High-affinity binding of silybin derivatives to the nucleotide-binding domain of a Leishmania tropica P-glycoprotein-like transporter and chemosensitization of a multidrug-resistant parasite to daunomycin

In order to overcome the multidrug resistance mediated by P-glycoprotein-li ke transporters in Leishmania spp., we have studied the effects produced by derivatives of the flavanolignan silybin and related compounds lacking the monolignol unit on (i) the affinity of binding to a recombinant C-terminal nucleotide-binding domain of the L. tropica P-glycoprotein-like transporte r and (ii) the sensitization to daunomycin on promastigote forms of a multi drug-resistant L. tropica line overexpressing the transporter. Oxidation of the flavanonol silybin to the corresponding flavonol dehydrosilybin, the p resence of the monolignol unit, and the addition of a hydrophobic substitue nt such as dimethylallyl, especially at position 8 of ring A, considerably increased the binding affinity. The in vitro binding affinity of these comp ounds for the recombinant cytosolic domain correlated with their modulation of drug resistance phenotype. In particular, 8-(3,3-dimethylallyl)-dehydro silybin effectively sensitized multidrug-resistant Leishmania spp. to dauno mycin. The cytosolic domains are therefore attractive targets for the ratio nal design of inhibitors against P-glycoprotein-like transporters.