Design And Synthesis Of Multi-aromatic Deri Vatives As HGF/c-met Protein Tyrosine Kinase Inhibitors

Malignant tumor is a serious threat to the mankind and its incidence was significantlyincreased. Consequently, there has been great interest in the development of novelagents for the treatment of the cancer. Recently, with the development of molecularbiological techniques and the celluar and molecular understanding of the pathogenicmechanism of cancer, choosing the key enzymes in the signaling cascade ofoncogenes and tumor development as therapeutic targets to develop effective, and lowtoxicity anticancer drugs has been an important research field. Targeting specificpathways to stop cancer growth can be less toxic to normal cells, and thus improve thetolerability.Protein tyrosine kinase (PTK) are an especially important target because they play animportant role in the modulation of growth factor signaling. In this group of targets,the c-met receptor tyrosine kinase plays an important role in increased cell growth,reduced apoptosis, altered cytoskeletal function, increased metastasis, and otherbiologic changes. Targeting of the HGF/c-met pathway is likely to improve currenttherapies in met-dependent malignancies.Based on the structure-activity relationships of c-met inhibitors,16compounds weredesigned and synthesized.And the primary biological activity evaluation of thesynthetic compounds were carried out.The several parts of the present research workswere summarized below:1. Summary the structure-activity relationships of c-met inhibitors,16compounds with diphenyl ether were designed and synthesized. Based onthe diphenyl ether structure, the different five-membered rings were connected on the para position or meta position of the ether bond. We hopethat these compounds containing the structure inhibit tumor cells while havethe analgesic effect. Through the formation of amide bond in the other paraposition of the ether bond to connect the different side chains, in order toobtain better activity.2. The activity to the c-met inhibitors of the16compounds synthsized wereevaluatede. It is found that most of these compounds have inhibition activityin the concentration of10μM when put XL880as positive control. And theresults showed that there were2compounds whose inhibition rates wereabove30%: T05and T13;5compounds around20%-30%: T08, T11, T12,T14,T16;4compounds around10%-20%: T01,T06, T10, T15;5compoundsaround0%-10%: T02, T03, T04, T07, T09.3. The structure-activity relationships of those novel moleculars were primarilyanalyzed. The results showed that multi-aromatic compounds with differentacyl side chains have different inhibition activity. The inhibition activity ofcompounds with urea substituents were superior to compounds withcyclopropyl diamide substituents. To these compounds containingcyclopropyl diamide substituted, the introduction of electron withdrawinggroups in favor of the activity improved and the inhibition activity isproportional to the number of electron withdrawing groups.