Design,Synthesis And Antitumor Activity Study Of 2-aminothiazole Derivatives

During the past few years,the role of Protein tyrosine kinases(PTKs)playing in the malignant Proliferation of tumour cell has been studied and revealed,and consequently the PTKs has been an important target to find a new drug.Many effective drugs of PTKs inhibitor have appeared on the market while much more drug molecules are ongoing clinical trials.2-aminothiazole has been proved a remarkably effect of Src family kinase inhibitor.We attempt to investigate whether introduction of methyl group,imino group,arylamino group,pyrimidine ring and aryl ring into thiazole at 2-,4-,or 5-position could enhance their anticancer activities or not.Thus,we constructed the basic structure of thiazole,and synthesized two series of novel thiazole-chalcones and thiazole-pyrimidines.These compounds were tested for their cytotoxic activity against several human tumor cell lines.It may be summarized as follows:1.According to the method of Hantzsch,eighteen 5-acetyl-4-methyl-2-arylamino-thiazole and isomer were prepared by arylthioureas and 3-bromo-acetylacetone under refluxing solvents.The structures of these compounds were confirmed by IR,1H NMR,MS and HRMS.The reaction conditions have been studied and influence of different temperatures and solvents on the ratio of isomers were discussed.The final ratio of aminothiazoles 2-3 and iminodihydrothiazoles 2-4 was depended on the equilibrium of intermediates,which might probably affected by the nature of solvents and in situ released hydrobromic acid might accelerate the formation of compounds 4.It could be speculated that non-polar solvents might enhance the yields of iminodihydrothiazoles 4 and the predominant aminothiazoles 2-3 in polar solvents.A plausible mechanism involving solvent effect was proposed.2.Based on the common structural features of chalcones reported in the literature,especially in the antitumor activities and we introduced the chalcones structure into thiazole at 5-position via Claisen-Schmidt condensation reaction.The total 37 compounds of(E)-1-(4-methyl-2-arylaminothiazol-5-yl)-3-arylprop-2-en-1-ones and(E)-1-(2-Imino-4-methyl-3-aryl-2,3-dihydro-thiazol-5-yl)-3-arylprop-2-en-1-ones were synthesized and tested for their cytotoxic activity against several human tumor cell lines in vitro.The structures of these compounds were confirmed by IR,1H NMR,MS and elemental analysis or HRMS.Primary SAR study indicated that utilizing of chalcones moiety as the linker was more beneficial for the activities.The most potent compound 3-26 exhibited significant activity against BGC-823 and NCI-H460 with IC50 of 9.70 and 6.31?M,respectively.The compounds 3-10 and 3-40 showed strong potential inhibitory in vitro and were further evaluated their antitumor activity in vivo in ICR mice bearing sarcoma 180 cells.The results showed that compound 3-10 and 3-40 through ig administration at dose of 50 mg/kg,exhibited moderate experimental therapeutic efficacy by 25%.3?The novel thirty-seven compounds of thiazol-pyrimidines were synthesized by the general pyrimidine condensation of Bredereck and tested for their cytotoxic activity against several human tumor cell lines in vitro by MTT.The structures of these compounds were confirmed by IR,1H NMR,MS and elemental analysis.Primary SAR study indicated that introduction of arylamino group and pyrimidine group into thiazole could enhance their anticancer activities.The compounds 4-9(IC50 1.99 and 2.99?M)and 4-30(IC50 7.98 and 1.52?M)showed strong potential inhibitory against Ishikawa and A549 with.The structure of compounds 4-15,4-23 and 4-35 were further confirmed by X-Ray Single Crystal Diffraction.