2. Academic Validation
  3. Synthesis and cytotoxic effects of 2-thio-3,4-dihydroquinazoline derivatives as novel T-type calcium channel blockers

Synthesis and cytotoxic effects of 2-thio-3,4-dihydroquinazoline derivatives as novel T-type calcium channel blockers

  • Bioorg Med Chem. 2020 Jun 1;28(11):115491. doi: 10.1016/j.bmc.2020.115491.
Yunchan Nam 1,  Ki Deok Ryu 1,  Changyoung Jang 1,  Yoon Hyoung Moon 1,  Misong Kim 1,  Dohyeong Ko 1,  Kyung-Sook Chung 2,  Maria A Gandini 3,  Kyung-Tae Lee 4,  Gerald W Zamponi 5,  Jae Yeol Lee 6
Affiliations

Affiliations

  • 1 Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 2 Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 3 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.
  • 4 Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: ktlee@khu.ac.kr.
  • 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.
PMID: 32327350 DOI: 10.1016/j.bmc.2020.115491
Abstract

In our previous work, a series of 2-amino-3,4-dihydroquinazoline derivativesusing 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.

Keywords

2-thio-3,4-dihydroquinazoline; Current inhibition; Cytotoxicity; T-type calcium channel.

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