120th General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Exhibition Hall 2+3
Time 10월 19일 (목요일) 11:00~12:30
Code MEDI.P-315
Subject Synthesis and Synergistic Effect of T-type Calcium Channel Blockers as a Anticancer Agents on Human Lung Cancer
Authors Hong bin Yoon, dawoon Jung1, Jae Yeol Lee*
Department of Chemistry, Kyung Hee University, Korea
1Chemistry, Kyung Hee University, Korea
Abstract We synthesized new 3,4-dihydroquinazoline derivative containing ureido group, KCP10043F and evaluated for T-type calcium channel inhibitory activity, cytotoxicity, and cell cycle arrest against human lung cancer (A549) cells. KCP10043F showed both weaker T-type Ca2+ channel inhibitory activity and less cytotoxicity against A549 cells than parent compound KYS05090S [4-(benzylcarbamoylmethyl)-3-(4-biphenylyl)-2-(N,N',N'-trimethyl-1,5-pentanediamino)-3,4-dihydroquinazoline 2 hydrochloride], but it exhibited more potent G1-phase arrest than KYS05090S in A549 cells. This was found to be accompanied by the downregulations of cyclin-dependent kinase (CDK) 2, CDK4, CDK6, cyclin D2, cyclin D3, and cyclin E at the protein levels. However, p27KIP1 as a CDK inhibitor was gradually upregulated at the protein levels and increased recruitment to CDK2, CDK4 and CDK6 after KCP10043F treatment. Based on the strong G1-phase cell cycle arrest of KCP10043F in A549 cells, the combination of KCP10043F with etoposide (or cisplatin) resulted in a synergistic cell death (combination index = 0.2–0.8) via the induction of apoptosis compared with either agent alone. Taken together with these overall results and the favorable in vitro ADME (absorption, distribution, metabolism, and excretion) profiles of KCP10043F, therefore, it could be used as a potential agent for the combination therapy on human lung cancer.
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