Structural characteristics of compounds that modulate P-glycoprotein-associated multidrug resistance.
Multidrug resistance is mediated by a membrane-bound protein, P-gp, that functions as an energy dependent efflux system to reduce the intracellular concentration of anticancer drugs by binding to these drugs and actively exporting them from the cell. Compounds that interact with P-gp and compete with anticancer drug binding modulate the degree of drug resistance and therefore enhance the cytotoxicity of anticancer drugs against the resistant cell. Effective modulators share certain physical and chemical properties including octanol/water partitioning and molecular size, but the physical properties of size and shape seem to correlate best with modulator effectiveness. Using a photoactivatable analog of vinblastine as a probe, together with a semi-synthetic series of structurally homologous reserpine and yohimbine analogs, the need for two planar aromatic domains and a basic nitrogen atom was established within the structural context of these compounds. The use of three-dimensional comparisons was extended to examine important structural features in other modulator types such as the condensed-ring aromatics. This approach indicates that structural similarities between different classes of compounds are present in compounds recognized by the MDR phenotype. These studies emphasize the importance of a ligand-receptor relationship for modulators of MDR, and begin to define the P-gp-binding pharmacophore. It is likely that this approach will be useful in directing the de novo synthesis of compounds that modulate MDR and help to further define the requirements for molecular recognition by this system.
Pearce
H L
HL
Lilly Research Laboratories, Indianapolis, Indiana.
Winter
M A
MA
Beck
W T
WT
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D008958:Models, Molecular; D008961:Models, Structural; D008968:Molecular Conformation; D009363:Neoplasm Proteins / Q000502:physiology*; D011487:Protein Conformation; D012110:Reserpine / Q000031:analogs & derivatives / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects*; D014747:Vinblastine / Q000494:pharmacology*; D015016:Yohimbine / Q000031:analogs & derivatives / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D015016:Yohimbine; D014747:Vinblastine; D012110:Reserpine