Development of a novel class of tubulin inhibitors with promising anticancer activities.

Abstract

UNLABELLED:

We have developed a novel class (2-amino-4-phenyl-4H-chromene-3-carboxylate) of inhibitors of tubulin assembly by modifying HA14-1, which is a Bcl-2 inhibitor discovered by our group. Three of these compounds, mHA1, mHA6, and mHA11, showed in vitro cytotoxicities against tumor cells that were more potent and more stable than the backbone compound HA14-1, with nM IC50 values. In contrast, the cytotoxic effects of these compounds on normal cells were minimal. Computational docking, colchicine-tubulin competitive binding, and tubulin polymerization studies demonstrated that these compounds bind at the colchicine-binding site on tubulin and inhibit the formation of microtubules. Treatment of HL-60/Bcl-2 leukemia and CRL5908 lung cancer cells with these mHA compounds led to pronounced microtubule density decreases, G2/M cell cycle arrest, and apoptosis, as determined by immunofluorescence microscopy, flow cytometry, and DNA fragmentation analysis. Combined, these data identify a novel class of compounds that inhibit tubulin assembly and limit cancer cell phenotypes.

IMPLICATIONS:

This study supports the continued development of novel anti-tubulin assembly inhibitors as potential anticancer agents.

• Authors: Jingle Xi, Xuejun Zhu, Yongmei Feng, Na Huang, Guifen Luo, Yongjun Mao, Xiaofeng Han, Wang Tian, Guirong Wang, Xiaobing Han, Rongcheng Luo, Ziwei Huang, Jing An
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 11 Issue 8 Pg. 856-64 (Aug 2013) ISSN: 1557-3125 [Electronic] United States
• PMID: 23666368 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Antineoplastic Agents
• Benzopyrans
• Nitriles
• Tubulin
• Tubulin Modulators
• ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
• Colchicine

Topics

• Adult
• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Apoptosis (drug effects)
• Benzopyrans (chemistry, metabolism, pharmacology)
• Binding Sites
• Bone Marrow Cells (drug effects)
• Cell Line, Tumor
• Colchicine (metabolism, pharmacology)
• DNA Fragmentation (drug effects)
• Drug Discovery
• G2 Phase (drug effects, genetics)
• HL-60 Cells
• Humans
• Microtubules (drug effects, metabolism)
• Molecular Docking Simulation
• Nitriles (chemistry, pharmacology)
• Tubulin (metabolism)
• Tubulin Modulators (chemistry, metabolism, pharmacology)