New Natural Eugenol Derivatives as Antiproliferative Agents: Synthesis, Biological Evaluation, and Computational Studies

Abstract

Semisynthetic modifications of natural products have bestowed us with many anticancer drugs. In the present work, a natural product, eugenol, has been modified synthetically to generate new anticancer agents. The final compounds were structurally confirmed by NMR, IR, and mass techniques. From the cytotoxicity results, compound <b>17</b> bearing morpholine was found to be the most active cytotoxic agent with IC₅₀ 1.71 (MCF-7), 1.84 (SKOV3), and 1.1 μM (PC-3) and a thymidylate synthase (TS) inhibitor with an IC₅₀ of 0.81 μM. Further cellular studies showed that compound <b>17</b> could induce apoptosis and arrest the cell cycle at the S phase in PC-3 carcinoma. The docking study strongly favors compound <b>17</b> to be a TS inhibitor as it displayed a similar interaction to 5-fluorouracil. The in silico pharmacokinetics and DFT computational studies support the results obtained from docking and biological evaluation and displayed favorable pharmacokinetic profile for a drug to be orally available. Compound <b>17</b> was found to be a promising TS inhibitor which could suppress DNA synthesis and consequently DNA damage in prostate cancer cells.