title: Design, synthesis and biological evaluation of 3,5-diaryl-isoxazoline/isoxazole-pyrrolobenzodiazepine conjugates as potential anticancer agents.
abstract: A series of 3,5-diaryl-isoxazoline/isoxazole linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates were prepared. These conjugates showed potent anticancer activity with GI(50) values in the range of <0.1-3.6 microM. Some of these PBD conjugates (6a-c) with promising anticancer activity were further investigated on the cell cycle distribution. Moreover, these PBD conjugates exhibited G0/G1 arrest, enhancement in the levels of p53 protein as well as mitochondrial-mediated intrinsic pathway, leading to release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent apoptotic cell death. Hence these PBD conjugates with 6a being the most potent one could be be taken up for preclinical studies either alone or in combination with existing therapies.
authors.affiliation: Division of Organic Chemistry, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India. ahmedkamal@iict.res.in
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.forename: J Surendranadha
authors.initials: JS
authors.lastname: Reddy
authors.forename: M Janaki
authors.initials: MJ
authors.lastname: Ramaiah
authors.forename: D
authors.initials: D
authors.lastname: Dastagiri
authors.forename: E Vijaya
authors.initials: EV
authors.lastname: Bharathi
authors.forename: M Ameruddin
authors.initials: MA
authors.lastname: Azhar
authors.forename: Farheen
authors.initials: F
authors.lastname: Sultana
authors.forename: S N C V L
authors.initials: SN
authors.lastname: Pushpavalli
authors.forename: Manika
authors.initials: M
authors.lastname: Pal-Bhadra
authors.forename: Aarti
authors.initials: A
authors.lastname: Juvekar
authors.forename: Subrata
authors.initials: S
authors.lastname: Sen
authors.forename: Surekha
authors.initials: S
authors.lastname: Zingde
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D007555:Isoxazoles; D001569:Benzodiazepines