Binding of hybrid molecules containing pyrrolo [2,1-c][1,4]benzodiazepine (PBD) and oligopyrrole carriers to the human immunodeficiency type 1 virus TAR-RNA

详细信息    查看全文

• 作者：Mischiati ; Carlo ; Finotti ; Alessia ; Sereni ; Alessia ; Boschetti ; Sindi ; Baraldi ; Pier Giovanni ; et. al.
• 关键词：HIV-1 ; human immunodeficiency virus ; type 1 ; AIDS ; acquired immunodeficiency syndrome ; LTR ; long terminal repeat ; PBD ; pyrrolo[2 ; 1-c][1 ; 4]benzodiazepine ; EMSA ; electrophoretic mobility shift assay ; CAT ; chloramphenicol acetyl transferase ; PAGE ; polyacryla
• 刊名：Biochemical Pharmacology
• 出版年：2004
• 出版时间：February 1, 2004
• 年：2004
• 卷：67
• 期：3
• 页码：401-410
• 全文大小：485 K

文摘

The binding properties of a set of four hybrids, prepared combining from one to four polypyrrole minor groove binders and pyrrolo [2,1-c][1,4]benzodiazepine (PBD), have been studied using as target molecule the HIV-1 TAR-RNA. We found that these hybrids bind to TAR-RNA and inhibit TAR/protein(s) interactions. The anti-proliferative activity of the hybrids has been tested in vitro on HL3T1 cells and compared to the anti-proliferative effects of the natural product distamycin A and PBD. The effects on HIV-1 LTR directed transcription were studied using the chloramphenicol-acetyltransferase gene reporter system, and structure–activity relationships are discussed. The results obtained demonstrate that the hybrids 22–25 exhibit different TAR-RNA binding activity with respect to both distamycin A and PBD. In addition, a direct relationship was found between number of pyrrole rings present in the hybrids 22–25 and anti-proliferative effects. It was found that increased length of the polypyrrole backbone leads to an increased in vitro anti-proliferative effect, i.e. the hybrid 25, containing the four pyrroles distamycin analogous, is more active than 22, 23 and 24 against cell proliferation. With respect to inhibition of HIV-1 LTR-driven transcription, it was found that the hybrids 23–25 containing two–four pyrroles are active. Therefore, when anti-proliferative effects are considered together with the inhibitory effects of HIV-1 LTR driven transcription, our results suggest that the hybrid 23 is the more interesting, since it exhibits low anti-proliferative activity and inhibits HIV-1 LTR driven transcription both in vitro and in ex vivo experiments.