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

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 G0/G1 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.

Among a series of indolinones synthesized and evaluated for differentiation activity, compound 25 induced completed differentiation of HL-60 cells when combined with all trans retinoic acid (ATRA).Figure optionsDownload as PowerPoint slide