Studies On Design, Synthesis And Antitumor Activities Of 3-Substituted Indolin-2-Ones

Tumor is the malignant disease that seriously damages human health,in present the five years survive rate of tumor patients still remains at a low level.Research results showed that cell unlimited proliferation induced by abnormal signal transduction pathway is the essence of cell carcinogenesis.The research and development tendency of anti-tumor drugs has transformed from traditional cytotoxic drugs to the drugs targeting abnormal signal transduction pathway.Protein Tyrosine Kinases(PTKs) are the most important substances during the process of cell signal transduction,which highly relate to the occurrence and development of tumors. Inhibition the abnormal activity of PTKs has effect on tumor's proliferation.From the year 2001,eight small molecular Protein Tyrosine Kinase Inhibitors(PTKIs) have been approved for tumor by FDA in USA and more than 100 candidates are in the clinical trials.In order to find more potent new 3-substituted indolin -2-ones PTKIs,using sunitinib as a leading compound,two series of 3-substituted indolin -2-ones have been synthesized based on the Structure and Activity Relationship(SAR) of 3-substituted indolin-2-one derivatives.The activities of the compounds were evaluated with HMEC (expressing high level of VEGFR-2) in vitro through measuring cell viability by MTT method;the anti-proliferative activities of the selected compoundsâ… -09 andâ… -11 were evaluated against cell lines of SGC7901,A549,HL-60,SK-BR-3,and HCT116 by MTT method with sunitinib used as a positive control.The result suggested that all the target compounds showed inhibitory activities against HMEC at the concentration of 10μmol/L,and compoundsâ… -09 andâ… -11 showed potent anti-proliferative activities.Compoundâ… -09 showed inhibition ratio of 69.80%against HMEC at the concentration of 10μmol/L and IC₅₀ of 3.60μmol/L against HL-60.Compoundâ… -09 was more potent than sunitinib and is on going in pharmacokinetics study.