A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase

PLoS One. 2014 Feb 25;9(2):e89889. doi: 10.1371/journal.pone.0089889. eCollection 2014.

Abstract

Uroporphyrinogen 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Epithelial Cells / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular*
  • Molecular Structure
  • Porphyrins / chemical synthesis*
  • Porphyrins / chemistry
  • Porphyrins / pharmacology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism*
  • Substrate Specificity
  • Uroporphyrinogen Decarboxylase / antagonists & inhibitors*
  • Uroporphyrinogen Decarboxylase / chemistry

Substances

  • PI-16 compound
  • Porphyrins
  • Recombinant Proteins
  • Uroporphyrinogen Decarboxylase