Synthesis and Evaluation of Strychnos Alkaloids as MDR Reversal Agents for Cancer Cell Eradication

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. Molec...

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Bibliographic Details
Main Authors: Munagala, Surendrachary, Sirasani, Gopal, Kokkonda, Praveen, Phadke, Manali, Krynetskaia, Natalia, Lu, Peihua, Sharom, Frances J, Chaudhury, Sidhartha, Abdulhameed, Mohamed D, Tawa, Gregory
Format: Report
Language:English
Subjects:
ABCB1
ASSAYING
Biology
CANCER
CANCER CELL ERADICATION
CELLS(BIOLOGY)
DOCKING
DRUGS
FLUORESCENCE
FLUORESCENCE QUENCHING
GLYCOPROTEINS
IN VITRO ANALYSIS
IN VITRO BINDING ASSAYS
IN VITRO PGP-ASSOCIATED ATPASE ASSAYS
INTERACTIONS
LIGAND-PROTEIN INTERACTIONS
LIGANDS
MDR REVERSAL AGENTS
MDR(MULTIDRUG RESISTANCE)
MOLECULAR MODELING
Organic Chemistry
PGP(P-GLYCOPROTEINS)
Pharmacology
QUENCHING(INHIBITION)
RECEPTOR SITES(PHYSIOLOGY)
RESENSITIZATION
RESISTANCE
STRYCHNOS ALKALOIDS
SYNTHESIS(CHEMISTRY)
TOTAL SYNTHESIS
VERAPAMIL
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Summary: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 = 4.4 lM), 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. Published in Bioorganic & Medicinal Chemistry, v22 p1148-1155, 2014. Prepared in cooperation with the Department of Chemistry, Temple University, Philadelphia, PA, the Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, and the Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada.