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

Syed Nazreen; Serag Eldin I Elbehairi; Azizah M Malebari; Nuha Alghamdi; Reem F Alshehri; Ali A Shati; Nada M Ali; Mohammad Y Alfaifi; Ahmed A Elhenawy; Mohammad Mahboob Alam

doi:10.1021/acsomega.3c00933

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

ACS Omega. 2023 May 15;8(21):18811-18822. doi: 10.1021/acsomega.3c00933. eCollection 2023 May 30.

Authors

Affiliations

¹ Department of Chemistry, Faculty of Science, Al-Baha University, Al-Baha 65799, Kingdom of Saudi Arabia.
² Department of Biology, Faculty of Science, King Khalid University, Abha 9004, Saudi Arabia.
³ Cell Culture Laboratory, Egyptian Organization for Biological Products and Vaccines, VACSERA Holding Company, Giza 2311, Egypt.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia.
⁵ Chemistry Department, Faculty of Science and Art, Taibah University, Al Ula, Madinah 16857, Kingdom of Saudi Arabia.
⁶ Chemistry Department, Faculty of Science, Al-Azhar Unuversity, 11884 Nasr City, Cairo 11751, Egypt.

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 17 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 17 could induce apoptosis and arrest the cell cycle at the S phase in PC-3 carcinoma. The docking study strongly favors compound 17 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 17 was found to be a promising TS inhibitor which could suppress DNA synthesis and consequently DNA damage in prostate cancer cells.