Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 101, Issue -, Pages 348-357Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.06.050
Keywords
Ipsocyclization; Oxaspiro[4,5]trienone; Azaspiro[4,5]trienone; Anticancer activity; Cell cycle analysis; Mitochondrial membrane potential (Delta Psi m); Western blot analysis; Apoptosis
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Funding
- CSIR, New Delhi [CSC-0301]
- UGC-New Delhi
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A series of twenty seven oxa/azaspiro[4,5]trienone derivatives were synthesized and their anticancer properties have been explored. GI(50) values of all these compounds were evaluated against four types of human cancer cell lines, i.e. MCF-7 (breast), DU-145 (prostate), A549 (lung) and HepG2 (liver). Five compounds of the series exhibited good anticancer potential against MCF-7 with GI(50) values less than 2 mu M. Detailed biological studies of the two representative compounds 9b and 9e revealed that they arrest cell cycle in G0/G1 phase and induce mitochondria mediated apoptosis, that was further confirmed by measurement of mitochondrial membrane potential (Delta Psi m), intracellular ROS generation, caspase 9 activity and Annexin V-FITC assay. Furthermore, western blot analysis suggested that these compounds up-regulate the levels of p53, p21, p27 and Bax, and down-regulate the level of Bcl-2 confirming the apoptosis inducing properties. (C) 2015 Elsevier Masson SAS. All rights reserved.
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