Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 102, Issue -, Pages 93-105Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.07.035
Keywords
Betulinic acid; Triazole derivative; Cytotoxic activities; Mitochondrial dysfunction; Caspase activation; DNA binding
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Funding
- CSIR network project ORIGIN [CSC0108]
- CSIR network project miND [BSC-0115]
- CSIR network project TREAT [BSC 0116]
- Department of Biotechnology (DBT), New Delhi
- UGC, Government of India
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A novel family of betulinic acid analogues, carrying a triazole unit at C-3 attached through a linker, was synthesized by the application of azide-alkyne Click reaction. These were screened for their anticancer activity against different cancer cells and normal human PBMC by MTF assay. Compound 2c [(3S)-3-(2(4-(hydroxymethyl-1H-1,2,3-triazol-1-ypacetyloxyylup-20(29)-en-28-oic acid] was found as the most potent inhibitor of cell line HT-29 with IC50 value 14.9 mu M. Its role as an inducer of apoptosis was investigated in this cell line by Annexin-V/PI binding assay and by following its capability for ROS generation, depolarization of mitochondrial transmembrane potential, activation of caspases, PARP cleavage, nuclear degradation and expression of pro- and anti-apoptotic proteins. It exhibited much higher cytotoxicity than the standard drug 5-fluorouracil but showed negligible cytotoxicity towards normal PBMC. Elevated level of ROS generation, activation of caspase 3 and caspase 9, DNA fragmentation, higher expression of Bax and Bad, lower expression of BcI2 and Bcl-xl, and increased level of Bax/Bc1-xl ratio identified 2c as a promising inducer of apoptosis that follows a mitochondria dependent pathway. Bio-physical studies indicate that compound 2c acts as a minor groove binder to the DNA. (C) 2015 Elsevier Masson SAS. All rights reserved.
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