title: Metalloprobes: synthesis, characterization, and potency of a novel gallium(III) complex in human epidermal carcinoma cells.
abstract: Multidrug resistance (MDR) mediated by overexpression of the MDR1 gene product, P-glycoprotein (Pgp), represents one of the best characterized barriers to chemotherapeutic treatment in cancer and may be a pivotal factor in progression of Alzheimer's disease (AD). Thus, agents capable of probing Pgp-mediated transport could be beneficial in biomedical imaging. Herein, we synthesized and structurally characterized a gallium(III) complex (5) of the naphthol-Schiff base ligand. The crystal structure revealed octahedral geometry for the metallodrug. Cytotoxicity profiles of 5 were evaluated in KB-3-1 (Pgp-) and KB-8-5 (Pgp+) human epidermal carcinoma cell lines. Compared with an LC(50) (the half-maximal cytotoxic concentration) value of 1.93 microM in drug-sensitive (Pgp-) cells, the gallium(III) complex 5 demonstrated an LC(50) value>100 microM in drug-resistant (Pgp+) cells, thus indicating that 5 was recognized by the Pgp as its substrate, thereby extruded from the cells and sequestered away from their cytotoxic targets. Radiolabeled analogues of 5 could be beneficial in noninvasive imaging of Pgp-mediated transport in vivo.
authors.affiliation: Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University Medical School, Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO 63110, United States.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Harpstrite
authors.forename: Julie L
authors.initials: JL
authors.lastname: Prior
authors.forename: Nigam P
authors.initials: NP
authors.lastname: Rath
authors.forename: Vijay
authors.initials: V
authors.lastname: Sharma
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D045744:Cell Line, Tumor; D005708:Gallium / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008670:Metals / Q000737:chemistry*; D008958:Models, Molecular; D015335:Molecular Probes; D012878:Skin Neoplasms / Q000737:chemistry* / Q000473:pathology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008670:Metals; D015335:Molecular Probes; D005708:Gallium