Synthesis of 2-aryl-1,2,4-oxadiazolo-benzimidazoles: Tubulin polymerization inhibitors and apoptosis inducing agents.

Autor: Kamal A; 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., Reddy TS; 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., Vishnuvardhan MVPS; Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India., Nimbarte VD; 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., Subba Rao AV; Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India., Srinivasulu V; Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India., Shankaraiah N; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: shankar@niperhyd.ac.in.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2015 Aug 01; Vol. 23 (15), pp. 4608-4623. Date of Electronic Publication: 2015 Jun 16.
DOI: 10.1016/j.bmc.2015.05.060
Abstrakt: 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.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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