TY - JOUR
T1 - Synthesis of 2-aryl-1,2,4-oxadiazolo-benzimidazoles
T2 - Tubulin polymerization inhibitors and apoptosis inducing agents
AU - Kamal, Ahmed
AU - Reddy, T. Srinivasa
AU - Vishnuvardhan, M. V.P.S.
AU - Nimbarte, Vijaykumar D.
AU - Subba Rao, A. V.
AU - Srinivasulu, Vunnam
AU - Shankaraiah, Nagula
N1 - Funding Information:
T.S.R., V.K.N. thanks NIPER, Hyderabad, India for the award of research fellowship and A.V.S.R., V.S. thanks CSIR, New Delhi for the award of the senior research fellowships. We also thank CSIR for financial support under the 12th Five Year plan project ‘ Affordable Cancer Therapeutics ’ ( CSC0301 ) and ‘ Small Molecules in Lead Exploration (SMiLE) ’ ( CSC0111 ).
Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.
PY - 2015/7/23
Y1 - 2015/7/23
N2 - 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.
AB - 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.
KW - 1,2,4-Oxadiazole
KW - Apoptosis
KW - Benzimidazole
KW - Cytotoxicity
KW - Molecular docking
KW - Tubulin polymerization
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U2 - 10.1016/j.bmc.2015.05.060
DO - 10.1016/j.bmc.2015.05.060
M3 - Article
C2 - 26169762
AN - SCOPUS:84937978703
SN - 0968-0896
VL - 23
SP - 4608
EP - 4623
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 15
ER -