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
Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.
Department of Chemistry, Institute for Cellular and Molecular Biology, the University of Texas at Austin, Austin, Texas, United States of America.
PLoS One. 2014 Feb 25;9(2):e89889. doi: 10.1371/journal.pone.0089889. eCollection 2014.
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.
尿卟啉原脱羧酶（UROD）在血红素生物合成过程中催化尿卟啉原转化为粪卟啉原。该酶最近被确定为一个潜在的抗癌靶点；对其抑制会导致活性氧增加，这可能是由芬顿反应介导的，从而降低癌细胞活力，并与放疗和/或顺铂协同作用。由于目前尚无适用于转化研究的化学UROD抑制剂，我们旨在设计、合成并表征这样一种化合物。最初基于计算机模拟的设计和对接分析确定了一种潜在的卟啉类似物，随后对其进行了合成。这种名为卟吩二甲烯（命名为PI-16）的化合物在酶活性测定中被发现可抑制UROD（IC50 = 9.9 μM），但在62.5 μM时不影响胆色素原脱氨酶，从而表现出特异性。在细胞实验中，PI-16降低了FaDu和ME-180癌细胞的活力，其半数最大有效浓度分别为22.7 μM和26.9 μM，对正常口腔上皮（NOE）细胞的影响极小。PI-16还能与放疗和顺铂有效联合，在FaDu细胞中，与顺铂联合时观察到了强效协同作用（Chou-Talalay联合指数<1）。这项工作展示了首个已知的合成UROD抑制剂，为设计、合成和表征更高亲和力、更有效的UROD抑制剂奠定了基础。
