Design, synthesis and tumor cell growth inhibitory activity of 3-nitro-2H-cheromene derivatives as histone deacetylaes inhibitors. Issue 15 (1st August 2017)

• Record Type: Journal Article
• Authors: Tan, Shuai; He, Feng; Kong, Tingting; Wu, Jingde; Liu, Zhaopeng
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 15(2017)
• Page Start: 4123
• Page End: 4132
• Publication Date: 2017-08-01
• Subjects: HDACs -- HDAC inhibitors -- 3-Nitro-2H-chromenes -- Coumarins -- Anticancer agents -- Zinc-dependent hydrolases -- Isoform selective; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.05.062
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: As a continuous research for the discovery of coumarin-based targeted anticancer agents, we designed and synthesized a series of novel histone deacetylases (HDAC) inhibitors using the 8-ethoxy-3-nitro-2 H -chromene as the surface binding or cap group, linear dicarboxylic acid or ω-amino acid moiety with different length as the linking motif, ortho -aminoanilides, amides or α-aminoamides as the zinc binding group and the internal cavity motifs. Most of these 3-nitro-2 H -chromene derivatives exhibited good growth inhibitory activity against K562, A549, MCF-7, PC3 and Hela cells and were more potent than the reference drug SAHA and MS-275. At the concentration of 10 µM, the ortho -aminoanilide series and thed -Phe derived α-aminoamide derivatives16a and16b displayed more potent activity toward HADC1 over HADC2, and only moderate to weak activity over HADC6. In contrast, the amide ZBG analogues, 12a and12b, 14 and15, were only moderate HDAC6 inhibitors, but more selective over HDAC1 and HDAC2. The ortho -aminoanilides9b, 9c, 10b, 10c, 11b, and the α-aminoamides16a and16b were potent HADC1 inhibitors with the IC50 values in the nanomolar ranges. The ortho -aminoanilides10b and10c with a phenyl internal cavity motif were more potent than MS-275 as HADC1 inhibitors and more selective over HADC2.