
摘要:
转录反式激活因子 (trans-activator of transcription, Tat) 在HIV-1的转录中起着重要的调控作用, 针对HIV-1 Tat中的β-转角结构, 采用2H-1, 4-苯并二氮
.gif)
-2-酮作为β-转角肽链骨架的模拟结构, 分别以对硝基氯苯/苯乙腈、对甲基苯胺/苯甲酰氯以及硝西泮为起始原料, 采用不同合成路线得到了19个2H-1, 4-苯并二氮-2-酮类化合物 (10～18、21～24、26～31)。初步活性评价表明, 化合物30在没有明显细胞毒作用的浓度下对Tat介导的荧光素酶的表达显示了较好的抑制作用, 其半数有效浓度EC50为25.0 μmol·L−1。Abstract:HIV-1 trans-activator of transcription (Tat) plays a critical role in HIV-1 transcription. Based on the β-turn motif present in HIV-1 Tat, a series of novel benzodiazepine analogs were designed as β-turn mimetics and prepared from p-chloro-nitrobenzene/2-phenylacetonitrile, p-toluidine/benzoyl chloride, or (Z)-7-nitro-5- phenyl-1H-benzoe1, 4diazepin-2(3H)-one (nitrazepam) through different synthetic routes. Preliminary biological evaluation indicated that compound 30 exhibited inhibitory activity on HIV-1 tat-mediated LTR transcription with EC50 of 25.0 μmol·L−1 and showed no obvious cytotoxic effects on TZM-Bl cells under the concentration of 100 μmol·L−1.
下载: