Synthesis, resolution, and biological evaluation of atropisomeric (aR)- and (aS)-16-methyllamellarins N: Unique effects of the axial chirality on the selectivity of protein kinases inhibition

Kenyu Yoshida, Ryosuke Itoyama, Masashi Yamahira, Junji Tanaka, Nadège Loaëc, Olivier Lozach, Emilie Durieu, Tsutomu Fukuda, Fumito Ishibashi, Laurent Meijer, Masatomo Iwao

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32 Citations (Scopus)

Abstract

The total synthesis of the optically active (aR)- and (aS)-16- methyllamellarins N (3a and 3b) was achieved via resolution on HPLC chiral stationary phase. The kinase inhibitory activities of both enantiomers were evaluated on eight protein kinases relevant to cancer and neurodegenerative diseases (CDK1/cyclin B, CDK2/cyclin A, CDK5/p25, GSK-3α/β, PIM1, DYRK1A, CLK3, and CK1). Isomer (aR)-3b exhibited potent but nonselective inhibition on all protein kinases except CK1, while (aS)-3a selectively inhibited only GSK-3α/β, PIM1, and DYRK1A. The different inhibition profiles of (aS)-3a and (aR)-3b were elucidated by docking simulation studies. Although parental lamellarin N (2) inhibited the action of topoisomerase I, both (aS)-3a and (aR)-3b showed no inhibition of this enzyme. The phenotypic cytotoxic activities of 2, (aS)-3a, and (aR)-3b on three cancer cell lines (HeLa, SH-SY5Y, and IMR32) changed according to their topoisomerase I and protein kinase inhibitory activities.

Original languageEnglish
Pages (from-to)7289-7301
Number of pages13
JournalJournal of Medicinal Chemistry
Volume56
Issue number18
DOIs
Publication statusPublished - Sep 26 2013

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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