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Vol. 61, Issue 3, 637-648, March 2002
Institutes of Medical Chemistry (P.C., S.K.), Pharmaceutical
Chemistry (G.E., B.P., W.H.), Applied Microbiology (W.E.), and the Mass
Spectrometry Unit (E.C.), University of Vienna, Austria
Energy dependent efflux pumps confer resistance to anticancer,
antimicrobial, and antiparasitic drugs. P-glycoprotein (Pgp, ABCB1)
mediates resistance to a broad spectrum of antitumor drugs. Compounds
that themselves are nontoxic to cells have been shown to act as
inhibitors of Pgp. The mechanism of binding and transport of
low-molecular-mass ligands by Pgp is still incompletely understood. This study introduces a series of propafenone-related photoaffinity ligands, which combine high specificity and selectivity for Pgp with
high labeling efficiency. Molecules are intrinsically photoactivatable in the arylcarbonyl group, which represents a pharmacophoric
substructure for this group of ligand molecules. A detailed study of
the structure-activity relationship for this type of photoligand is
presented. In subsequent experiments, these ligands were used to
characterize the drug-binding domain of propafenone-type analogs.
Matrix-assisted laser desorption/ionization
time-of-flight (MALDI-TOF)
mass spectrometry shows that propafenone-type ligands preferentially
label fragments assigned to putative transmembrane segments 3, 5, 6, 8, 10, 11, and 12. Labeled fragments are also identified in a highly
charged region of 15 amino acids in the second cytoplasmic loop. This
region corresponds to the so-called EAA-like motif, which has been
proposed to play a role in the interaction between transmembrane domain
and nucleotide binding domain of peroxisomal ATP-binding
cassette transporters. In addition, a region in cytoplasmic loop
3 and between TM12 and the N terminus of the Walker A sequence of NBD2
are labeled by the ligands. Therefore, a number of confined protein
regions contribute to the drug-binding domain of propafenone-type analogs.
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