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Novel Pyridine‐Based Hydroxamates and 2′‐Aminoanilides as Histone Deacetylase Inhibitors: Biochemical Profile and Anticancer Activity
Author(s) -
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
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000854
Subject(s) - chemistry , stereochemistry , ic50 , cancer cell , cell culture , pyridine , biochemistry , cancer , biology , in vitro , medicinal chemistry , genetics
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‐analogues, 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 (IC 50 : 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 (IC 50 HDAC3 =0.113 μM). 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 IC 50 values at single‐digit to sub‐micromolar level.