Synthesis and Evaluation of Strychnos Alkaloids as MDR Reversal Agents for Cancer Cell Eradication
BIOTECHNOLOGY HIGH PERFORMANCE COMPUTING SOFTWARE APPLICATIONS INST FREDERICK MD
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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.
- Organic Chemistry