Synthesis and cytotoxic effects of 2-thio-3,4-dihydroquinazoline derivatives as novel T-type calcium channel blockers
| Autor: | Dohyeong Ko, Misong Kim, Yunchan Nam, Ki Deok Ryu, Yoon Hyoung Moon, Gerald W. Zamponi, Maria A. Gandini, Kyung-Sook Chung, Kyung-Tae Lee, Jae Yeol Lee, Changyoung Jang |
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| Rok vydání: | 2019 |
| Předmět: |
Stereochemistry
Cell Survival Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents 01 natural sciences Biochemistry chemistry.chemical_compound Calcium Channels T-Type Structure-Activity Relationship Drug Discovery Tumor Cells Cultured Moiety Humans Guanidine Molecular Biology Cell Proliferation Voltage-dependent calcium channel Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Calcium channel Organic Chemistry T-type calcium channel Biological activity Calcium Channel Blockers 0104 chemical sciences 3. Good health 010404 medicinal & biomolecular chemistry chemistry Quinazolines Molecular Medicine Pharmacophore Drug Screening Assays Antitumor Lead compound |
| Zdroj: | Bioorganicmedicinal chemistry. 28(11) |
| ISSN: | 1464-3391 |
| Popis: | In our previous work, a series of 2-amino-3,4-dihydroquinazoline derivatives using an electron acceptor group was reported to be potent T-type calcium channel blockers and exhibit strong cytotoxic effects against various cancerous cell lines. To investigate the role of the guanidine moiety in the 2-amino-3,4-dihydroquinazoline scaffold as a pharmacophore for dual biological activity, a new series of 2-thio-3,4-dihydroquniazoline derivatives using an electron donor group at the C2-position was synthesized and evaluated for T-type calcium channel blocking activity and cytotoxic effects against two human cancerous cell lines (lung cancer A549 and colon cancer HCT-116). Among them, compound 6g showed potent inhibition of Cav3.2 currents (83% inhibition) at 10 µM concentrations. The compound also exhibited IC50 values of 5.0 and 6.4 µM against A549 and HCT-116 cell lines, respectively, which are comparable to the parental lead compound KYS05090. These results indicate that the isothiourea moiety similar to the guanidine moiety of 2-amino-3,4-dihydroquinazoline derivatives may be an essential pharmacophore for the desired biological activities. Therefore, our preliminary work can provide the opportunity to expand a chemical repertoire to improve affinity and selectivity for T-type calcium channels. |
| Databáze: | OpenAIRE |
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