title: 2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition.
abstract: This study reports the synthesis of a series of 2-aroylquinoline-5,8-diones (11-23) on the basis of scaffold hopping. The presence of a methoxy group at C6 assists the highly regioselective incorporation with various amines, and simplifies the structural identification process. Among the synthetic compounds, 6-dimethylamino-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (12) and 7-pyrrolidin-1-yl-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (23) exhibit remarkable anti-proliferative activity against the cancer cell lines tested with mean IC50 values of 0.14 and 0.27 μM, respectively. Compound 23 showed moderate inhibitory activity against tubulin polymerization with an IC50 value of 5.9 μM. In a western blot analysis, 23 caused induction of HSP70 and degradation of Akt, revealing that it possesses HSP90 inhibitory activity.
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan. hyl@tmu.edu.tw.
authors.forename: Kunal
authors.initials: K
authors.lastname: Nepali
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.forename: Hsiang-Ling
authors.initials: HL
authors.lastname: Huang
authors.forename: Fei-Chiao
authors.initials: FC
authors.lastname: Kuo
authors.forename: Cheng-Hsin
authors.initials: CH
authors.lastname: Lee
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Kuo
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Li
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
authors.forename: Hsueh-Yun
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D050884:HSP72 Heat-Shock Proteins / Q000096:biosynthesis; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007624:KB Cells; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000609231:2-aroylquinoline-5,8-dione; D000970:Antineoplastic Agents; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D015363:Quinolones; D014404:Tubulin; D050257:Tubulin Modulators; D051057:Proto-Oncogene Proteins c-akt