Synthesis and biological evaluation of a novel betulinic acid derivative as an inducer of apoptosis in human colon carcinoma cells (HT-29).

Abstract

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 MTT assay. Compound 2c [(3S)-3-{2-(4-(hydroxymethyl-1H-1,2,3-triazol-1-yl)acetyloxy}-lup-20(29)-en-28-oic acid] was found as the most potent inhibitor of cell line HT-29 with IC50 value 14.9 μM. 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 Bcl2 and Bcl-xl, and increased level of Bax/Bcl-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.

• Authors: Biswajit Chakraborty, Debasmita Dutta, Sanjukta Mukherjee, Supriya Das, Nakul C Maiti, Padma Das, Chinmay Chowdhury
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 102 Pg. 93-105 (Sep 18 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 26248310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Pentacyclic Triterpenes
• Reactive Oxygen Species
• Triterpenes
• Betulinic Acid

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• HT29 Cells
• Humans
• Molecular Structure
• Pentacyclic Triterpenes
• Reactive Oxygen Species (metabolism)
• Structure-Activity Relationship
• Triterpenes (chemistry, pharmacology)
• Betulinic Acid