Design, synthesis and biological evaluation of bisindole derivatives as anticancer agents against Tousled-like kinases

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題名:	Design, synthesis and biological evaluation of bisindole derivatives as anticancer agents against Tousled-like kinases
作者:	李學耘 Sung-Bau Lee, Ting-Yu Chang, Nian-Zhe Lee, Zih-Yao Yu, Chi-Yuan Liu, Hsueh-Yun Lee
貢獻者:	藥學系藥物科學學科
關鍵詞:	Keywords: Bisindole;Tousled-like kinases;Anti-cancer agents;DNA replication;Genome instability
日期:	2022-01
上傳時間:	2025-03-31 14:48:34 (UTC+8)
摘要:	Abstract: This study presents the design, synthesis, and characterization of bisindole molecules as anti-cancer agents against Tousled-like kinases (TLKs). We show that compound 2 composed of an indirubin-3′-oxime group linked with a (N-methylpiperidin-2-yl)ethyl moiety possessed inhibitory activity toward both TLK1 and TLK2 in?vitro and diminished the phosphorylation level of the downstream substrate anti-silencing function 1 (ASF1) in replicating cells. The treatment of compound 2 impaired DNA replication, slowed S-phase progression, and triggered DNA damage response in replicating cells. Structure optimization further discovered six derivatives exhibiting potent TLK inhibitory activity and revealed the importance of the tertiary amine-containing moiety of the side chain. Moreover, the derivatives 6, 17, 19, and 20 strongly suppressed the growth of triple-negative breast cancer MDA-MB-231?cells, non-small cell lung cancer A549?cells, and colorectal cancer HCT-116?cells, while normal lung fibroblast MRC5 and IMR90?cells showed a lower response to these compounds. Taken together, this study identifies tertiary amine-linked indirubin-3′-oximes as potent anticancer agents that inhibit TLK activity.
關聯:	European Journal of Medicinal Chemistry, Volume 227, 2022, 113904
描述:	【110-2 升等】臺北醫學大學教師升等專門著作職別：專任送審等級：教授著作送審
資料類型:	article
顯示於類別:	[教師升等送審著作] 110

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