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Indexed by:Journal Papers

Date of Publication:2020-05-01

Journal:Archiv der Pharmazie

Included Journals:PubMed

Volume:353

Issue:5

Page Number:e2000005

ISSN No.:1521-4184

Key Words:Bcl-2/Mcl-1 dual inhibitor,anticancer activities,apoptosis

Abstract:Based on our previously reported Bcl-2/Mcl-1 dual inhibitor 4-thiomorpholinyl-2-cyano-3-amidinophenalenone (A1) that simultaneously occupies the p2 and p4 hydrophobic pockets of Bcl-2 and Mcl-1, we optimized molecules with different bond angles of the groups extending to the p4 pocket and bulky hydrophobic groups to explore p2. Research on structure-activity relationship resulted in a new derivative B4 that is capable of occupying both the p2 and p4 more deeply and completely than A1, with Ki values determined by fluorescence polarization assay (FPAs) improving to 0.31 μM for Bcl-2 and 0.16 μM for Mcl-1. Furthermore, B4 exhibited selective lethality on cancer cells over normal cells. It showed stronger apoptosis induction than (-)-gossypol on a Bcl-2/Mcl-1-dependent cancer cell line and killed an Mcl-1-dependent cell line which is resistant to ABT-199 treatment.© 2020 Deutsche Pharmazeutische Gesellschaft.