Accession Number:

ADA598551

Title:

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

Descriptive Note:

Journal article

Corporate Author:

BIOTECHNOLOGY HIGH PERFORMANCE COMPUTING SOFTWARE APPLICATIONS INST FREDERICK MD

Report Date:

2014-01-01

Pagination or Media Count:

9.0

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 4.4 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.

Subject Categories:

  • Biology
  • Pharmacology
  • Organic Chemistry

Distribution Statement:

APPROVED FOR PUBLIC RELEASE