title: Synthesis, anticancer activity and apoptosis inducing ability of bisindole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates.
abstract: A series of bisindole-pyrrolobenzodiazepine conjugates (5a-f) linked through different alkane spacers was prepared and evaluated for their anticancer activity. All compounds exhibited significant anticancer potency and the most potent compounds 5b and 5e were taken up for detailed studies on MCF-7 cell line. Cell cycle effects were examined apart from investigating the inhibition of tubulin polymerization for compounds 2a, 2b, 5b and 5e at 2μM. FACS analysis showed that at higher concentrations (4 and 8μM) there was an increase of sub-G1 phase cells and decrease of G2/M phase cells, thus indicating that compounds 5b and 5e are effective in causing apoptosis in MCF-7 cells. It was also observed that compounds 5b and 5e showed the down regulation of histone deacetylase protein levels such as HDAC1, 2, 3, 8 and increase in the levels of p21, followed by apoptotic cell death. The apoptotic nature of these compounds was further evidenced by increased expression of cleaved-PARP and active caspase-7 in MCF-7 cells.
authors: Division of Organic Chemistry, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India. ahmedkamal@iict.res.in
authors: Ahmed
authors: A
authors: Kamal
authors: Y V V
authors: YV
authors: Srikanth
authors: M Janaki
authors: MJ
authors: Ramaiah
authors: M Naseer Ahmed
authors: MN
authors: Khan
authors: M
authors: M
authors: Kashi Reddy
authors: Md
authors: M
authors: Ashraf
authors: A
authors: A
authors: Lavanya
authors: S N C V L
authors: SN
authors: Pushpavalli
authors: Manika
authors: M
authors: Pal-Bhadra
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002469:Cell Separation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004032:Diet; D015195:Drug Design; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D007211:Indoles; D011758:Pyrroles; D013778:Tetrazolium Salts; D013844:Thiazoles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; D011065:Poly(ADP-ribose) Polymerases; C022616:thiazolyl blue