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Bioorg Med Chem. 2017 Sep 1;25(17):4656-4664. doi: 10.1016/j.bmc.2017.07.010. Epub 2017 Jul 8.

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

Author information

1
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
2
Molecular Recognition Research Center, Future Convergence Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
3
Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: ktlee@khu.ac.kr.
4
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary T2N 4N1, Canada.
5
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary T2N 4N1, Canada. Electronic address: zamponi@ucalgary.ca.
6
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: ljy@khu.ac.kr.

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.

KEYWORDS:

3,4-Dihydroquinazoline; Bioisostere; Cytotoxic activity; Inflammatory pain; Liver microsomal stability; T-type calcium channel

PMID:
28720332
DOI:
10.1016/j.bmc.2017.07.010
[Indexed for MEDLINE]

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