A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase

• Published in: PloS one Vol. 9; no. 2; p. e89889
• Main Authors: Yip, Kenneth W, Zhang, Zhan, Sakemura-Nakatsugawa, Noriko, Huang, Jui-Wen, Vu, Nhu Mai, Chiang, Yi-Kun, Lin, Chih-Lung, Kwan, Jennifer Y Y, Yue, Shijun, Jitkova, Yulia, To, Terence, Zahedi, Payam, Pai, Emil F, Schimmer, Aaron D, Lovell, Jonathan F, Sessler, Jonathan L, Liu, Fei-Fei
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.02.2014; Public Library of Science (PLoS)
• Subjects: Biology; Biophysics; Biosynthesis; Cancer; Cancer therapies; Cell Line, Tumor; Cell Survival - drug effects; Chemical properties; Chemistry; Chemotherapy; Cisplatin; Design; Docking; Drug delivery systems; Enzymes; Epithelial Cells - drug effects; Health care networks; Heme; Hemoglobin synthesis; Humans; Hydroxymethylbilane synthase; Inhibitors; Inhibitory Concentration 50; Medical research; Medicine; Models, Molecular; Molecular biology; Molecular Structure; Oxygen; Photodynamic therapy; Physiological aspects; Porphyrins - chemical synthesis; Porphyrins - chemistry; Porphyrins - pharmacology; Radiation; Radiation (Physics); Radiation therapy; Reactive oxygen species; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Substrate Specificity; Uroporphyrinogen decarboxylase; Uroporphyrinogen Decarboxylase - antagonists & inhibitors; Uroporphyrinogen Decarboxylase - chemistry; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0089889

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.