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

Semisynthetic modifications of natural products havebestowed uswith many anticancer drugs. In the present work, a natural product,eugenol, has been modified synthetically to generate new anticanceragents. The final compounds were structurally confirmed by NMR, IR,and mass techniques. From the cytotoxicity results, compound 17 bearing morpholine was found to be the most active cytotoxicagent with IC50 1.71 (MCF-7), 1.84 (SKOV3), and 1.1 mu M(PC-3) and a thymidylate synthase (TS) inhibitor with an IC50 of 0.81 mu M. Further cellular studies showed that compound 17 could induce apoptosis and arrest the cell cycle at theS phase in PC-3 carcinoma. The docking study strongly favors compound 17 to be a TS inhibitor as it displayed a similar interactionto 5-fluorouracil. The in silico pharmacokinetics and DFT computationalstudies support the results obtained from docking and biological evaluationand displayed favorable pharmacokinetic profile for a drug to be orallyavailable. Compound 17 was found to be a promising TSinhibitor which could suppress DNA synthesis and consequently DNAdamage in prostate cancer cells.