Molecular Design And Activity Evaluation Of The C-Met Kinase Inhibitor Compounds Based On2-indolone Derivatives

Protein tyrosine kinase (PTK)was widely used as the target of antitumor drugsbecause of its key factor in tumor signal transduction. Hepatocyte growth factor (HGF)receptor (c-Met) is highly expressed in a variety of tumor cells, and it plays animportant role in promoting cell growth, reducing apoptosis, altering cytoskeletalfunction, increasing metastasis and other biological changes. Thus, targeting of theHGF/c-met pathway is likely to improve current therapies in met-dependentmalignancies.Solid-phase synthesis has been developed from the initial peptide synthesis to allkinds of small organic molecules and complex natural products since its emergence.Solid phase synthesis required solid phase carrier and linker molecules that connectedcarrier with reactants, the correct choice of carrier and linker molecule determines thesuccess of the solid-phase synthesis. Glass is a kind of material with low price and iseasy to get, so it can be used as solid phase carrier after being processed into aspecific particle size and being modificated on its surface.In this paper，two aspects of work were carried out. One of them was design andsynthesis of a series of compounds based on2-indolone, according to thestructure-activity relationships of tyrosine kinase inhibitors. Furthermore, preliminaryc-Met kinase inhibitory activity was evaluated. The other one was the synthesis of anew solid phase carrier based on glass beads, in order to lay the foundation forsolid-phase combinatorial synthesis of this kind of compounds in the future, aproposal was put forward which was about the solid phase synthesis of someintermediates using the new solid phase carrier.The several parts of the present research works were summarized below:1. On the basis of some literature and our preliminary research summary on thestructure-activity relationships, and using L029and SU11274as lead compounds,21new compounds was designed and synthesed based on2-indolone. CompoundsT1-T18were synthesed that inbridged derivatives of vanillin/isovanillin at3-positionof2-indolone, so conjugated doule bonds of the lead compounds was conserved.Compound T19was synthesed to keep a better stability by introducing3-N,N-dimethyl-propyl at N-1position of the compound L029. Compounds T21weresynthesed that inbridged derivatives of isovanillin at3-position of2-indolone. Allcompounds were confirmed by NMR and mass spectrometric detection.2. The inhibitory activity and the cell proliferation activity of the21compounds with2-indolone structure were evaluated, and most compounds had inhibitory activity,among which, compound T15inhibitory activity was significantly higher than L029,the result showed that in the concentration of1μM, the inhibition rate was30.3%inc-Met kinase screening experiment. So it was concluded that when c-Met kinaseinhibitors were prepared basing on2-indolone, inhibitory activity more excellentinbridging the double bond at the3-position with vanillin derivative. Compounds withsulfonamide group or fluorine at5-position both had inhibitory activity. In MCF-7anti-proliferation experiment, it was found that the activity of compound T19washigher than that of SU11274, the GI50of the former is2.85μM, compared with10.85μM of the latter.3. Solid phase carrier was made basing on glass beads, after modification ofhydroxylation, and amino-silanization on its surface, amino-group was detected withdensity of0.0089mmol/g. Linker was connected, so a novel kind of solid phase carrierwas made with a similar structure with wang resin. According to successfulconnection and removal glycine from the linker, the feasibility of modified glassbesds as a solid phase carrier was proved. Furthermore, proposal of the new carrier’sapplications in preparation of the intermediate M4-M19was carried out.In this paper,21new compounds were synthesed based on2-indolone, and c-Metkinase inhibitory activity was evaluated. The preliminary activity screening result andthe structure-activity relationship analysis played an important role in designing newkind of c-Met kinase inhibitor with more inhibitory activity while with low toxicity. Inthis theses, the preparation method of new solid phase carrier and the suggestionabout its applicaton laid the foundation for the2-indolone series compounds.