2. Academic Validation
  3. Unraveling the interaction of pyranocoumarins with P-glycoprotein: Implications for overcoming multidrug resistance in cancer therapy

Unraveling the interaction of pyranocoumarins with P-glycoprotein: Implications for overcoming multidrug resistance in cancer therapy

  • Bioorg Chem. 2025 May:158:108314. doi: 10.1016/j.bioorg.2025.108314.
Mohamed H Helal 1,  Mosa H Alsehli 2,  Al-Anood M Al-Dies 3,  Ziad Moussa 4,  Walid E Elgammal 5,  Ahmed H Halawa 5,  Ahmed A Elhenawy 6,  Ahmed M El-Agrody 7
Affiliations

Affiliations

  • 1 Center for Scientific Research and Entrepreneurship, Northern, Border University, Arar 73213, Saudi Arabia.
  • 2 Chemistry Department, College of Science, Taibah University, Medina 30002, Saudi Arabia.
  • 3 Chemistry Department, Umm Al-Qura University, Al-Qunfudah University College, Al-Qunfudah 21912, Saudi Arabia.
  • 4 Department of Chemistry, College of Science, United Arab Emirates University, P. O. Box 15551, Al Ain, United Arab Emirates.
  • 5 Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City 11884, Cairo, Egypt.
  • 6 Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City 11884, Cairo, Egypt.; Al-Baha University, Faculty of Sciences, Department of Chemistry, Saudi Arabia.. Electronic address: elhenawy_sci@hotmail.com.
  • 7 Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City 11884, Cairo, Egypt.. Electronic address: elagrody_am@azhar.edu.eg.
PMID: 40058220 DOI: 10.1016/j.bioorg.2025.108314
Abstract

This study aimed to investigate the antiproliferative activity and P-glycoprotein (P-gp) inhibitory potential of a series of novel pyranocoumarin derivatives. Compounds 4a-c and 4f-i showed the most potent activity against MCF-7 (breast Cancer), MCF-7/ADR (human breast Cancer cell) resistant to Adriamycin (ADR), and Caco-2 (colon carcinoma) cell lines compared to Sorafenib and Doxorubicin, while all the compounds 4a-i demonstrated week growth inhibitory impact toward two normal cell lines, HFL-1 and WI-38 with IC50 values between 56.5 and 81.8 μM. Compounds 4b, 4g, and 4h, featuring trifluoromethyl, ethoxy, and benzyloxy substituents, demonstrated significant efficacy against P-glycoprotein-mediated multidrug resistance in MCF-7/ADR cells, with IC50 values between 15.88 and 21.96 μM, outperforming Doxorubicin (IC50 = 50.9 μM). Flow cytometric efflux assays confirmed increased intracellular accumulation of Rho123 in MCF-7/ADR cells treated with pyranocoumarin derivatives (4g, 4h). Mechanistic studies, including molecular docking and molecular dynamic (MD), leading to inhibition of P-glycoprotein (P-gp) function. Compound 4h exhibited the strongest binding affinity, and molecular dynamics simulations of the 4h-4ASD complex indicated a stable association with the binding site. These findings enhance our understanding of the binding mechanisms and potential functional implications of compound 4h's inhibition of P-glycoprotein.

Keywords

Antitumor activity; Molecular docking; Molecular dynamic; P-glycoprotein; Pyranocoumarin; Rhodamine 123 accumulation assay.

Figures
Products