Design,Synthesis And Antitumor Activities Of Thieno[3,2-d] Pyrimidine Derivatives

Malignant tumors are one of the major diseases that seriously threaten human health and life.Drugs still play an important role in the treatment of malignant tumors.However,the efficacy of traditional cytotoxic drugs is often unsatisfactory due to their toxic and side effects,drug resistance together with poor selectivity.There is an urgent need for highly effective,low toxicity and high specificity antineoplastic drugs in clinic.In recent years,targeting drugs have brought malignant tumors into a new era of"targeted therapy".It has been found that new antitumour drugs with high efficiency,low toxicity and strong specificity selectively acting on specific targets have become an important direction in the research and development of antitumor drugs nowadays.The research and development of drugs targeting protein tyrosine kinase has become one of the international hot spots in this field.Among them,epidermal growth factor receptor?EGFR?tyrosine kinase is one of the main protein tyrosine kinases.Its biochemical process as an anti-tumor target is being gradually elucidated.Aromatic quinazoline drugs such as gefitinib and erlotinib have been widely used in clinic,and the research of EGFR inhibitors has good prospects.However,quinazoline core is not necessary for EGFR inhibitors.According to the bioisosterism,thieno[3,2-d]pyrimidine core can be regarded as a bioisostere of quinazoline core.Based on the structure,properties and pharmacological activities of arylaminoquinazoline EGFR inhibitors,thieno[3,2-d]pyrimidine was used as the mother nucleus to modify and modify their structures.Novel compounds containing thioeno[3,2-d]pyrimidine core rather than quinazoline nucleus were designed and synthesized in order to screen out the lead structures of new antineoplastic drugs.Isothiocyanate,ethyl cyanoacetate and chloroacetonitrile as starting materials,ethyl 4-amino-5-cyano-2-?alkylamino?thiophene-3-carboxylate was first synthesized.After condensation,cyclization-Dimroth rearrangement and deesterification,three series of 36 target products,N⁶-alkyl-N⁴-arylthieno[3,2-d]pyrimidine-4,6-diamines were obtained.At the same time,the synthetic conditions of the reaction were discussed,and the reaction results under microwave irradiation and traditional heating conditions were compared.The structures of the target compounds were characterized by EI-MS,¹H NMR,¹³C NMR.The crystal structures of compounds I4k and IIe were further analyzed by X-ray single crystal diffraction.Preliminary in vitro antitumor activity tests showed that some of the target compounds of series I have good inhibitory activity against hepatocellular carcinoma?HepG2?and breast cancer cells?MCF-7?.Most of the target compounds of series?have good inhibitory activity on HepG2,but have poor inhibitory effect on MCF-7.The target compounds of series III exhibit excellent inhibitory activity against HepG2,and some compounds also exhibit certain inhibitory activity against MCF-7.In addition,the inhibitory activities of EGFR and ErbB2 enzymes in vitro were also tested for some compounds in series I.The target compound Il is superior to the commercialized EGFR/ErbB2 dual-target drug erlotinib in both enzymes,which laid a foundation for further study on the structure-activity relationship and further syntheses.The structures of the three series target compounds are as follows:???N⁶-Phenyl-N⁴-arylthieno[3,2-d]pyrimidine-4,6-diamines??????N⁶-Methyl-N⁴-arylthieno[3,2-d]pyrimidine-4,6-diamines??????N⁶-Benzyl-N⁴-arylthieno[3,2-d]pyrimidine-4,6-diamines???...