Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects.

Abstract

As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Cav3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Cav3.2 currents (>90% inhibition) at 10μM concentration and exhibited cytotoxic effect (IC50=5.9μM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Cav3.2 channels.

• Authors: Jin Han Kim, Hui Rak Jeong, Da Woon Jung, Hong Bin Yoon, Sun Young Kim, Hyoung Ja Kim, Kyung-Tae Lee, Vinicius M Gadotti, Junting Huang, Fang-Xiong Zhang, Gerald W Zamponi, Jae Yeol Lee
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 25 Issue 17 Pg. 4656-4664 (09 01 2017) ISSN: 1464-3391 [Electronic] England
• PMID: 28720332 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Analgesics
• Calcium Channel Blockers
• Calcium Channels, T-Type
• KCP10068F
• KYS 05090
• Quinazolines
• Fluorine
• hydroquinidine
• Quinidine

Topics

• A549 Cells
• Analgesics (chemical synthesis, chemistry, toxicity)
• Animals
• Calcium Channel Blockers (chemical synthesis, chemistry, toxicity)
• Calcium Channels, T-Type (chemistry, genetics, metabolism)
• Cell Survival (drug effects)
• Drug Stability
• Fluorine (chemistry)
• HEK293 Cells
• Humans
• Inhibitory Concentration 50
• Microsomes, Liver (metabolism)
• Patch-Clamp Techniques
• Quinazolines (chemical synthesis, chemistry, toxicity)
• Quinidine (analogs & derivatives, chemical synthesis, chemistry, toxicity)
• Rats