Design,Synthesis And Antitumor Activity Research Of 2-Aminothiazole Derivatives

With the development of society and the changes of human living environment,the incidence of tumors shows increasing trend.Tumors,especially malignant tumors often lead to the death of humans,is a kind of disease that has a serious threat to human life.According to estimates there are 14 million new cancer patients each year,and cancer is the second largest cause of death in humans.Research and development of antitumor drugs is still one of the hot spots in the field of medicinal chemistry.Aminothiazole derivatives is a class of compounds containing thiazole heterocyclic and has variety of biological activities,including antioxidant,antitumor,anti AIDS,antibacterial,diuretic,anti-inflammatory,anti-tuberculosis etc.Its antitumor mechanism is action on protein kinase associated with tumor cells,inhibit the production of tumor cells and induce the apoptosis of tumor cells.Compared with traditional antitumor drugs role in DNA,effect on protein kinase antitumor drugs has better selectivity and low toxicity,which is a new field of anti-tumor agents research and development.SNS-032（BMS-387032）is a kind of aminothiazole compounds,originally developed by the United States Bristol-Myers Squibb research institution.Then it was found that SNS-032 has selective inhibitory activity against CDK 2,7 and 9,and show good effect in phase I clinical trial of chronic lymphocytic leukemia and multiple myeloma patients.We investigated the structure of SNS-032 and the other antineoplastic agent,their common characteristic is that the active structure is aminothiazole ring,and anti-tumor mechanisms is acting on the kinase.So we kept the ring structure of 2-aminothiazole,tinkered with its side chain structure modification.As we can know from the structure-activity relationship of SNS-032,aminothiazole ring connected with hydrophobic group at 5-position on the core has better ability to bind CDK.introduction of polar groups which can forming hydrogen bond into the 2-position of 2-aminothiazole has better activity.Thus we respectively made a structural modification at 4-position or5-position on the core with hydrophobic group to made hydrophobic effect with kinase receptor.Connecting with amide group and primary amines at 5-position on the core as the main characteristics,so it can form hydrogen bond interaction with the target point,which can achieve strong binding.We have established a library containing about 500 2-aminothiazole compounds and selected top 50 as target and then synthesized forty-three of them.The structure of the compounds are identified by ¹H-NMR、¹³C-NMR、IR.All the structure of 43compounds are correct.The preliminary pharmacological test was carried out.The human lung cancer cell line H1299 and human glioma cell line SHG-44 are cultured,and the in vitro biological activity of the synthesized compounds are tested by MTT method.The compound of No.34（4,5,6,7-tetrahydrobenzo[d]thiazole）exhibited excellent growth inhibitory activity against both of the cell lines with GI values of 81.1%and 92.7%at a single dose of 5μM.Our objective is to explore antitumor activity of 2-aminothiazole derivatives,preliminarily explain the structure-activity relationship of these compounds,and pave the way for further development of new activity of this structure.