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

ID: ALA5143513

Journal: Eur J Med Chem

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

Authors: Lee SB, Chang TY, Lee NZ, Yu ZY, Liu CY, Lee HY.

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.

CiteXplore: 34662748

DOI: 10.1016/j.ejmech.2021.113904

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