Synthesis and in vitro Activity of Eugenyl Benzoate Derivatives as BCL-2 Inhibitor in Colorectal Cancer with QSAR and Molecular Docking Approach

Objective: This study is aimed to acquiring new compounds of Eugenyl benzoate (2-methoxy-4-(prop-2-en-1-yl) phenyl benzoate) derivatives that can inhibit HT29 colorectal cancer cells. Methods: In this research, we used several chemical reactions to synthesize novel compounds, such as Esterification, Demethylation, Halohydrin, and Sharpless reaction. Cytotoxicity assays were performed to test the inhibitory activity of compounds against HT29 colon cancer cells. QSAR analysis were carried out to analyse the relationship of chemical structure of the novel compounds with their cytotoxic activity. Result: Ten novel compounds were successfully synthesized and tested in vitro against the HT29 cell. The IC₅₀ of the novel compounds were between 26.56 μmol/ml - 286.81 μmol/ml which compound 4-[(2S)-2,3-dihydroxypropyl]-2-methoxyphenyl 2-hydroxybenzoate (9) showed as best active compound as BCL-2 inhibitors better than other synthesized compounds and Eugenol as well. QSAR analysis of the in vitro results gave a Log equation: 1/IC₅₀ = -0.865-0.210 (LogP)² + 1,264 (logP)-0.994 CMR (n = 10; r = 0.706; SE: 0.21; F = 0.497, sig = 7.86). The equation shows the log variable P and CMR affect IC₅₀. The properties of hydrophobicity (log P) are more instrumental than the ones of steric (CMR). Conclusion: The active compound (9) given best activities as BCL-2 inhibitors than other eugenol derivatives. QSAR indicates the logP and CMR have effect on its colorectal cytotoxic activity which the hydrophobicity parameter (logP) plays more role than the steric parameter (CMR).