Design, synthesis and biological evaluation of novel artemisinin derivatives as potent P-glycoprotein modulators for overcoming multidrug resistance.
4 affiliations
- 1Universidad Católica de Córdoba Córdoba Argentina.
- 2Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras GR-26504 Patras Greece [email protected].
- 3Institute of Chemistry and Biochemistry, IQUIBIM, College of Exact and Natural Sciences, Universidad Nacional de Mar del Plata - QUIAMM - INBIOTEC CONICET Mar del Plata Argentina [email protected].
- 4Fine Chemical and Natural Products Laboratory, CIDIE CONICET-UCC, Universidad Católica de Córdoba Córdoba Argentina [email protected].
Abstract
Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp, ABCB1) remains a major obstacle to successful chemotherapy, underscoring the need for potent and safe agents capable of blocking P-gp function and restoring drug sensitivity. To address this challenge, we synthesized and systematically evaluated a library of novel artemisinin derivatives. Screening identified compounds A7, A12, A13, A14 and A15 as effective molecules, significantly reducing rhodamine 123 (Rho123) efflux at minimum effective concentrations (MECs) ranging from 0.19 to 6 µM. Notably, compounds A16 and A20 displayed the highest potency, with MECs as low as 0.049 µM. These derivatives also efficiently inhibited P-gp-mediated doxorubicin (Dox) efflux, with a MEC value of 0.19 µM for compound A16 and 0.049 µM for compound A20. Consistent with these findings, both compounds markedly enhanced Dox cytotoxicity by sensitizing K562/Dox cells at concentrations of 0.050 and 0.005 µM, respectively. Molecular dynamics simulations and multiscale QM/MM calculations yielded useful clues for understanding the binding modes of the derivatives and identified key structural determinants and key amino acid residues that would be involved in P-gp modulation. The potent P-gp-modulating activity of compounds A16 and A20, together with the absence of cytotoxicity toward normal PBMCs at the nanomolar concentrations at which they modulated P-gp activity, highlights these artemisinin derivatives as promising scaffolds for the development of novel P-gp modulators. Collectively, the computational and experimental findings provide mechanistic insights into P-gp inhibition and establish a framework for the rational design of artemisinin-based P-gp modulators.
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BibTeX
@article{laiolo2026design,
title = {{Design, synthesis and biological evaluation of novel artemisinin derivatives as potent P-glycoprotein modulators for overcoming multidrug resistance.}},
author = {Jerónimo Laiolo and Artemis Tsirogianni and Cecilia L Barbieri and Mariana Belén Joray and Dafni G Graikioti and Dimitra Toumpa and Jazmín Lavallén and Nicolás A Rodriguez and D Mariano A Vera and Constantinos M Athanassopoulos and María C Carpinella},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra07164c},
url = {https://europepmc.org/article/MED/42936332},
note = {CC BY},
}
RIS
TY - JOUR
TI - Design, synthesis and biological evaluation of novel artemisinin derivatives as potent P-glycoprotein modulators for overcoming multidrug resistance.
AU - Jerónimo Laiolo
AU - Artemis Tsirogianni
AU - Cecilia L Barbieri
AU - Mariana Belén Joray
AU - Dafni G Graikioti
AU - Dimitra Toumpa
AU - Jazmín Lavallén
AU - Nicolás A Rodriguez
AU - D Mariano A Vera
AU - Constantinos M Athanassopoulos
AU - María C Carpinella
PY - 2026
DA - 2026/10/26
JO - RSC advances
DO - 10.1039/d6ra07164c
UR - https://europepmc.org/article/MED/42936332
AB - Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp, ABCB1) remains a major obstacle to successful chemotherapy, underscoring the need for potent and safe agents capable of blocking P-gp function and restoring drug sensitivity. To address this challenge, we synthesized and systematically evaluated a library of novel artemisinin derivatives. Screening identified compounds A7, A12, A13, A14 and A15 as effective molecules, significantly reducing rhodamine 123 (Rho123) efflux at minimum effective concentrations (MECs) ranging from 0.19 to 6 µM. Notably, compounds A16 and A20 displayed the highest potency, with MECs as low as 0.049 µM. These derivatives also efficiently inhibited P-gp-mediated doxorubicin (Dox) efflux, with a MEC value of 0.19 µM for compound A16 and 0.049 µM for compound A20. Consistent with these findings, both compounds markedly enhanced Dox cytotoxicity by sensitizing K562/Dox cells at concentrations of 0.050 and 0.005 µM, respectively. Molecular dynamics simulations and multiscale QM/MM calculations yielded useful clues for understanding the binding modes of the derivatives and identified key structural determinants and key amino acid residues that would be involved in P-gp modulation. The potent P-gp-modulating activity of compounds A16 and A20, together with the absence of cytotoxicity toward normal PBMCs at the nanomolar concentrations at which they modulated P-gp activity, highlights these artemisinin derivatives as promising scaffolds for the development of novel P-gp modulators. Collectively, the computational and experimental findings provide mechanistic insights into P-gp inhibition and establish a framework for the rational design of artemisinin-based P-gp modulators.
SN - 2046-2069
ER -