Synthesis and Anticancer Activity of Novel Derivatives of α,β-Unsaturated Ketones Based on Oleanolic Acid: in Vitro and in Silico Studies against Prostate Cancer Cells.

Herein, new derivatives of α,β-unsaturated ketones based on oleanolic acid (4 a-i) were designed, synthesized, characterized, and tested against human prostate cancer (PC3). According to the in vitro cytotoxic study, title compounds (4 a-i) showed significantly lower toxicity toward healthy cells (HUVEC) in comparison with the reference drug doxorubicin. The compounds with the lowest IC values on PC3 cell lines were 4 b (7.785 μM), 4 c (8.869 μM), and 4 e (8.765 μM). 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 4 b, 4 c, and 4 e, 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 4 b had the highest calculated affinity for PARP1, while compound 4 c 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.