Pyrophosphate-bridged complexes with picomolar toxicity.
Recently, we have observed the emergence of a new series of pyrophosphate-bridged coordination complexes. Such complexes have been prepared by overcoming the ready hydrolysis of the pyrophosphate moiety. To date, no exploration has been conducted on the cytotoxicity of such complexes. Three pyrophosphate-bridged complexes, namely {[Ni(phen)(2)](2)(mu-P(2)O(7))}.27H(2)O, {[Cu(phen)(H(2)O)](2)(mu-P(2)O(7))}.8H(2)O and {[Co(phen)(2)](2)(mu-P(2)O(7))}.6MeOH, (where phen is 1,10'-phenanthroline) were chosen for their comparative structural similarities and suitable aqueous solubility. Cytotoxicity studies in the adriamycin-resistant ovarian cancer cell line A2780/AD demonstrated highly significant efficacy, with values as low as 160pM for the cobalt complex at 72h. The underlying mechanism for such exceptional toxicity is investigated focusing on DNA interactions, topoisomerase I enzyme inhibition and oxidative stress (followed by intracellular glutathione levels). The role of hydrolysis in uptake and toxicity is also explored (followed by electronic absorption spectroscopy, (31)P NMR, and confocal microscopy) and the complexes are compared to cisplatin controls. Overall a clear picture of the extraordinary toxicity emerged. The results demonstrate a new class of prodrugs with significant potential for future development for the treatment of drug-resistant cancer cell lines.
Ikotun
Oluwatayo F
OF
Department of Chemistry, Syracuse University, NY 13244-4100, United States.
Higbee
Elizabeth M
EM
Ouellette
Wayne
W
Doyle
Robert P
RP
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002942:Circular Dichroism; D003035:Cobalt; D003300:Copper; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D011756:Diphosphates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009532:Nickel; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010618:Phenanthrolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013054:Spectrophotometry, Atomic; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D002614:Chelating Agents; D011756:Diphosphates; D007202:Indicators and Reagents; D008024:Ligands; D009942:Organometallic Compounds; D010618:Phenanthrolines; D011355:Prodrugs; D059004:Topoisomerase I Inhibitors; D003035:Cobalt; D003300:Copper; D009532:Nickel; D004247:DNA; C427203:calf thymus DNA