title: Tolyporphin Macrocycles from the Cyanobacterium Tolypothrix nodosa Selectively Bind Copper and Silver and Reverse Multidrug Resistance.
abstract: Tolyporphins are glycosylated macrocycles isolated from lipophilic soil extracts of the cyanobacterium, Tolypothrix nodosa, and found to potentiate the cytotoxicity of antitumor drugs like vinblastine and adriamycin. Here we find that, unlike porphyrins, tolyporphins are not able to form complexes with most metal ions. However, they do react strongly with copper(II) and silver(II), forming square-planar metal complexes with an unpaired electron in a dx2-y2orbital of the metal delocalized onto the ligating tolyporphin nitrogen atoms. Complexes were characterized by visible absorption spectra, mass spectrometry (EI, FAB, ESI, LDI-TOF, and MALDI-TOF) and multifrequency continuous-wave electron paramagnetic resonance spectra. Copper(II) and silver(II) complexes of tolyporphins A and E were found to have the interesting property of reversing multidrug resistance (MDR), with the copper complexes being less toxic than free tolyporphins. Reactive oxygen-free radicals were implicated in both the cytotoxic and MDR-reversing effects of free and metalated tolyporphins.
authors.affiliation: Department of Chemistry, University of Waikato , Private Bag 3105, Hamilton 3240, New Zealand.
authors.forename: Michèle R
authors.identifier: http://orcid.org/0000-0001-6967-4642
authors.initials: MR
authors.lastname: Prinsep
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Appleton
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Hanson
authors.affiliation: Institute for Molecular Bioscience, University of Queensland , Brisbane 4072, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Lane
authors.affiliation: Department of Pharmacology, Fox Chase Cancer Center , Philadelphia, Pennsylvania 19111, United States.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Smith
authors.affiliation: Department of Chemistry, University of Waikato , Private Bag 3105, Hamilton 3240, New Zealand.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Puddick
authors.affiliation: Institute for Molecular Bioscience, University of Queensland , Brisbane 4072, Australia.
authors.forename: David P
authors.identifier: http://orcid.org/0000-0002-7856-8566
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D000458:Cyanobacteria / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology*; D012834:Silver / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D047028:Macrocyclic Compounds; D011166:Porphyrins; C091793:tolyporphin; D012834:Silver; D003300:Copper