Design, Synthesis and Anticancer Activity of Novel Pyrimidine Derivatives as Cdk2 Inhibitors

Abstract

Cancer is one of the fatal diseases in world leads to death when diagnosed at the latter stage. There are many types of cancers such as lung, blood, breast, skin, etc. which are induced in human body due to certain carcinogens and many other reasons. Preventive measures for protection from cancer include avoiding smoking, chewing tobacco, exposure to the chemicals, etc. Skin cancer is one of the cancers which occurs due to the exposure to UV radiation and can lead to very dangerous effects in normal healthy body. According to the WHO report, 7.6 million people worldwide died from cancer in 2008.70% death occurs in low and middle income countries. Currently between 2 to 3 million people are affected by non-melanoma skin cancer and 132,000 people affected by melanoma skin cancer globally each year. Currently, available drugs in the market for the treatment of basal cell carcinoma includes fluorouracil, Imiquimod, Vasodegib and for melanoma, drugs are Dacarbazine, vemurafenib. Objective of present study was to develop new series of molecules which would act on the CDK2 receptors and which may help in the prevention of the skin cancer. CDK2 is responsible for the cell cycle. P53 protein is natural inhibitor of the CDK2 but mutations in the P53 protein results in the excessive amount of CDK2 which causes uncontrolled cell proliferation. Hence in the present study we had tried to develop the novel heterocyclic compounds which would act on the CDK2 and can be used in the prevention of skin cancer. Here, we have used various computational tools like pharmacophore modelling, virtual screening, molecular docking, in-silico ADMET studies, etc. for designing new molecules. Eight compounds were selected from already published literatures which are having remarkable activity on the CDK2 receptor. Pharmacophore models were developed by using GALAHAD module of Sybyl X1.3. The best model was selected having 5 features viz. 2 donor atoms, 1 acceptor atom and 2 hydrophobic atoms. This model was taken as a query and virtual screening was performed using NCI database. 72,959 molecules were obtained after virtual screening and after applying Lipinski filter, 21,119 molecules were obtained. Various molecules having higher Qfitvalue (> 80 %) were docked on the co-crystal structure of CDK2 (PDB Id: 1AQ1) to predict binding orientation of drug candidates onto the receptor structure. Five molecules showed comparable/higher docking score but the virtual hit which consist of pyrimidine moiety showed same binding interactions with highest docking score as that of the 5-FU and hence pyrimidine core ring structure is considered for the further designing. Fourteen (14) novel substituted pyrimidine derivatives were designed and synthesized. Among them, compound (79) showed higher docking score with similar binding interaction as that of the ATP and 5-FU. It also showed drug likeliness in OSIRIS property explorer. Fourteen synthesized compounds were taken for in-vitro analysis on A-375 skin cancer cell line. (79) was also found to be potent. Based on the docking study and in-vitro cell line study, (79) was selected for further in vivo study in DMBA and croton oil induced skin cancer. It was found that treatment with compound (79) showed favourable action against skin cancer and treated the tumours. The designed series can further modified to discover novel lead for the treatment of skin cancer.