Design, Synthesis and Evaluation of Fluorescent Dihydropyridine-Dihydropyrimidinone Hybrids as Inducer of Cell-Cycle Arrest in Prostate Cancer Cell Line via Aurora Kinase interactions

Abstract

The fluorescent Dihydropyridine-Dihydropyrimidinone (DHP-DHPM) hybrids were easily synthesized through the combination of Hantzsch and Biginelli multicomponent reactions followed by the Copper-Catalyzed Azide-Alkyne Cycloaddition reaction (CuAAC, Click Chemistry) protocol. Nine hybrids showed promising antitumor activity for prostate PC3 cancer cell line, notably compounds 9d and 9g. Both hybrids exhibited high selectivity for tumor cells, with significant selectivity indices (SI), particularly 9g (SI > 68.8). Selectivity was qualitatively observed by the internalization of fluorescent hybrid through high-resolution confocal laser scanning microscopy (CLSM). Investigations in silico and western blotting analysis showed a selective inhibition of the isoform C of Aurora Kinase by hybrid 9d. A mechanism of action including cell cycle arrest at the G0/G1 phase, inhibition of cell migration and invasion, and modulation of key signaling pathways such as MAPK, AKT, and mTOR are discussed.