Design,Synthesis And Antitumor Activity Of New Thiazolyl Pyrimidine Analogs As Cyclin-Dependent Kinase 2 Inhibitors

90s of last century,scientists proposed that the tumor is a cell cycle disease and cell cycle control in any part of the change may lead to the occurrence of tumors.With the in-depth study of cell cycle control mechanisms,especially since Leland H.Hartwell and others discovered the nucleus of cell cycle-dependent regulation of cell cycle-dependent kinase(CDK)and won the 2001 Nobel Prize in Physiology and Medicine,CDK has become a hot area for the development of new anti-cancer drugs.So far,there are three major types of molecules that have been found to be involved in the regulation of the cell cycle:Cyclins,CDKs,and CKIs.Among them,cyclin Dependent kinases(CDKs)are the core of the cell cycle regulatory network.The abnormal function of CDK is closely related to the occurrence and development of tumors.Currently,there are more than 20 subtypes of cyclin-dependent kinases,of which CDK1,CDK2,CDK4,and CDK6 are mainly involved in the regulation of cell cycle,and the retinoblastoma protein(RB)and The transcription factor E2F binds to and inhibits the activity of the transcription factor E2F,leaving the tumor cells in the GO phase.Under the stimulation of external mitogenic signals,tumor cells enter the mitotic G1 phase,increase the synthesis of cyclin D,and bind to CDK4/6,resulting in the phosphorylation of retinoblastoma protein(RB),partially abrogating the inhibitory effect of RB on E2F.The expression of the cyclin E and the like required for the cell cycle to increase is increased.In the late phase of mitosis G1,the cyclin E binds to CDK2 and further phosphorylates retinoblastoma protein(RB),The activity of the transcription factor E2F is released and the malignant tumor cells enter the S phase through the G1/S restriction point.At this time,the cyclin A substitutes for the cyclin E,which binds to cyclin kinase CDK2 and participates in DNA replication.In late S phase of malignant cell mitosis,cyclin A and CDK1 form a complex,and malignant cells begin to enter G2 phase.At this time,the cyclin B binds to CDK1,which drives the mitosis of the tumor cells,promotes the tumor cells to pass through the M phase,and finally completes all the processes of cell mitosis.Over the past decade or so,with the rapid development of drug design techniques,such as the analysis of the combination of the two forms of the X-ray crystal structure formed by the cyclin CDK and CDK inhibitors,not only inhibitors can be found.With competitive binding,small molecule inhibitor binding sites can also be found.As of now,dozens of CDK inhibitors have entered clinical phase I or clinical phase ? studies.At present,the small molecule inhibitors of CDK2 targets reported in the literature are numerous and diverse in structure.Among them,the structure of CDK2 inhibitors often has a pyrimidine nucleus due to the diversity of substituent groups and substitution sites on the pyrimidine ring.The anti-tumor activity of pyrimidine compounds has multi-target characteristics.Among them,2,4-diaminopyrimidine compounds based on cyclin-dependent kinase CDK particularly exhibited better anti-tumor activity.Based on the above background studies,in order to find a new lead compound with high efficiency and low toxicity and good anti-tumor activity,we select the cyclin-dependent kinase as a research target of anti-tumor drugs,and our group previously foundpyrimidine compound BZ-19 with high anti-tumor activity.In this paper,we use the compound BZ-19 as a lead,designed and synthesized a total of 51 series of two novel pyrimidine derivatives.The general structure is as follows:In addition,the synthetic methods,chemical structures,spectral properties and bioactivities of target compounds were studied,and the structure-activity relationship,we summary of the biological activity of the structure-activity relationship preliminary.The specific research contents are as follows:1.The progress of research on the chemical structure,antitumor activity and mechanism of pyrimidine compounds with antitumor activity were summarized.2.We selected the cyclin-dependent kinaseas a target,and BZ-19 as the lead compound,designed and synthesized 51 novel pyrimidine derivatives.3.Cytotoxic activities of all target compounds were tested by MTT method.human colon cancer cell line(HCT116),Human cervical cancer cell line(HeLa),human prostate cancer cell line(PC-3),human hepatocellular carcinoma cell line(HepG2)were selected for antitumor activity in vitro.4.On the basis of tumor inhibitory activity in vitro,the representative compound with good activity was selected and the inhibitory activity of cyclin CDK2 was tested by using AZD5438 as a positive control.