title: Synthesis of 2-aryl-1,2,4-oxadiazolo-benzimidazoles: Tubulin polymerization inhibitors and apoptosis inducing agents.
abstract: A new series of 2-aryl 1,2,4-oxadiazolo-benzimidazole conjugates have been synthesized and evaluated for their antiproliferative activity in the sixty cancer cell line panel of the National Cancer Institute (NCI). Compounds 5l (NSC: 761109/1) and 5x (NSC: 761814/1) exhibited remarkable cytotoxic activity against most of the cancer cell lines in the one dose assay and were further screened at five dose concentrations (0.01, 0.1, 1, 10 and 100 μM) which showed GI50 values in the range of 0.79-28.2 μM. Flow cytometric data of these compounds showed increased cells in G2/M phase, which is suggestive of G2/M cell cycle arrest. Further, compounds 5l and 5x showed inhibition of tubulin polymerization and disruption of the formation of microtubules. These compounds induce apoptosis by DNA fragmentation and chromatin condensation as well as by mitochondrial membrane depolarization. In addition, structure activity relationship studies within the series are also discussed. Molecular docking studies of compounds 5l and 5x into the colchicine-binding site of the tubulin, revealed the possible mode of interaction by these compounds.
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: ahmedkamal@iict.res.in.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: T Srinivasa
authors.initials: TS
authors.lastname: Reddy
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: M V P S
authors.initials: MVPS
authors.lastname: Vishnuvardhan
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Vijaykumar D
authors.initials: VD
authors.lastname: Nimbarte
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: A V
authors.initials: AV
authors.lastname: Subba Rao
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Vunnam
authors.initials: V
authors.lastname: Srinivasulu
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: shankar@niperhyd.ac.in.
authors.forename: Nagula
authors.initials: N
authors.lastname: Shankaraiah
mesh_terms: D017304:Annexin A5 / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D062105:Molecular Docking Simulation; D058105:Polymerization; D011419:Propidium / Q000737:chemistry
chemical_list: D017304:Annexin A5; D001562:Benzimidazoles; D011419:Propidium
keywords: 1,2,4-Oxadiazole; Apoptosis; Benzimidazole; Cytotoxicity; Molecular docking; Tubulin polymerization