Design, Synthesis and Biological Evaluation of Novel Chalcone Analogs as Potential Therapeutic Agents for Castration-Resistant Prostate Cancer

Prostate cancer (PCa) is the second most frequently diagnosed malignancy, as well as a leading cause of cancer-related mortality in men globally. Despite the initial response to hormone targeted therapy, the majority of patients ultimately progress to a lethal form of the disease, termed as castration-resistant prostate cancer (CRPC), which currently lacks curative therapeutic options and is associated with poor prognosis. Therefore, the development of alternative treatments for PCa is urgently needed. Chalcones, also known as 1,3-diphenyl-2-propen-1-ones, are among the highly attractive scaffolds being investigated for their antitumor activities. Three series of 18 cyclic (tetralone-based) and two acyclic chalcone analogs, in which ring B was either substituted with nitrogen mustard or replaced by pyrrole or pyridine heterocyclic rings, were designed, synthesized and evaluated as potential therapies for CRPC. Compounds were synthesized by Claisen-Schmidt condensation reaction, purified using column-chromatography or recrystallization, and characterized by 1H-NMR, 13C-NMR and LC-MS. The compounds' in-vitro cytotoxicity was evaluated against three prostate cancer cell lines (PC3, DU145, and LNCaP). Among the tested compounds, OH14, OH19 and OH22 showed potent antiproliferative activities at low micromolar levels with IC50 values ranging between 4.4 and 10 M against PC3 and DU145 cell lines. Detailed biological studies of the lead molecule OH19 revealed that it significantly induced apoptosis through upregulation of Bax and downregulation of BCL-2. In addition, OH19 potently inhibited colony formation and reduced cell migration of androgen independent PCa cell lines (PC3 and DU145). Mechanistically, the anticancer activity of OH19 was associated with attenuation in the phosphorylation of Akt and ERK. Furthermore, OH19 inhibited blood vessel formation in the chick chorioallantoic membrane (CAM) model as compared to control. These results indicate that OH19 could serve a potential promising lead molecule for the treatment of CRPC and thus, further in-vitro and in-vivo testing is warrante