Design, Synthesis And Biological Activity Evaluation Of Purine Derivates As Cyclin-dependent Kinase Inhibitors

Cancer has constituted major threat to human health. According to the World Cancer Report2008, over12million people are suffered from cancer, and accounting for7.6million deaths in2008. Deaths from cancer worldwide are projected to continue rising, new cancer case are expected to rise form12million to nearly27million annually and lead to17million people death every year by2030. Therefore, cancer has emerged as main threat to public health. A more detail understanding the molecular mechanism and the changes that occur during tumorigenesis as well as the search for a lower toxicity and higher efficiency anticancer agent has become a major task of medical field. Scientists found that the abnonnal regulation of cell cycle expression is a hallmark of cancer, and which frequently associated with dysregulation of CDK/cyclin. Thus, pharmacological inhibition of CDKs activity is an important molecular target for the development of potential new anticancer drugs, and the discovery of highly efficacious and selective CDKs inhibitors have increasingly attracted much attention among the medicinal chemistry researchers.R-roscovitine is a potent, selective, orally bioavailable purine inhibitor of CDKs and is currently been tested in phase II clinical trials. According to the binding mode of R-roscovitine and NU2058in complex with CDK2, further development of purine-derived CDK inhibitors has been mainly focus on the modification of the R-roscovitine molecule in its substitution positions. Three series of purine derivatives have been designed and synthesized in order to increase their binding affinity towards CDK2ATP pocket, and also keep the hydrogen bond in hinge region and ribose/phosphate region of R-roscovitine and NU2058. Total26new compounds were synthesized and their structures have been validated by the1H-NMR, ESI-MS and HRMS. Preliminary enzyme inhibitory activities against CDK1/cyclin B of all compounds in vitro indicated that W7, Q1, Q3, Q4, Q8and Dl are more potent than reference compound Roscovitine at10μM concentration. Some compounds, for example, W5, W9, Q6, D7and D8exerted similar enzyme activities compared with Roscovitine. Cytotoxicity activity against HCT116, MDA-MB231and PC-3cell lines were measured and exhibited that most of target compounds displayed better anti-proliferation potency than R-roscovitine, and moderate selectivity towards the human colon adenocarcinaoma cell line HCT116. SAR studies identified that the presence of cyclohexylamino group in Q series could increase the anticancer activity compared with that of benzylamino group substituted at C6position in W series. Moreover, the anti-proliferative activity of compound Dl is in line with aforementioned discovery in which cyclohexylamino group resulted in increased activity. Furthermore, introduction of amino acid in C2position of the purine scaffold, such as D3, D4and D9, completely reverses their anti-proliferative activity. Replacement of C2by other aminoalcohol moiety (compound Q2, Q5, Q6, Q7and Q8) also failed to yield more potent growth inhibition effects against tumor cell lines.In summary, the CDKs comprise an attractive protein kinase target for novel anticancer drug discovery. Three series of small molecule CDK inhibitors have been designed based on the3D-structure of CDK2and its ATP binding mode. The biological activities of target compounds have confirmed that Ql, Q3, Q4and Q8exhibited the excellent CDK1/cyclin B and anti-cancer activities, which could be developed as CDK inhibitors for further evaluation. Moreover, compound Ql, Q3, Q4and Q8represents a novel lead compound which may be further modified and optimized to provide more potent therapeutic CDKs inhibitors.