Exploring the Gallic and Cinnamic Acids Chimeric Derivatives as Anticancer Agents over HeLa Cell Line: An in silico and in vitro Study

Abstract

Cervical cancer is one of the most aggressive and important cancer types in the female population, due to its low survival rate. Actually, the search for new bioactive compounds, like gallic and cinnamic acid, is one of the most employed options to finding a treatment. In the present study, 134 phenolic compounds with cytotoxic activity over HeLa cell line were used to generate a descriptive ( $R^2$ =0.76) and predictive ( $Q^2$ =0.69 and $Q_{ext}^2$ =0.62) QSAR model. Structural, electronic, steric, and hydrophobic features are represented as different molecular descriptors in our QSAR model. From this model, nine gallate-cinnamate ester derivatives (N1-N9) were designed and synthesized. Furthermore, in vitro cytotoxic activity was evaluated against HeLa and non-tumorigenic cells. Derivatives N6, N5, N1, and N9 were the most active molecules with IC_50ExpHeLa values from 7.26 to 11.95 μM. Finally, the binding of the synthesized compounds to the colchicine binding site on tubulin was evaluated by molecular docking as a possible action mechanism. N1, N5 and N6 can be considered as templates for the design of new cervical anticancer compounds.

Keywords: Gallic Acid; HeLa cell line; QSAR; anticancer; chimeric drugs; cinnamic acid; molecular docking; tubulin.