Simplified Derivatives of Tetrandrine as Potent and Specific P‑gp Inhibitors to Reverse Multidrug Resistance in Cancer Chemotherapy

Targeted inhibition of a drug efflux transporter P-glycoprotein
(P-gp) is an important strategy to reverse multidrug resistance in
cancer chemotherapy. In this study, a rationally structural simplification
to natural tetrandrine was performed based on molecular dynamics simulation
and fragment growth, leading to an easily prepared, novel, and simplified
compound OY-101 with high reversal activity and low cytotoxicity.
Its excellent synergistic anti-cancer effect with vincristine (VCR)
against drug-resistant cells Eca109/VCR was confirmed by reversal
activity assay, flow cytometry, plate clone formation assay, and drug
synergism analysis (IC50 = 9.9 nM, RF = 690). Further mechanism
study confirmed that the OY-101 was a specific and efficient
P-gp inhibitor. Importantly, OY-101 increased VCR sensitization in vivo without obvious toxicity. Overall, our findings
may provide an alternative strategy for the design of novel specific
P-gp inhibitor as an anti-tumor chemotherapy sensitizer.