Discovery of 4-Aryl-4H-Chromenes as Potent Apoptosis Inducers Using a Cell- and Caspase-Based Anti-Cancer Screening Apoptosis Program (ASAP): SAR Studies and the Identification of Novel Vascular Disrupting Agents

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)


Volume 16, 12 Issues, 2016


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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  • 27th of 59 in Chemistry, Medicinal

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Editor-in-Chief:
Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
France


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Discovery of 4-Aryl-4H-Chromenes as Potent Apoptosis Inducers Using a Cell- and Caspase-Based Anti-Cancer Screening Apoptosis Program (ASAP): SAR Studies and the Identification of Novel Vascular Disrupting Agents



Anti-Cancer Agents in Medicinal Chemistry, 9(4): 437-456.

Author(s): Sui Xiong Cai, John Drewe and William Kemnitzer.

Affiliation: EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.

Abstract

Many cancer cells are known to have defects in the apoptosis machinery. Therefore identification of compounds that can activate or promote apoptosis in cancer cells is an attractive approach for targeted therapies. By applying a novel cell- and caspase-based Anti-cancer Screening Apoptosis Program (ASAP) HTS assay, 4-aryl-4H-chromenes were identified as potent apoptosis inducers. 4- Aryl-4H-chromenes were found to induce nuclear fragmentation and PARP cleavage, as well as to arrest cells at the G2/M stage followed by apoptosis as determined by the flow cytometry analysis assay in multiple human cell lines (e.g. Jurkat, T47D). These compounds were found to be highly active in the growth inhibition MTT assay, including for paclitaxel resistant, p-glycoprotein overexpressed, MESSA/ DX5 tumor cells. Functionally, they were found to be potent inhibitors of tubulin polymerization and to effectively inhibit the binding of colchicine to tubulin. In addition, several 4-aryl-4H-chromenes were also found to be effective vascular disrupting agents (VDA). One of the lead compounds, EPC2407, is currently in clinical trials as a novel tumor vascular disrupting agent.

Keywords:

Apoptosis inducers, HTS assay, anti-cancer drug, SAR studies, tubulin inhibitors, vascular disrupting agent (VDA).



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Article Details

Volume: 9
Issue Number: 4
First Page: 437
Last Page: 456
Page Count: 20
DOI: 10.2174/1871520610909040437
Price: $58
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