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

Jin Han Kim; Hui Rak Jeong; Da Woon JungHong Bin YoonSun Young KimHyoung Ja KimKyung-Tae LeeVinicius M. GadottiJunting HuangFang-Xiong ZhangGerald W. ZamponiJae Yeol Lee

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

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

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Graphical abstract Display Omitted 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 (Ca v 3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Ca v 3.2 currents (90 inhibition) at 10 μM concentration and exhibited cytotoxic effect (IC 50 = 5.9 μM) 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 Ca v 3.2 channels. >

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《Bioorganic and medicinal chemistry》 |2017年第17期|4656-4664|共9页
作者
Jin Han Kim; Hui Rak Jeong; Da Woon JungHong Bin YoonSun Young KimHyoung Ja KimKyung-Tae LeeVinicius M. GadottiJunting HuangFang-Xiong ZhangGerald W. ZamponiJae Yeol Lee;
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作者单位

Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee;

Molecular Recognition Research Center, Future Convergence Research Division, Korea Institute of;

Department of Life and Nanopharmaceutical Science, Kyung Hee UniversityDepartment of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s;

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正文语种英语
中图分类药学;
关键词
T-type calcium channel; 3; 4-Dihydroquinazoline; Bioisostere; Cytotoxic activity; Inflammatory pain; Liver microsomal stability;

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

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