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Background: c-Met signaling has been implicated in oncogenesis especially in cells with c-met gene amplification. Since 20 % of gastric cancer patients show high level of c-Met expression, c-Met has been identified as a good candidate for targeted therapy in gastric cancer. Herein, we report our newly synthesized c-Met inhibitor by showing its efficacy both in vitro and in vivo.Methods: Compounds with both triazolopyrazine and pyridoxazine scaffolds were synthesized and tested using HTRF c-Met kinase assay. We performed cytotoxic assay, cellular phosphorylation assay, and cell cycle assay to investigate the cellular inhibitory mechanism of our compounds. We also conducted mouse xenograft assay to see efficacy in vivo.Results: KRC-00509 and KRC-00715 were selected as excellent c-Met inhibitors through biochemical assay, and exhibited to be exclusively selective to c-Met by kinase panel assay. Cytotoxic assays using 18 gastric cancer cell lines showed our c-Met inhibitors suppressed specifically the growth of c-Met overexpressed cell lines, not that of c-Met low expressed cell lines, by inducing G1/S arrest. In c-met amplified cell lines, c-Met inhibitors reduced the downstream signals including Akt and Erk as well as c-Met activity. In vivo Hs746T xenograft assay showed KRC-00715 reduced the tumor size significantly.Conclusions: Our in vitro and in vivo data suggest KRC-00715 is a potent and highly selective c-Met inhibitor which may have therapeutic potential in gastric tumor with c-Met overexpression. [ABSTRACT FROM AUTHOR]

Polyanion-cis-diammineplatinum(II) complexes were synthesized by the reaction of cis-[Pt(NH3)2(OH2)2](NO 3)2 with the polyanions containing vic- dicarboxylate ions along the polymer chain. The eleven polyanions used for this synthesis were the hydrolysis products of polymers obtained by radical alternating copolymerizations of maleic anhydride with dihydropyran deriva tives. For example, poly[(tetrahydropyran-5,6-diyl)(1,2-dicarboxyethylene)] de rivatives were synthesized, which contained substituents, such as hydroxy, methoxy, ethoxy, acetoxy, methoxycarbonyl and acetoxymethyl groups, on the 2, 3 and 4-positions of the tetrahydropyran ring. The complex formation of cis diammineplatinum(II) with vic-dicarboxylate groups was confirmed by the absorption at 1350 cm -1 for γs(CO) coordinated with Pt(II). By changing the mole ratios of the reactants, the platinum content in the polyanion complexes can be controlled and every 5-15 repeating units of the polymers were found to contain one cis-diammineplatinum(II). The biological activity of the poly anion-Pt complexes as measured in vitro against A-549 nonsmall cell lung, SK-OV-3 ovarian, HCT-15 colon, XF-498 CNS and L1210 leukemia. After select ing active complexes, the increased life spans were measured against L1210 and found to be 244, 143 and 178% for the complexes (8), (13) and (16), respec tively. [ABSTRACT FROM PUBLISHER]