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Combretastatin A4-based coumarins: synthesis, anticancer, oxidative stress-relieving, anti-inflammatory, biosafety, and in silico analysis

Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq

E-mail: Dr.yassermustafa@uomosul.edu.iq

Received: 9 October 2023 Accepted: 23 January 2024

Abstract:

A potent natural combretastatin, combretastatin A-4 (COMA4) targets the condylon active pocket to produce anticancer effects. Studies on inflammation and oxidative stress have been linked to cancer, indicating that lowering these risk variables may have an adverse effect on the progression of cancer. This study utilized COMA4 as a building block to create 28 coumarins with improved therapeutic effects. The first coumarin derivative, COMA4-COU-1, was activated by thionyl chloride and then coupled with various phenols, resulting in 27 COMA4-COU derivatives. Biomedical-related activities were conducted using COMA4 as a reference, including anticancer activity assayed against eight cancerous cellular populations, antioxidant activity evaluated on H₂O₂-treated human SH-SY5Y populations, and anti-inflammatory activity tested against three enzymatic mediators of inflammation. The biosafety studies included testing the effects of COMA4 and its coumarins on the normal growth of three cell populations and on human erythrocyte hemolysis. Finally, the pharmacokinetic indexes of the building block and its derivatives were computerized using two web-based programs. The results indicated that the biomedical activities are directly improved by the presence of an electron-donating group on the off-side aromatic ring. Also, these activities were increased when this group substituted at the para or meta position. The maximum activities were revealed when this aromatic ring was trisubstituted with this group type, with privilege activities for the trimethoxy aromatic ring. Concerning the biocompatibility studies, the synthetic coumarins demonstrated a high level of compatibility with the tested normal cells and also with human erythrocytes. Moreover, the in silico analysis demonstrated the capacity of the synthetic coumarins to present potential drug candidates. The author concluded that the coumarin-structural modification can open the door for developing new, potent, and biosafe COMA4 derivatives. In this regard, this study afforded many insights about the structure–function relationships of the synthesized compounds that can guide future research about COMA4-based derivatives.

Keywords: Anticancer; Anti-inflammatory; Antioxidant; Biosafety; Combretastatin A-4; Coumarin; In silico study

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-024-03341-5

Chemical Papers 78 (6) 3705–3720 (2024)