Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects
- Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects
- 김형자; Jin Han Kim; Hui Rak Jeong; Da Woon Jung; Hong Bin Yoon; Sun Young Kim; Kyung-Tae Lee; Vinicius M. Gadotti; Junting Huang; Fang-Xiong Zhang; Gerald W. Zamponi; Jae Yeol Lee
- T-type calcium channel; 3,4-Dihydroquinazoline; Bioisostere; Cytotoxic activity; Inflammatory pain; Liver microsomal stability
- Issue Date
- Bioorganic & medicinal chemistry
- VOL 25, NO 17-4664
- 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 mu M concentration and exhibited cytotoxic effect (IC50 = 5.9 mu M) 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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