Potent and Nontoxic Chemosensitizer of P‑Glycoprotein-Mediated Multidrug Resistance in Cancer: Synthesis and Evaluation of Methylated Epigallocatechin, Gallocatechin, and Dihydromyricetin Derivatives

We
are interested in developing novel natural product-derived P-gp inhibitors
to reverse cancer drug resistance. Here, we have synthesized 55 novel
derivatives of methylated epigallocatechin (EGC), gallocatechin (GC),
and dihydromyricetin (DHM). Three EGC derivatives (23, 35, and 36) and three GC derivatives
(50, 51, and 53) are significantly
better than epigallocatechin gallate (EGCG) with a relative fold (RF)
ranging from 31.4 to 53.6. The effective concentration (EC50) of 23 and 51 ranges from 102 to 195 nM.
Compounds 23 and 51 are noncytotoxic to
fibroblasts with IC50 > 100 μM. Compound 23 is specific for P-gp without modulating activity toward
MRP1 or BCRP. Compounds 23 and 51 are non-P-gp
substrates. Important pharmacophores for P-gp modulation were identified.
In summary, methylated EGC and GC derivatives represent a new class
of potent, specific, noncytotoxic, and nonsubstrate P-gp modulators.