TiO2 Nanoparticles Catalyzed Synthesis, Pharmacological Evaluation, and Molecular Docking Studies of New Pyrido[2,3-d]Pyrimidine Derivatives as CDK1 Inhibitors
摘要
Targeting cyclin-dependent kinases (CDKs) presents a promising approach to cancer therapy. Therefore, creating CDK inhibitors is crucial for effective cancer treatment. This study discloses the green synthesis of nine pyrido[2,3-d]pyrimidines derivatives 6–14 as CDK1 inhibitors by applying TiO2 nanoparticles as a catalyst. The structures of the reported compounds were verified using various techniques, including IR and NMR spectroscopy, as well as elemental analysis. The reported derivatives were assessed for their in vitro cytotoxicity against three human cancer cells (HCT-116, HepG2, and MCF-7) using LDH assay compared to doxorubicin as a reference. The results indicated that all nine compounds showed moderate activities against HepG2 human cancer cells and superior cytotoxic activities on HCT-116, while six compounds (namely, 12, 9, 14, 7, 13, and 11) demonstrated similar activities against MCF-7 human cancer cell type relative to that of doxorubicin. Additionally, the therapeutic potential of the reported derivatives was evaluated by determining their selectivity index (SI), which indicated their promise as candidates for human colon cancer drugs due to their higher SI compared to the reference drug. Furthermore, a molecular docking study was performed on the synthesized derivatives to study their binding affinities inside the active pocket of the CDK1 enzyme (PDB code: 6gu7) compared with the co-crystalized ligand. The results of the docking study aligned well with the cytotoxicity evaluations that were reflected by their high binding affinities (docking score = − 6.75 to − 8.94) towards the pocket of the CDK1 enzyme compared to the co-crystallized ligand (docking score = − 7.03). The outcomes of this study open new doors for designing additional pyrido[2,3-d]pyrimidines with potential anticancer activities.