A Porphodimethene Chemical Inhibitor of Uroporphyrinogen Decarboxylase

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dc.creatorYip, Kenneth W.en
dc.creatorZhang, Zhanen
dc.creatorSakemura-Nakatsugawa, Norikoen
dc.creatorHuang, Jui-Wenen
dc.creatorVu, Nhu Maien
dc.creatorChiang, Yi-Kunen
dc.creatorLin, Chih-Lungen
dc.creatorKwan, Jennifer Y. Y.en
dc.creatorYue, Shijunen
dc.creatorJitkova, Yuliaen
dc.creatorTo, Terenceen
dc.creatorZahedi, Payamen
dc.creatorZahedi, Payamen
dc.creatorPai, Emil F.en
dc.creatorSchimmer, Aaron D.en
dc.creatorLovell, Jonathan F.en
dc.creatorSessler, Jonathan L.en
dc.creatorLiu, Fei-Feien
dc.date.accessioned2014-12-15T17:10:45Zen
dc.date.available2014-12-15T17:10:45Zen
dc.date.issued2014-02-25en
dc.descriptionKenneth W. Yip, Noriko Sakemura-Nakatsugawa, Jennifer Y. Y. Kwan, Shijun Yue, Yulia Jitkova, Terence To, Payam Zahedi, Emil F. Pai, Aaron D. Schimmer, Fei-Fei Liu, Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canadaen
dc.descriptionZhan Zhang, Nhu Mai Vu, Jonathan L. Sessler, Department of Chemistry, Institute for Cellular and Molecular Biology, the University of Texas at Austin, Austin, Texas, United States of Americaen
dc.descriptionJui-Wen Huang, Yi-Kun Chiang, Chih-Lung Lin, Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsin-chu, Taiwanen
dc.descriptionEmil F. Pai, Aaron D. Schimmer, Fei-Fei Liu, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canadaen
dc.descriptionEmil F. Pai, Department of Biochemistry, University of Toronto, Ontario, Canadaen
dc.descriptionEmil F. Pai, Department of Molecular Genetics; University of Toronto, Ontario, Canadaen
dc.descriptionJonathan F. Lovell, Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York, United States of Americaen
dc.descriptionFei-Fei Liu, Department of Radiation Oncology, Princess Margaret Cancer Centre, UHN, Toronto, Ontario, Canadaen
dc.descriptionFei-Fei Liu, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canadaen
dc.description.abstractUroporphyrinogen decarboxylase (UROD) catalyzes the conversion of uroporphyrinogen to coproporphyrinogen during heme biosynthesis. This enzyme was recently identified as a potential anticancer target; its inhibition leads to an increase in reactive oxygen species, likely mediated by the Fenton reaction, thereby decreasing cancer cell viability and working in cooperation with radiation and/or cisplatin. Because there is no known chemical UROD inhibitor suitable for use in translational studies, we aimed to design, synthesize, and characterize such a compound. Initial in silico-based design and docking analyses identified a potential porphyrin analogue that was subsequently synthesized. This species, a porphodimethene (named PI-16), was found to inhibit UROD in an enzymatic assay (IC50 = 9.9 µM), but did not affect porphobilinogen deaminase (at 62.5 µM), thereby exhibiting specificity. In cellular assays, PI-16 reduced the viability of FaDu and ME-180 cancer cells with half maximal effective concentrations of 22.7 µM and 26.9 µM, respectively, and only minimally affected normal oral epithelial (NOE) cells. PI-16 also combined effectively with radiation and cisplatin, with potent synergy being observed in the case of cisplatin in FaDu cells (Chou-Talalay combination index <1). This work presents the first known synthetic UROD inhibitor, and sets the foundation for the design, synthesis, and characterization of higher affinity and more effective UROD inhibitors.en
dc.description.catalogingnoteEmail: Fei-Fei.Liu@rmp.uhn.on.caen
dc.description.departmentChemistryen
dc.description.departmentInstitute for Cellular and Molecular Biologyen
dc.description.sponsorshipThis work was funded by Canadian Institutes of Health Research Proof of Principle and Operating Grants [Grants PPP-102202, MOP-102497]. Support from the Cancer Prevention and Research Institute of Texas [Grant CP RP101501] is also gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.identifier.Filenamejournal.pone.0089889.pdfen
dc.identifier.citationYip KW, Zhang Z, Sakemura-Nakatsugawa N, Huang J-W, Vu NM, et al. (2014) A Porphodimethene Chemical Inhibitor of Uroporphyrinogen Decarboxylase. PLoS ONE 9(2): e89889. doi:10.1371/journal.pone.0089889en
dc.identifier.doiDOI: 10.1371/journal.pone.0089889en
dc.identifier.urihttp://hdl.handle.net/2152/27926en
dc.language.isoEnglishen
dc.publisherPLOS Oneen
dc.rightsAdministrative deposit of works to UT Digital Repository: This works author(s) is or was a University faculty member, student or staff member; this article is already available through open access at http://www.plosone.org. The public license is specified as CC-BY: http://creativecommons.org/licenses/by/4.0/. The library makes the deposit as a matter of fair use (for scholarly, educational, and research purposes), and to preserve the work and further secure public access to the works of the University.en
dc.subjectcarcinomasen
dc.subjectchemical precipitationen
dc.subjectcrystal structureen
dc.subjectenzyme assaysen
dc.subjecthemeen
dc.subjectNMR spectroscopyen
dc.subjectporphyrinsen
dc.subjectreversed-phase high performance liquid chromatographyen
dc.titleA Porphodimethene Chemical Inhibitor of Uroporphyrinogen Decarboxylaseen
dc.typeArticleen

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