“Molecular Modeling, Synthesis and Anticancer Activity of Pyrazolo-Triazine Derivatives”

Abstract

Cancer represents a pathological manifestation of uncontrolled cell division leading to uncontrolled proliferative growth and the spread of aberrant cells from their site of origin. There were many pieces of evidence to support that the inhibition of CDKs could play vital role in suppressing cancer. Human kinome is constituted by a total of 518 kinases out of which 388 are serine/threonine (Ser/Thr) kinases. 20 of these Ser/Thr kinases are further classified as Cyclin-dependent kinase (CDK). CDK2 is a member of protein kinase family. It plays an important role in regulating various events of eukaryotic cell division cycle. Accumulated evidences indicated that over expression of CDK2 should cause the abnormal regulation of cell-cycle. Therefore, CDK2 was regarded as a potentially therapeutic target for cancer therapy. Among the ten pharmacological inhibitors of CDK2 are currently in clinical trials, a potent CDK2 inhibitor with purine scaffold has been synthesized, such as roscovitine (Seliciclib®) which undergoing phase 2 trials against non-small cell lung (NSCL) and nasopharyngeal cancers. The aim of this study was designed to generate more potent analogues of roscovitine. In this work, a series of pyrazolo[1,5-a][1,3,5]triazine substituted with different amines was designed and synthesized in an attempt to improve inhibitory activity against CDK2/cyclinA. The design focused on exploration of the previous revealed SAR studies, bioisosteric modifications of the lead compound studies, and identification of the key interactions with the binding site. Synthesis of the designed compounds was t