Design And Synthesis Study Of 2-indolinone Derivatives As Inhibitors Of Receptor Tyrosine Kinase And The Screening Of Compoud-activities

Malignant tumor, also called as cancer, is a serious threat to the health and life of the mankind, the death caused by malignant tumors is in the second place among the death of all disease. Consequently, there has been a great interest in the development of novel agents for curing the cancer. Traditional chemotherapy agents are designed to non-specifically block cell division and/or induce cell death, and therefore can be toxic to normal cells of tissues and organs as well as cancer cells.Targeting specific pathways to stop cancer growth can be less toxic to normal cells, and thus improve the tolerability. Anticancer drug discovery has shifted from an empiric random screening approach to a more rational and mechanistic, target- directed approach, where specific abnormalities in cell functioning are targeted. Protein tyrosine kinase (PTK) is an especially important target because they play an important role in the modulation of growth factor signaling. In this group of targets, the c-Met receptor tyrosine kinase is crucial to increased cell growth, altered cytoskeletal function, increased metastasis, reduced apoptosis, and other biological changes. Targeting of the HGF/c-Met pathway is likely to improve current therapies in Met-dependent malignancies.Based on the structure- activity relationships of tyrosine kinase inhibitors, 8 2-indolinone compounds were designed and synthesized. And the primary biological activity evaluation of the synthetic compounds was carried out. The several parts of the present research works were summarized below:1. 8 compounds with 2-indolinone structure were designed and synthesized with SU5416 as a lead compound. With the attempts to get compounds with high activity, the 2-indolinone in the structure was retained to conserve conjugated double bonds, at the same time pyrrole was subsitituted by 3-hydroxypyrrolidine at 3-position of 2-indolinone via CH=CH-linker. Meanwhile in order to enhance their solubility, sulfonamide group at the 5-position of indolinone was introduced. The structure of these compounds was confirmed by 1H-NMR.2. The activity to PTK inhibitors of 8 compounds synthesized were evaluated, most of them have inhibitory activity in concentration of 400μM. And the results showed that there were 5 compounds whose inhibition rates were around 40%-60%: HK02, HK03, HK004, HK05 and HK07; 1 compound around 20%-40%: HK01; 2 compounds below 15%: HK06, HK08.3. The activity to c-Met kinase inhibitors of the compounds with 2-indolinone structure were evaluated, the results showed that 4 compounds could inhibit TPR-MET-induced Ba/F3 cell growth in the concentration of 1μM: HK02, HK04, HK05, HK07.4. Structure-activity relationships could be found from the results of pharmacological test above. Introducing sulfonamide group to 5-position of the 2-indolinone could facilitate active improvement. The inhibition activity of the compounds with aromatic amine subsitituents was superior to compound with aliphatic amine substituents.