| Tyrosine kinases regulate cell proliferation, survival, invasion and angiogenesis during tumor initiation and progression. The Abelson (ABL) family of protein kinases comprises ABL1 and ABL2, which link diverse extracellular stimuli to signaling pathways that control cell growth, survival, invasion, adhesion, and migration. Inhibition of ABLs has been implied in numerous types of hematopoietic malignancies and solid tumors. The pyrido[2,3- d]pyrimidin-7-one (I) structure has been identified as a privileged pharmacophore for the inhibitors of protein kinases. Drugs and drug candidates derived from this pharmacophore are represented by Parke-Davis compounds PD0332991, PD173955, and PD180970, of which PD0332991 was recently approved by FDA and marketed as PalbociclibRTM for the treatment of breast cancer. PD173955 and PD180970 are two well-known Bcr-Abl inhibitors. The synthesis of pyrido[2,3-d]pyrimidin-7-one analogs typically requires expensive starting materials that contains a pyrimidine ring, and involves a lengthy synthesis to build the pyridopyrimidinone core. Interestingly, the structure of pyrano[2,3-d]pyrimidin-7-one (II), which is a close structure of I, has not been extensively studied in synthetic chemistry and pharmacology. Hence, synthesized the pyrano[2,3- d]pyrimidin-7-one as a novel pharmacophore, and derived novel analogs. In this communication, will report synthesis, molecular modeling and pharmacological evaluation of these novel pyrano[2,3-d]pyrimidin-7-one against the ABL1 kinase. |
