Synthesis, Cytotoxicity Evaluation and Molecular Docking Studies of Xanthyl-Cinnamate Derivatives as Potential Anticancer Agents

Abstract

A new series of xanthyl-cinnamate hybrid compounds (4a-d) have been synthesized and screened through in vitro assay against four human cancer cell lines, i.e., HeLa, T47D, A549, and WiDr. The results revealed that xanthone hybridization with cinnamic acid increases the selectivity of the compounds with SI values of 2.75–209.03 compared to its parent oxygenated-xanthone. Compound 1,3-dihydroxyxanthen-6-yl cinnamate (4c) showed high cytotoxic activity against WiDr cell lines with an IC50 value of 39.57 µM. Molecular docking studies revealed the possible binding modes of all hybrid compounds with EGFR protein. A complex of 3,6-dihydroxyxanthen-1-yl cinnamate (4d)-EGFR, as the best binding model, exhibited higher predicted EGFR inhibitory activity than erlotinib and oxygenated-xanthone with a ΔG and Ki value of -35.02 kJ/mol and 0.74 µM, respectively. Compounds 4c and 4d were chosen as the most potent derivates from the study.

Molecular Docking and Molecular Dynamic Investigations of Xanthone-Chalcone Derivatives against Epidermal Growth Factor Receptor for Preliminary Discovery of Novel Anticancer Agent

“…Molecular hybridization of chalcone with other structures, such as benzimidazole and carbazole, as well as molecular hybridization of xanthone with pyran, cinnamate, and acridone carboxamides, have been reported. It was found that the hybrid compounds gave stronger anticancer and antiproliferative activities than the individual structures, revealing a synergistic effect on molecular hybridization due to multiple non-covalent interactions that could be made with the cancer cells' receptors [35][36][37][38][39]. In light of the above findings, a molecular hybridization of xanthone and chalcone could yield novel anticancer agents to be developed in the future.…”

Evaluation of The Anticancer Activity of Hydroxyxanthones Against Human Liver Carcinoma Cell Line

“…Their chemical structures are shown in Figure 1(a). However, the isolation of natural xanthones is laborious work as the isolation yield sometimes does not exceed 0.1% [20].…”

“…[20][21][22].Either 1,3,6,7-tetrahydroxyxanthone (IC 50 = 23.7 μM) or 1,3,6,8-tetrahydroxyxanthone (IC 50 = 9.18 μM) or 1,3,4,5,6-pentahydroxyxanthone (IC 50 = 12.6 μM) exhibit stronger anticancer activity than xanthone with no hydroxyl group (IC 50 = 85.3 μM), 1hydroxyxanthone (IC 50 = 43.2 μM), 3hydroxyxanthone (IC 50 = 85.3 μM), 1,3dihydroxyxanthone (IC 50 = 71.4 μM), and 1,3,6trihydroxyxanthone (IC 50 = 45.9 μM). The 1,3,6,7tetrahydroxyxanthone (IC 50 = 23.7 μM) gave weaker anticancer activity against HepG2 cancer cell line than 1,3,6,8-tetrahydroxyxanthone (IC 50 = 9.18 μM) due to the presence of 7-hydroxyl which was inactive as aforementioned above.…”