Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 24, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/ijms24108875
Keywords
amino acid; antitumor; cancer; docking; ursolic acid
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A series of new derivatives of ursolic acid (UA) were designed and synthesized by substituting various amino acids (AAs) or dipeptides (DP) at the C-3 position of the steroid skeleton. These conjugates exhibited cytotoxic activity against hormone-dependent and triple-negative breast cancer cells. Mechanistic studies revealed the activation of apoptotic pathways for some compounds and the induction of autophagy for others. Additionally, the synthesized compounds showed potential as anticancer agents based on their ADME properties and molecular docking to the estrogen receptor.
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 (l-seryloxy-, l-prolyloxy- and l-alanyl-l-isoleucyloxy-) showed micromolar IC50 values and reduced the concentrations of matrix metalloproteinases 2 and 9. Further studies revealed that for two compounds (l-seryloxy- and l-alanyl-l-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 (l-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-a 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.
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