In vitro cytotoxicity on human ovarian cancer cells by T-type calcium channel blockers.

Abstract

The growth inhibition of human cancer cells via T-type Ca(2+) channel blockade has been well known. Herein, a series of new 3,4-dihydroquinazoline derivatives were synthesized via a brief SAR study on KYS05090 template and evaluated for both T-type Ca(2+) channel (Cav3.1) blockade and cytotoxicity on three human ovarian cancer cells (SK-OV-3, A2780 and A2780-T). Most of compounds except 6i generally exhibited more potent cytotoxicity on SK-OV-3 than mibefradil as a positive control regardless of the degree of T-type channel blockade. In particular, eight compounds (KYS05090, 6a and 6c-6h) showing strong channel blockade exhibited almost equal and more potent cytotoxicity on A2780 when compared to mibefradil. On A2780-T paclitaxel-resistant human ovarian carcinoma, two compounds (KYS05090 and 6d) were 20-fold more active than mibefradil. With respect to cell cycle arrest effect on A2780 and A2780-T cells, KYS05090 induced large proportion of sub-G1 phase in the cell cycle progression of A2780 and A2780-T, meaning the induction of cancer cell death instead of cell cycle arrest via blocking T-type Ca(2+) channel. Among new analogues, compounds 6g and 6h induced cell cycle arrest at G1 phase of A2780 and A2780-T cells in dose-dependent manner and exhibited strong anti-proliferation effects of ovarian cancer cells by blocking T-type Ca(2+) channel. Furthermore, 6g and 6h possessing strong cytotoxic effects could induce apoptosis of A2780 cells, which was detected by confocal micrographs using DAPI staining.

• Authors: Sun Jeong Jang, Heung Woo Choi, Doo Li Choi, Sehyeon Cho, Hong-Kun Rim, Hye-Eun Choi, Ki-Sun Kim, Minghua Huang, Hyewhon Rhim, Kyung-Tae Lee, Jae Yeol Lee
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 24 Pg. 6656-62 (Dec 15 2013) ISSN: 1464-3405 [Electronic] England
• PMID: 24220170 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Calcium Channel Blockers
• Calcium Channels, T-Type
• KYS 05090
• Quinazolines

Topics

• Calcium Channel Blockers (chemical synthesis, chemistry, toxicity)
• Calcium Channels, T-Type (chemistry, metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Female
• Humans
• Ovarian Neoplasms (metabolism, pathology)
• Quinazolines (chemical synthesis, chemistry, toxicity)
• Structure-Activity Relationship