Fragment-based design, synthesis, and biological evaluation of N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide derivatives as novel Mcl-1 inhibitors
Release Time:2019-03-09 Hits:
Indexed by: Journal Article
Date of Publication: 2013-02-01
Journal: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Included Journals: Scopus、PubMed、SCIE
Volume: 60
Page Number: 410-420
ISSN: 0223-5234
Key Words: Fragment-based; Apoptosis; Mcl-1; LE; FQ
Abstract: We have previously reported a nanomolar inhibitor of antiapoptotic Mcl-1 protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1). S1 plays its function by binding to the BH3 groove of Mcl-1. Basing on this spacial structural characteristic, we developed a novel class of Mcl-1 inhibitor using fragment-based drug discovery approach. By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment. In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments. A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds Mcl-1 with an IC50 value of 54 nM was obtained. Compound 12c demonstrated a better aqueous solubility than S1. (C) 2012 Elsevier Masson SAS. All rights reserved.