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Synthesis and evaluation of Strychnos alkaloids as MDR reversal agents for cancer cell eradication.
Munagala, Surendrachary; Sirasani, Gopal; Kokkonda, Praveen; Phadke, Manali; Krynetskaia, Natalia; Lu, Peihua; Sharom, Frances J; Chaudhury, Sidhartha; Abdulhameed, Mohamed Diwan M; Tawa, Gregory; Wallqvist, Anders; Martinez, Rogelio; Childers, Wayne; Abou-Gharbia, Magid; Krynetskiy, Evgeny; Andrade, Rodrigo B.
Afiliación
  • Munagala S; Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
  • Sirasani G; Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
  • Kokkonda P; Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
  • Phadke M; Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19122, United States.
  • Krynetskaia N; Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19122, United States.
  • Lu P; Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
  • Sharom FJ; Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
  • Chaudhury S; Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, United States.
  • Abdulhameed MD; Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, United States.
  • Tawa G; Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, United States.
  • Wallqvist A; Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, United States.
  • Martinez R; Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19122, United States.
  • Childers W; Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19122, United States.
  • Abou-Gharbia M; Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19122, United States.
  • Krynetskiy E; Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19122, United States.
  • Andrade RB; Department of Chemistry, Temple University, Philadelphia, PA 19122, United States. Electronic address: randrade@temple.edu.
Bioorg Med Chem ; 22(3): 1148-55, 2014 Feb 01.
Article en En | MEDLINE | ID: mdl-24405813
ABSTRACT
Natural products represent the fourth generation of multidrug resistance (MDR) reversal agents that resensitize MDR cancer cells overexpressing P-glycoprotein (Pgp) to cytotoxic agents. We have developed an effective synthetic route to prepare various Strychnos alkaloids and their derivatives. Molecular modeling of these alkaloids docked to a homology model of Pgp was employed to optimize ligand-protein interactions and design analogues with increased affinity to Pgp. Moreover, the compounds were evaluated for their (1) binding affinity to Pgp by fluorescence quenching, and (2) MDR reversal activity using a panel of in vitro and cell-based assays and compared to verapamil, a known inhibitor of Pgp activity. Compound 7 revealed the highest affinity to Pgp of all Strychnos congeners (Kd=4.4µM), the strongest inhibition of Pgp ATPase activity, and the strongest MDR reversal effect in two Pgp-expressing cell lines. Altogether, our findings suggest the clinical potential of these synthesized compounds as viable Pgp modulators justifies further investigation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Resistencia a Antineoplásicos / Strychnos / Alcaloides / Antineoplásicos Fitogénicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Resistencia a Antineoplásicos / Strychnos / Alcaloides / Antineoplásicos Fitogénicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos
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