Studies On Design And Synthesis Of Anti-cancer Drugs Based On C-Met And HDAC Pathways

The lethality of most malignant tumors is the result of local invasion and metastasis from the primary tumors to other tissues. The overwhelming idea is that, because c-Met is at the crossing of many roads leading to tumorigenesis and metastasis, targeting this receptor could be a relatively simple way to inte Rfere with many pathways simultaneously. Because of the sufficient evidence favoring the role of aberrant HGF/Met signaling in the pathogenesis of various human cancers, various inhibitors have been employed to therapeutically target this receptor, among which the small molecule inhibitor of c-Met kinase has become first and foremost. In the previous investigations, we occasionally found that SU5416 which can significantly inhibit the tyrosine kinase activity of VEGF receptor Flk-1/KDR also had the ability to suppress tyrosine phosphorylation of c-Met. We designed and synthesized some novel compounds based on the further analysis of SU5416 and its pharmacological profiles. In addition, HDAC is another one highly associated with growth regulation of many kinds of tumor cells and has become a new target for the discovery of drugs against cancer. It is already apparent that HDACIs can collaborate with diverse pharmacological and biological anticancer agents to mediate synergistic apoptosis via various mechanisms including lowering apoptotic threshold of tumor cells, simultaneously activating multiple apoptotic pathways and suppressing the anti-apoptotic effects by other factors. Thus, the potential drugs with the above dual targets will possibly produce more positive effects than those from the either one. We also designed and synthesized series of compounds targeted either or both of c-Met and HDAC.The present dissertation covered 6 portions:1.A series of compounds (70 ones) with simper structure were designed and synthesized using SU5416 as lead compound that was found as effective c-Met inhibitor in our previous investigation.2.The activity of some compounds was assayed targeted c-Met kinase and one coded as "NMC-14" was discovered as significant inhibition of the motility of MDCK and HepG2 cells in cattering and invasiveness assay at the level of micromolar and nanomolar concentrations respectively. Especially, it showed no inhibition of the normal cells while suppressing the proliferation of the tumor ones. The optimizations of the process and quality control over NMC-14 have also been accomplished and its test on animal model is under way.3.In light of the excellent anti-cancer capacity of certain symmetric bifunctional intercalators, a group of such kinds of compounds (17 ones) were synthesized. In the synthesis of these compounds, highly selective syntheses of tris(2,4-dimethyl-3-carbethoxypyrrolyl)-methane M34 and its dipyrrolic intermediate M33 and pyrrolic one M31 were discovered and described. Tripyrrolic compounds have attracted much attention recently and been developed in diverse fields, M31 was the key intermediate for some tyrosine kinase inhibitors, including newly-launched Sutent(?), and M33 formed the basis for some well-known routes to porphyrins including the regiospecific synthesis.4.Some compounds dual-targeted at c-Met and HDAC (42 ones) were designed and synthesized using 3-(3,5-dimethyl-pyrrol-2-methylene)-2-indolone as nucleus with three kinds of active functional groups of carboxylic acid, short-chained and long-chained hydroxamic acid respectively.5.The activity of some compounds has also been assayed targeted HDAC and the inhibition rate for 7 of them was higher than 50%. So far, the similar studies have never been reported.6.A group of compounds targeted HDAC characteristic of existing a saturated bond on the 3 position outside the oxindole cycle were designed and synthesized (11 ones) based on the analysis of the above unexpected HDACIs, and the preliminary study on SAR was also conducted.In conclusion, we designed and synthesized 140 compounds, 126 of which are new and 14 are known. Meanwhile, 39 intermediates were also synthesized. NMC-14 showed more potent profile for c-Met compared with SU5416.At present, its study at molecular and cell level has been finished and its animal test is being conducted. In addition, the structures of newly-discovered HDACIs in this project were completely different from those of the existing HDACIs and represent promising leads for the development of more potent ones.