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

Sung Bau Lee, Ting Yu Chang, Nian Zhe Lee, Zih Yao Yu, Chi Yuan Liu, Hsueh Yun Lee

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number113904
JournalEuropean Journal of Medicinal Chemistry
Volume227
DOIs
Publication statusPublished - Jan 5 2022

Keywords

  • Anti-cancer agents
  • Bisindole
  • DNA replication
  • Genome instability
  • Tousled-like kinases

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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