Synthesis and biological evaluation of 2-indolinone derivatives as potential antitumor agents

Three series of 3-substituted-indolin-2-ones and azaindolin-2-ones have been synthesized and showed potential antiproliferative activity to cancer cell lines. The inhibition activities on VEGF-induced VEGFR phosphorylation were observed for selected 2-indolinones. Among the compounds synthesized, 5-fluoroindolin-2-one derivative 23 with a pyridone unit showed the most significant enzymatic and cellular activities. Flow cytometric analysis indicates that 23 plays a role in suppressing HCT-116 cell proliferation via G1 phase arrest and apoptosis in a dose dependent manner. The binding mode of compound 23 complexed with VEGFR-2 was predicted using FlexX algorithm. Described here are the chemistry and biological testing for these series which will guide the design and optimization of novel 2-indolione antitumor agents. Three series of 2-indolinone derivatives were designed and synthesized with potent cytotoxicity especially the 5-fluoroindolin-2-one derivative 23 with a pyridone unit showed the most significant enzymatic and cellular activities. [Display omitted] ►Three series of 2-indolinone derivatives were synthesized. ►Potential antiproliferative activity was observed on six human cancer cell lines. ►One compound with a pyridone unit showed the most significant activities. ►Dose dependent manner of G1 phase arrest and apoptosis was observed. ►VEGFR inhibition test and docking model indicate it to be a VEGFR inhibitor.