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Original Article

Design, Synthesis and In-Silico Studies of Novel Chalcones as Anti-Prostate Cancer and Cathepsin B Inhibitors

Dalia Hussein Soliman, Amel Mostafa Farrag, Ola Omran.

The high mortality rate in prostate cancer patients could be mainly attributed to the invasiveness and metastasis of advanced prostate cancer. Cathepsin B, a lysosomal cysteine, that proved to play a significant role in the invasion and metastasis of prostate cancer, therefore, the search for selective cathepsin B inhibitors could be considered an active area of research. Chalcones have proved to be effective anticancer agents against most human malignancies, they have also been reported to exhibit significant cathepsin B inhibition. In the present study, a series of novel N-(4-3-(pheny)-1-prop-2-en-1-one phenyl)benzamide derivatives (5a-p) were synthesized, characterized and evaluated for their anti-prostate cancer activities against PC-3 prostate adenocarcinoma cell line using the SRB method. The cathepsin B inhibition potential was further tested by the using enzyme-linked immunosorbent assay. Moreover, a pharmacophore model was constructed, a QSAR study was carried out where a model was successfully built from which the physicochemical parameters were correlated to the activity. Furthermore, molecular docking studies were also carried out to determine the binding mode of the active compounds into the active site of Cathepsin B enzyme. The furyl derivative 5p was the most active candidate, (IC50 = 5.597 μΜ), against prostate cancer cell line, PC-3. This derivative also demonstrated 50.4% reduction in concentration of cathepsin B, additionally, compounds 5b and 5m showed 53.2 and 56.6% reduction in concentration of cathepsin B, respectively. In conclusion, compounds 5b, 5m and 5p showed good activity both as antiproliferative and as inhibitors of Cathepsin B production. The developed QSAR model was found statistically significant and has good predictive power. Docking studies of the active derivatives maintained the essential key interactions, specially with the cysteine residue, Cys29.

Key words: prostate cancer; cathepsin B; chalcones.

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