Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity

0555060 - BTÚ 2023 RIV CH eng J - Journal Article
Ibrahim, H. - Abdelsalam, M. - Zeyn, Y. - Zessin, M. - Mustafa, A. - Fischer, M. - Zeyen, P. - Sun, P. - Buelbuel, E. - Vecchio, A. - Erdmann, F. - Schmidt, M. - Robaa, D. - Bařinka, Cyril - Romier, C. - Schutkowski, M. - Kraemer, O. - Sippl, W.
Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity.
International Journal of Molecular Sciences. Roč. 23, č. 1 (2022), č. článku 369. E-ISSN 1422-0067
R&D Projects: GA ČR(CZ) GA21-31806S
Institutional support: RVO:86652036
Keywords : EFFICIENT GENERATION * EPIGENETIC THERAPY * AM1-BCC MODEL
OECD category: Biochemistry and molecular biology
Impact factor: 5.6, year: 2022
Method of publishing: Open access
https://www.mdpi.com/1422-0067/23/1/369

Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.
Permanent Link: http://hdl.handle.net/11104/0332121