Synthesis and biological evaluation of fluoro-substituted 3, 4-dihydroquinazoline derivatives for cytotoxic and analgesic effects. Issue 17 (1st September 2017)

• Record Type: Journal Article
• Authors: Kim, Jin Han; Jeong, Hui Rak; Jung, Da Woon; Yoon, Hong Bin; Kim, Sun Young; Kim, Hyoung Ja; Lee, Kyung-Tae; Gadotti, Vinicius M.; Huang, Junting; Zhang, Fang-Xiong; Zamponi, Gerald W.; Lee, Jae Yeol
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 17(2017)
• Page Start: 4656
• Page End: 4664
• Publication Date: 2017-09-01
• Subjects: T-type calcium channel -- 3, 4-Dihydroquinazoline -- Bioisostere -- Cytotoxic activity -- Inflammatory pain -- Liver microsomal stability; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.07.010
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 (Cav 3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Cav 3.2 currents (>90% inhibition) at 10 μM concentration and exhibited cytotoxic effect (IC50 = 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, compound8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Cav 3.2 channels.