Tietz Ole, Dzandzi James, Bhardwaj Atul, Valliant John F, Wuest Frank
Department of Oncology, University of Alberta, Canada.
Department of Chemistry and Chemical Biology, McMaster University, Canada.
Bioorg Med Chem Lett. 2016 Mar 15;26(6):1516-1520. doi: 10.1016/j.bmcl.2016.02.029. Epub 2016 Feb 11.
Cyclooxygenase-2 (COX-2) is the key enzyme in the prostaglandin synthesis pathway which is involved in various pathophysiological conditions. The enzyme is membrane bound and located inside of the endoplasmic reticulum and nuclear membrane. Effective perfusion of inhibitors to the active site requires lipophilic drugs, which consequently display high unspecific background accumulation, for example, in fatty tissues. The objective of this work was the development of a small molecule radiolabeled with a long-lived iodine radioisotope to enable longer imaging times and better target-to-background ratios. A group of iodinated compounds (8-10) was synthesized and identified as selective COX-2 inhibitors (COX-2 IC50=0.85-13 μM). Molecular docking results provided the theoretical support for the experimental COX-2 inhibition data. Furthermore, a novel (125)I-containing trifluoro-pyrimidine compound ([(125)I]Pyricoxib) was prepared via radioiododestannylation reaction as potent and selective COX-2 inhibitor. Radiosynthesis of [(125)I]Pyricoxib was accomplished with innovative fluorous chemistry using fluorous chloroamine-T (F-CAT) as novel oxidizing agent in high radiochemical yields of 91 ± 4%.
环氧化酶-2（COX-2）是前列腺素合成途径中的关键酶，参与多种病理生理过程。该酶与膜结合，位于内质网和核膜内。要使抑制剂有效灌注到活性位点需要亲脂性药物，因此这类药物会在例如脂肪组织中出现较高的非特异性背景蓄积。本研究的目的是开发一种用长寿命碘放射性同位素标记的小分子，以实现更长的成像时间和更好的靶本底比。合成了一组碘化化合物（8-10）并鉴定为选择性COX-2抑制剂（COX-2 IC50 = 0.85-13 μM）。分子对接结果为实验性COX-2抑制数据提供了理论支持。此外，通过放射性碘脱锡反应制备了一种新型含（125）I的三氟嘧啶化合物（[(125)I]吡罗昔康），作为强效且选择性的COX-2抑制剂。[(125)I]吡罗昔康的放射性合成采用创新的氟化学方法，使用氟代氯胺-T（F-CAT）作为新型氧化剂，放射化学产率高达91±4%。
