Zwergel, Clemens; Di Bello, Elisabetta; Fioravanti, Rossella; Conte, Mariarosaria; Nebbioso, Angela; Mazzone, Roberta; Brosch, Gerald; Mercurio, Ciro; Varasi, Mario; Altucci, Lucia; Valente, Sergio; Mai, Antonello published their research in ChemMedChem in 2021. The article was titled ãNovel Pyridine-Based Hydroxamates and 2-Aminoanilides as Histone Deacetylase Inhibitors: Biochemical Profile and Anticancer Activityã?Reference of 6-Bromopyridin-3-amine The article contains the following contents:
Starting from the N-hydroxy-3-((4-(2-phenylbutanoyl)amino)phenyl)acrylamide (5 b) previously described by us as a HDAC inhibitor, we prepared four aza-analogs, 6-8, 9 b, as regioisomers containing the pyridine nucleus. Preliminary screening against mHDAC1 highlighted the N-hydroxy-5-((2-(2-phenylbutanoyl)amino)pyridyl)acrylamide (9 b) as the most potent inhibitor. Thus, we further developed both pyridylacrylic- and nicotinic-based hydroxamates (9 a, 9 c-f, and 11 a-f) and 2-aminoanilides (10 a-f and 12 a-f), related to 9 b, to be tested against HDACs. Among them, the nicotinic hydroxamate 11 d displayed sub-nanomolar potency (IC50: 0.5 nM) and selectivity up to 34 000 times that of HDAC4 and from 100 to 1300 times that of all the other tested HDAC isoforms. The 2-aminoanilides were class I-selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12 d being the most effective (IC50HDAC3=0.113μM). When tested in U937 leukemia cells, the hydroxamates 9 e, 11 c, and 11 d blocked over 80% of cells in G2/M phase, whereas the anilides did not alter cell-cycle progress. In the same cell line, the hydroxamate 11 c and the anilide 10 b induced about 30% apoptosis, and the anilide 12 c displayed about 40% cytodifferentiation. Finally, the most potent compounds in leukemia cells 9 b, 11 c, 10 b, 10 e, and 12 c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC50 values at single-digit to sub-micromolar level.6-Bromopyridin-3-amine(cas: 13534-97-9Reference of 6-Bromopyridin-3-amine) was used in this study.
6-Bromopyridin-3-amine(cas: 13534-97-9) belongs to anime. Large quantities of aliphatic amines are made synthetically. The most widely used industrial method is the reaction of alcohols with ammonia at a high temperature, catalyzed by metals or metal oxide catalysts (e.g., nickel or copper). Mixtures of primary, secondary, and tertiary amines are thereby produced.Reference of 6-Bromopyridin-3-amine