Design, synthesis and biological evaluation of novel chalcone analogs against castration-resistant prostate cancer

Prostate cancer (PCa) is one of the most frequent malignancies in men worldwide. To date, significant progress has been made in PCa treatment; however, many patients eventually develop castration-resistant prostate cancer (CRPC), a lethal form of the disease that lacks curative therapies and is associated with poor survival. Chalcones are valuable compounds with diverse biological effects, including anticancer activity. We herein present novel chalcone analogs as potential therapy for CRPC. A library of 16 novel cyclic or acyclic chalcones was designed and synthesized, incorporating substituted heterocyclic rings (pyrrole or pyridine) or nitrogen mustard. Notably, thienyl-pyridine-containing analogs (OH13, OH15, OH16) showed potent cytotoxic activity, with IC₅₀ values ranging from 4.32 to 6.47 µM against androgen receptor-negative PCa cell lines (PC3 and DU145). Compound OH16 potently suppressed colony formation and inhibited cell migration at 5 and 10 µM treatment concentrations. Additionally, OH16 effectively induced apoptosis, as evidenced by increased cleavage of Caspase-3 and PARP. The antiproliferative activity of compound OH16 is associated with the suppression of the ERK1/2 and Akt signaling pathways. Moreover, OH16 exhibited anti-angiogenic activity using the chorioallantoic membrane (CAM) of the chicken embryo model. Structure-activity relationship analysis of the synthesized analogs demonstrated that the tetralone ring is detrimental to activity, while the presence of the thienyl-pyridine ring highly enhances potency. Additionally, in silico ADMET screening showed that OH16 exhibits favorable predicted drug-likeness properties. These findings suggest that thienyl-pyridine-based chalcones may serve as promising lead compounds against CRPC; thus, further in vitro and in vivo studies are warranted.