Inhibition of NF-kB/DNA Interactions and HIV-1 LTR Directed Transcription by Hybrid Molecules Containing Pyrrolo [2,1-c] [1,4] Benzodiazepine (PBD) and Oligopyrrole Carriers

The DNA binding properties and the effects on protein/DNA interactions of a series of four hybrids prepared combining oligopyrrole minor groove binders and pyrrolo [2,1-c][1,4] benzodiazepine (PBD) were studied. In addition, the effects on in vitro and ex vivo transcription directed by the long terminal repeat (LTR) of the human immunodeficiency type 1 virus (HIV-1) were analysed and structure-activity relationships developed. These hybrids (compounds 2–5) contain from one to four pyrrole units, respectively. To investigate sequence-selectivity and stability of drugs/DNA complexes, DNase I foothyphen-printing, filter binding, and arrested polymerase-chain reaction (PCR) were performed on HIV-1 LTR gene sequences. The antiproliferative activity of the hybrids was tested in vitro on T-lymphoid Jurkat cell lines and compared to antiproliferative effects of the natural product distamycin A 1 and pyrrolo [2,1-c][1,4] benzodiazepine (PBD 6). The results obtained demonstrate that hybrids 2–5 exhibit different DNA-binding activity with respect to both distamycin A 1 and PBD 6. A direct relationship was found between number of pyrrole rings present in the hybrids 2–5 and stability of drugs/DNA complexes. With respect to antiproliferative effects, it was found that the increase in the length of the polypyrrole backbone leads to an increase of in vitro antiproliferative effects, i.e., the hybrid 5, containing the four pyrroles distamycin analogs, is more active than 2, 3 and 4 against the Jurkat cell lines. With respect to inhibition of HIV-1 LTR driven transcription, it was found that the hybrid 5 containing the four pyrroles distamycin analogs, is more active than 2, 3 and 4. Interestingly, the present results suggest that the hybrid 3 exhibits low antiproliferative activity on Jurkat cell lines, being still active in inhibiting HIV-1 LTR driven transcription both in vitro and ex vivo