Synthesis, Biological Activity, ADME and Molecular Docking Studies of Novel Ursolic Acid Derivatives as Potent Anticancer Agents

oleh: Olga Michalak, Marcin Cybulski, Wojciech Szymanowski, Agnieszka Gornowicz, Marek Kubiszewski, Kinga Ostrowska, Piotr Krzeczyński, Krzysztof Bielawski, Bartosz Trzaskowski, Anna Bielawska

Format: Article
Diterbitkan: MDPI AG 2023-05-01

Deskripsi

A series of new ursolic acid (UA) derivatives substituted with various amino acids (AAs) or dipeptides (DP) at the C-3 position of the steroid skeleton was designed and synthesized. The compounds were obtained by the esterification of UA with the corresponding AAs. The cytotoxic activity of the synthesized conjugates was determined using the hormone-dependent breast cancer cell line MCF-7 and the triple-negative breast cancer cell line MDA. Three derivatives (<i><span style="font-variant: small-caps;">l</span></i>-seryloxy-, <i><span style="font-variant: small-caps;">l</span></i>-prolyloxy- and <i><span style="font-variant: small-caps;">l</span></i>-alanyl-<i><span style="font-variant: small-caps;">l</span></i>-isoleucyloxy-) showed micromolar IC<sub>50</sub> values and reduced the concentrations of matrix metalloproteinases 2 and 9. Further studies revealed that for two compounds (<i><span style="font-variant: small-caps;">l</span></i>-seryloxy- and <i><span style="font-variant: small-caps;">l</span></i>-alanyl-<i><span style="font-variant: small-caps;">l</span></i>-isoleucyloxy-), a possible mechanism of their antiproliferative action is the activation of caspase-7 and the proapoptotic Bax protein in the apoptotic pathway. The third compound (<i><span style="font-variant: small-caps;">l</span></i>-prolyloxy- derivative) showed a different mechanism of action as it induced autophagy as measured by an increase in the concentrations of three autophagy markers: LC3A, LC3B, and beclin-1. This derivative also showed statistically significant inhibition of the proinflammatory cytokines TNF-α and IL-6. Finally, for all synthesized compounds, we computationally predicted their ADME properties as well as performed molecular docking to the estrogen receptor to assess their potential for further development as anticancer agents.