title: Synthesis of 1-substituted 3-pyridinylmethylidenylindolin-2-ones and 1-substituted 3-quinolinylmethylidenylindolin-2-ones as the enhancers of ATRA-induced differentiation in HL-60 cells.
abstract: As part of our continuing search for potential differentiation agents, 1-benzyl-3-(4-pyridinylmethylidenyl)indolin-2-one (14) was selected as lead compound, and its new pyridinyl and quinolinyl analogs were synthesized and evaluated for differentiation-inducing activity toward HL-60 cells. Most of the tested compounds enhanced the ATRA-induced differentiation; among them, 1-(1-phenylethyl)-3-(3-quinolinylmethylidenyl)indolin-2-one (25) was the most promising one. The two isomers, 25Z and 25E; consisting 25 were found to have similar differentiation activity. The combination of 25 with all trans retinoic acid (ATRA) was found to induce complete differentiation of HL-60 cells and arrest the cells in the G(0)/G(1) phase of the cell cycle. Beside its excellent differentiation activity, 25 also exhibited relatively low cytotoxicity toward normal cells. Therefore, compound 25 is recommended as a candidate for further development of novel enhancer of ATRA-induced differentiation in HL-60 cells.
authors.affiliation: Biomedical Engineering Center, Industrial Technology Research Institute, Hsinchu, Taiwan.
authors.forename: Chi-Ying
authors.initials: CY
authors.lastname: Hung
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Hsu
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
authors.forename: Chrong-Shiong
authors.initials: CS
authors.lastname: Hwang
authors.forename: On
authors.initials: O
authors.lastname: Lee
authors.forename: Chen-Yi
authors.initials: CY
authors.lastname: Wu
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D011743:Pyrimidines; D011804:Quinolines; D014212:Tretinoin; C037219:quinoline; C030986:pyrimidine