2. Academic Validation
  3. Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein

Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein

  • Sci Rep. 2024 Jan 2;14(1):70. doi: 10.1038/s41598-023-49939-9.
Jerónimo Laiolo # 1,  Dafni G Graikioti # 2,  Cecilia L Barbieri 3,  Mariana B Joray 4,  Antonia I Antoniou 2,  D Mariano A Vera 5,  Constantinos M Athanassopoulos 6,  María C Carpinella 7
Affiliations

Affiliations

  • 1 Fine Chemical and Natural Products Laboratory, IRNASUS CONICET-UCC, Universidad Católica de Córdoba, Córdoba, Argentina.
  • 2 Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, 26504, Patras, Greece.
  • 3 Department of Chemistry and Biochemistry, College of Exact and Natural Sciences, Universidad Nacional de Mar del Plata - QUIAMM - INBIOTEC CONICET, Mar del Plata, Argentina.
  • 4 Fine Chemical and Natural Products Laboratory, IRNASUS CONICET-UCC and CIDIE CONICET-UCC, Universidad Católica de Córdoba, Córdoba, Argentina.
  • 5 Department of Chemistry and Biochemistry, College of Exact and Natural Sciences, Universidad Nacional de Mar del Plata - QUIAMM - INBIOTEC CONICET, Mar del Plata, Argentina. dmavera@yahoo.com.
  • 6 Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, 26504, Patras, Greece. kath@upatras.gr.
  • 7 Fine Chemical and Natural Products Laboratory, IRNASUS CONICET-UCC and CIDIE CONICET-UCC, Universidad Católica de Córdoba, Córdoba, Argentina. ceciliacarpinella@ucc.edu.ar.
  • # Contributed equally.
PMID: 38167542 DOI: 10.1038/s41598-023-49939-9
Abstract

Chemotherapy is a powerful means of Cancer treatment but its efficacy is compromised by the emergence of multidrug resistance (MDR), mainly linked to the efflux transporter ABCB1/P-glycoprotein (P-gp). Based on the chemical structure of betulin, identified in our previous work as an effective modulator of the P-gp function, a series of analogs were designed, synthesized and evaluated as a source of novel inhibitors. Compounds 6g and 6i inhibited rhodamine 123 efflux in the P-gp overexpressed leukemia cells, K562/Dox, at concentrations of 0.19 µM and 0.39 µM, respectively, and increased the intracellular accumulation of doxorubicin at the submicromolar concentration of 0.098 µM. Compounds 6g and 6i were able to restore the sensitivity of K562/Dox to Dox at 0.024 µM and 0.19 µM, respectively. Structure-activity relationship analysis and molecular modeling revealed important information about the structural features conferring activity. All the active compounds fitted in a specific region involving mainly transmembrane helices (TMH) 4-6 from one homologous half and TMH 7 and 12 from the other, also showing close contacts with TMH 6 and 12. Compounds that bound preferentially to another region were inactive, regardless of their free energy of binding. It should be noted that compounds 6g and 6i were devoid of toxic effects against peripheral blood mononuclear normal cells and erythrocytes. The data obtained indicates that both compounds might be proposed as scaffolds for obtaining promising P-gp inhibitors for overcoming MDR.

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