title: 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.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ferrara, Via Luigi Borsari 46, 44100 Ferrara, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Mischiati
authors.forename: Alessia
authors.initials: A
authors.lastname: Finotti
authors.forename: Alessia
authors.initials: A
authors.lastname: Sereni
authors.forename: Sindi
authors.initials: S
authors.lastname: Boschetti
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Giordana
authors.initials: G
authors.lastname: Feriotto
authors.forename: Kuan-Teh
authors.initials: KT
authors.lastname: Jeang
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Bianchi
authors.forename: Monica
authors.initials: M
authors.lastname: Borgatti
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D004214:Distamycins / Q000494:pharmacology; D006678:HIV / Q000187:drug effects / Q000235:genetics; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D006801:Humans; D009687:Nuclear Proteins; D011758:Pyrroles / Q000494:pharmacology*; D012367:RNA, Viral / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000998:Antiviral Agents; D004214:Distamycins; D009687:Nuclear Proteins; D011758:Pyrroles; D012367:RNA, Viral; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; C030000:stallimycin