Synthesis and Anticancer Activity of Novel Derivatives of a,β-Unsaturated Ketones Based on Oleanolic Acid: <i>in Vitro</i> and <i>in Silico</i> Studies against Prostate Cancer Cells

Herein, new derivatives of a,ss-unsaturated ketones based on oleanolic acid (4a-i) were designed, synthesized, characterized, and tested against human prostate cancer (PC3). According to the in vitro cytotoxic study, title compounds (4a-i) showed significantly lower toxicity toward healthy cells (HUVEC) in comparison with the reference drug doxorubicin. The compounds with the lowest IC50 values on PC3 cell lines were 4b (7.785 mu M), 4c (8.869 mu M), and 4e (8.765 mu M). The results of the ADME calculations showed that the drug-likeness parameters were within the defined ranges according to Lipinski's and Jorgensen's rules. For the most potent compounds 4b, 4c, and 4e, a molecular docking analysis using the induced fit docking (IFD) protocol was performed against three protein targets (PARP, PI3K, and mTOR). Based on the IFD scores, compound 4b had the highest calculated affinity for PARP1, while compound 4c had higher affinities for mTOR and PI3K. The MM-GBSA calculations showed that the most potent compounds had high binding affinities and formed stable complexes with the protein targets. Finally, a 50 ns molecular dynamics simulation was performed to study the behavior of protein target complexes under in silico physiological conditions.