Design,Synthesis And Biological Evaluation Of Novel ALK Inhibitors And The Construction Of Drug-like Libraries

Cancer which threats to human health has become one of the most important public health problems in the world nowadays.Lots of recent research suggests that the formation of ALK fusion gene leads to activation of ALK gene,abnormal ALK activity can inhibit the apoptosis of cells,which plays an essential role in the occurrence and development of malignant tumors.As ALK signaling pathway is so important in human cancers,ALK has been emerged as an attractive target for the development of antitumor drugs.As the first approved ALK inhibitor for the treatment of ALK positive non-small cell lung cancer,Crizotinib has a good clinical effect.However,Crizotinib has encountered the resistance problems over time.Therefore,structure optimization on the basis of Crizotinib in order to develop novel ALK inhibitors with better effects has important scientific significance.Based on the SAR studies of a series of ALK inhibitors,ligand and ALKL1196M target protein binding model in the literatures,four series of 2-aminopyridine derivatives were designed and synthesized by incorporating a 2-pyridone motif at the C-5 position of the 2-aminopyridine scaffold according to the combination principles of drug design.Through the analysis of the virtual docking results,there is a hydrogen bonding interaction between the carbonyl of 2-pyridone and the Asp1203 of ALKL1196M.Partial synthesized compounds potently inhibited the proliferation of selected ALK positive cancer cell lines,including Karpas299,NCI-H2228,SK-N-BE2 and SH-SY5Y.The assay on the kinases including ALKWT and ALKL1196M also performed well.The in vitro biological activities of GXI-26,GXI-27 and GXI-29 are comparable to that of the reference drug Crizotinib.Cell cycle arrest results showed that compound GXI-29 revealed anti proliferation inhibition in the G1 phase of the cell.Liver S9 metabolism systems had weak metabolism ability to compound GXI-29,indicating that the compound had high metabolic stability.High throughput screening of compound libraries in order to discovery lead compounds plays a crucial role in the development of new drugs,especially in the early stages.Consequently,it is of great importance to construct huge heterocyclic compound libraries.During the Ph.D.Program,four structurally diverse libraries were developed.Among them,2-pyridone containing Sorafenib derivatives which were designed and synthesized according to the combination principles were evaluated in the corresponding tumor cells in vitro,and a promising lead compound SF-9 was selected for the further biological assay.Meanwhile,functionalized 2-aminoimidazole derivatives were synthesized via a three-component domino reaction of a-nitroepoxides and cyanamide with a series of amines under mild conditions without the need for any additives.Polysubstituted imidazoles were synthesized via a simple and direct reaction of a-nitroepoxides and amidines.Multisubstituted thiadiazine derivatives were synthesized via a rapid and convenient reaction of hydrazonyl chlorides and 2,5-dihydroxy-1,4-dithiane.Further extensive biological evaluation of heterocyclic compounds is undergoing and will be reported in due course.