title: Synthesis, pharmacophores, and mechanism study of pyridin-2(1H)-one derivatives as regulators of translation initiation factor 3A.
abstract: Twenty-seven 1,5-disubstituted-pyridin-2(1H)-one derivatives were synthesized and evaluated for their anti-cancer and anti-fibrosis activity by A549 and NIH3T3 cell viability assays, respectively. To study the selectivity between the cancer and fibrosis cell lines, pharmacophore models (F1-F4) were built in advance for compounds with pyridin-2(1H)-one scaffold, which revealed the relationship between the occupation of the aromatic sub-site F4 and potent anti-cancer activity. The relationship between structure and anti-cancer activity for all target compounds is also reported herein: 1-Phenyl-5-((m-tolylamino)methyl)pyridine-2(1H)-one (22) displayed both potency and selectivity (IC50=0.13 mM) toward the A549 cell line through the inhibition of translation initiation, especially by eIF3a suppression, and can be treated as a lead for the design of novel eIF3a regulators and anti-lung cancer agents.
authors: Chemistry Section, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
authors: Weixing
authors: W
authors: Zhu
authors: Jie
authors: J
authors: Shen
authors: Qianbin
authors: Q
authors: Li
authors: Qi
authors: Q
authors: Pei
authors: Jun
authors: J
authors: Chen
authors: Zhuo
authors: Z
authors: Chen
authors: Zhaoqian
authors: Z
authors: Liu
authors: Gaoyun
authors: G
authors: Hu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D039621:Eukaryotic Initiation Factor-3 / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D041681:NIH 3T3 Cells; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C105988:EIF3A protein, human; D039621:Eukaryotic Initiation Factor-3; D011728:Pyridones
keywords: Eukaryotic translation initiation factor 3, subunit A (eIF3a); Fibrosis; Lung cancer; Pyridin-2(1H)-one; Regulators