Design and synthesis of fused bicyclic inhibitors targeting the L5 loop site of centromere-associated protein E. Issue 17 (1st September 2016)

• Record Type: Journal Article
• Authors: Hirayama, Takaharu; Okaniwa, Masanori; Banno, Hiroshi; Kakei, Hiroyuki; Ohashi, Akihiro; Ohori, Momoko; Nambu, Tadahiro; Iwai, Kenichi; Kawamoto, Tomohiro; Yokota, Akihiro; Miyamoto, Maki; Ishikawa, Tomoyasu
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 17(2016)
• Page Start: 4296
• Page End: 4300
• Publication Date: 2016-09-01
• Subjects: DIPEA N, N-diisopropylethylamine -- HATU hexafluorophosphate O-(7-azabenzotriazol-1-yl)-N, N, N′, N′-tetramethyluronium -- PD pharmacodynamic; CENP-E -- Electrostatic potential map (EPM) -- 2, 3-Dihydro-1-benzothiophene 1, 1-dioxide derivatives -- Anti-cancer agent -- Anti-mitotic agent; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.07.038
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Centromere-associated protein-E (CENP-E) is a mitotic kinesin which plays roles in cell division, and is regarded as a promising therapeutic target for the next generation of anti-mitotic agents. We designed novel fused bicyclic CENP-E inhibitors starting from previous reported dihydrobenzofuran derivative( S )-(+)-1 . Our design concept was to adjust the electron density distribution on the benzene ring of the dihydrobenzofuran moiety to increase the positive charge for targeting the negatively charged L5 loop of CENP-E, using predictions from electrostatic potential map (EPM) analysis. For the efficient synthesis of our 2, 3-dihydro-1-benzothiophene 1, 1-dioxide derivatives, a new synthetic method was developed. As a result, we discovered 6-cyano-7-trifluoromethyl-2, 3-dihydro-1-benzothiophene 1, 1-dioxide derivative(+)-5d (Compound A ) as a potent CENP-E inhibitor with promising potential for in vivo activity. In this Letter, we discuss the design and synthetic strategy used in the discovery of(+)-5d and structure–activity relationships for its analogs possessing various fused bicyclic L5 binding moieties.