Design, synthesis, and biological activity evaluation of photocaged cyclin-dependent kinase 2 inhibitors

This study aimed to design and synthesize a series of novel photocaged compounds based on the precise binding mode of cyclin-dependent kinase 2 (CDK2) inhibitor AT7519 with its target, to achieve precise optical control over molecular activity. Using AT7519 as the structural foundation, different types of photoremovable protecting groups were introduced at its key interaction sites (the NH of the pyrazole ring and the NH of the piperidine ring), resulting in the synthesis of eight dual-photocaged compounds. Their structures were confirmed by NMR and mass spectrometry, and their photochemical properties—including photolysis wavelength, photolysis time, and photolysis efficiency—were systematically evaluated. The optically controlled inhibitory effects of the compounds on HCT116 cell proliferation were assessed using MTT assay. The photoresponsive characteristics of the photocaged compounds were significantly influenced by the type of photoremovable protecting group and its introduction site. Among them, compounds 1a, 1b, and 2d exhibited excellent photolysis efficiency, each achieving a rate exceeding 90%. Particularly, compounds 1b and 2d demonstrated excellent optically controlled activity: under dark conditions, their half maximal inhibitory concentration (IC₅₀) values were both greater than 150 µmol/L, indicating negligible cell proliferation inhibitory activity; however, upon irradiation, their cell proliferation inhibitory activity significantly increased, with IC₅₀ values comparable to those of the positive control AT7519. The obtained compounds 1b and 2d possess excellent optically controlled properties, and can be further investigated as potential candidates for optically controlled CDK2 inhibitors.