Design, Synthesis, and Biological Evaluation of 2‐Aminobenzanilide Derivatives as Potent and Selective HDAC Inhibitors

Abstract

Epigenetic regulation is an essential process for the normal functioning of genes. Therefore, targeting epigenetic dysregulation in cancer may be a valid therapeutic approach for the treatment of this severe disease. Histone deacetylases (HDACs) are enzymes involved in the regulation of epigenetic post-translational modifications; because they are overexpressed in many types of cancer, HDACs are valuable targets for the development of new anticancer agents. A large series of 2-aminobenzanilides linked at the 4'-position to α-amino acid amides, arenes, and heteroarenes through a methylene bridge were designed, synthesized, and tested as novel HDAC inhibitors. Several compounds showed IC(50) values in the two-digit nanomolar range in hrHDAC1 inhibition assays, lower than that of the reference compound MS-275. They also showed interesting selectivity profiles, as confirmed by western blot assays.

Structural Basis for the Inhibition of Histone Deacetylase 8 (HDAC8), a Key Epigenetic Player in the Blood Fluke Schistosoma mansoni

“…Fluorescence was measured in a plate reader (BMG Polarstar) with excitation at λ = 390 nm and emission at λ = 460 nm. Inhibition data for human HDACs 1, 3 and 6 were obtained according to published procedures with Z(Ac)Lys-AMC as the substrate and trypsin as the developing agent [67]. HDAC1, 3 and 6 were purchased from BPS Bioscience.…”

New 5-Aryl-Substituted 2-Aminobenzamide-Type HDAC Inhibitors with a Diketopiperazine Group and Their Ameliorating Effects on Ischemia-Induced Neuronal Cell Death

“…1 ). Compound 1a inhibited HDAC1 and 2 selectively and suppressed the growth of cancer cells, similar to the same type of HDAC inhibitors 5 – 21 . However, 1a averted the death of HCT116 human colorectal cancer cells by a mechanism involving activation of the survival signal-related proteins Akt/mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (p70S6K) 22 , 23 .…”

Design, synthesis and anti-tumor activity study of novel histone deacetylase inhibitors containing isatin-based caps and o -phenylenediamine-based zinc binding groups

“…21,22 The 14 Å cavity as an escaping route for acetate following deacetylation could be used for the design of HDAC1/2 selective inhibitors. 23,24 Thereby, we designed and synthesized several 5-substituted- o -phenylenediamines 23a – 23d , which should be HDAC1/2 selective over HDAC3. Moreover, one 4-fluorine- o -phenylenediamine analogue 30 was also synthesized.…”