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Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2017 Sep 01; Vol. 25 (17), pp. 4656-4664. Date of Electronic Publication: 2017 Jul 08. - Publication Year :
- 2017
-
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 <subscript>v</subscript> 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 <subscript>v</subscript> 3.2 currents (>90% inhibition) at 10μM concentration and exhibited cytotoxic effect (IC <subscript>50</subscript> =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 Ca <subscript>v</subscript> 3.2 channels.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Subjects :
- A549 Cells
Analgesics chemistry
Analgesics toxicity
Animals
Calcium Channel Blockers chemistry
Calcium Channel Blockers toxicity
Calcium Channels, T-Type chemistry
Calcium Channels, T-Type genetics
Calcium Channels, T-Type metabolism
Cell Survival drug effects
Drug Stability
Fluorine chemistry
HEK293 Cells
Humans
Inhibitory Concentration 50
Microsomes, Liver metabolism
Patch-Clamp Techniques
Quinazolines chemical synthesis
Quinazolines toxicity
Quinidine chemical synthesis
Quinidine chemistry
Quinidine toxicity
Rats
Analgesics chemical synthesis
Calcium Channel Blockers chemical synthesis
Quinazolines chemistry
Quinidine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 25
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28720332
- Full Text :
- https://doi.org/10.1016/j.bmc.2017.07.010