In order to find and develop new active compounds against prostate cancer, (–)-cleistenolide (1) and its 24 new analogs were evaluated for in vitro cytotoxic activity against PC-3 cell line and normal cell line (MRC-5). All tested compounds were in silico examined in order to predict their physicochemical properties, drug ability and ADME-Tox characteristics. Furthermore, the predictive 3D-QSAR model was constructed using Comparative Molecular Field Analysis method. The obtained results revealed that most potent antiproliferative activity against PC-3 cells had 4-methoxy cinnamate 12 (IC50 = 0.11 μM). This compound showed approximately 260-fold stronger antiproliferative activity than lead 1, but at the same time it demonstrated over 40-fold greater potency compared to the commercial antitumor agent cisplatin. The presence of an electron-donating group at the C-4' position in the 4,6-di-O-acetyl derivative 12, significantly increases its activity compared to both non-substituted analogs. Evaluation of structural features through predictive 3D-QSAR modelling identified steric field features at the aromatic ring of cinnamoyl group, as well as around the OAc group at the C-4 position. In silico ADME-Tox analysis suggests that most of the analyzed compounds, including the most potent one, have desirable ADME-Tox properties for drug candidates and high potential in drug development, which recommend them for further research in the treatment of prostate cancer. Furthermore, the obtained 3D-QSAR model is able to successfully identify (–)-cleistenolide analogs that have significant cytotoxic activity against PC-3 cell line and provide information essential for screening and designing new analogs capable of inhibiting the growth of prostate cancer cells.
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This work was supported by research grants from the Ministry of Education, Science and Technological Development of the Republic of Serbia (Contracts No. 451-03-68/2020-14/200125 and 451-03-9/2021-14/200134). This work has also received funding from the Serbian Academy of Sciences and Arts under Strategic projects programme (Grant agreement No. 01-2019-F65), as well as by a research project from the same institution (Grant No. F-130).
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Vukic, V.R., Vukic, D.V., Benedekovic, G. et al. (–)-cleistenolide and its Analogs as New Potential Antitumor Compounds Against PC-3 Cells. Pharm Chem J 56, 619–626 (2022). https://doi.org/10.1007/s11094-022-02686-z
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DOI: https://doi.org/10.1007/s11094-022-02686-z