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Chem."],"abstract":"<jats:p>Inhibition of histone deacetylases (HDACs) has been extensively studied in the development of anticancer drugs. In the discovery of potent HDAC inhibitors with novel structures, the 2-substituted phenylquinoline-4-carboxylic acid group was introduced to the cap moiety of HDAC inhibitors. In total, 30 compounds were synthesized with hydroxamic acid or hydrazide zinc-binding groups. In the enzyme inhibitory test, active compound <jats:bold>D28<\/jats:bold> and its analog <jats:bold>D29<\/jats:bold> exhibited significant HDAC3 selectivity against HDAC1, 2, 3, and 6. However, compared with <jats:bold>D28<\/jats:bold>, the hydrazide-bearing compounds (<jats:bold>D29<\/jats:bold> and <jats:bold>D30<\/jats:bold>) with remarkably improved enzyme inhibitory activities did not exhibit significant antiproliferative potency in the <jats:italic>in vitro<\/jats:italic> anticancer study. Further K562 cell-based mechanistic results revealed that induction of G2\/M cell cycle arrest and promotion of apoptosis make important contributions to the anticancer effects of molecule <jats:bold>D28<\/jats:bold>. Collectively, an HDAC3 selective inhibitor (<jats:bold>D28<\/jats:bold>) with potent <jats:italic>in vitro<\/jats:italic> anticancer activity was developed as a lead compound for the treatment of cancer.<\/jats:p>","DOI":"10.3389\/fchem.2022.937225","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T05:54:07Z","timestamp":1657778047000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Discovery of 2-Phenylquinoline-4-Carboxylic Acid Derivatives as Novel Histone Deacetylase Inhibitors"],"prefix":"10.3389","volume":"10","author":[{"given":"Qian","family":"Hui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhong","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"13708","DOI":"10.1073\/pnas.250477697","article-title":"Genomewide Studies of Histone Deacetylase Function in Yeast","volume":"97","author":"Bernstein","year":"2000","journal-title":"Proc. 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