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Synthesis and Biological Evaluation of Iodoglucoazomycin (I‐GAZ), an Azomycin–Glucose Adduct with Putative Applications in Diagnostic Imaging and Radiotherapy of Hypoxic Tumors
Author(s) -
Kumar Piyush,
Elsaidi Hassan R. H.,
Zorniak Bohdarianna,
Laurens Evelyn,
Yang Jennifer,
Bacchu Veena,
Wang Monica,
Wiebe Leonard I.
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600213
Subject(s) - chemistry , adduct , biodistribution , glucose transporter , excretion , radiochemistry , biochemistry , medicine , in vitro , organic chemistry , insulin
Iodoglucoazomycin (I‐GAZ; N ‐(2‐iodo‐3‐(6‐ O ‐glucosyl)propyl)‐2‐nitroimidazole), a non‐glycosidic nitroimidazole–6‐ O ‐glucose adduct, was synthesized, radioiodinated, and evaluated as a substrate of glucose transporter 1 (GLUT1) for radiotheranostic (therapy+diagnostic) management of hypoxic tumors. Nucleophilic iodination of the nosylate synthon of I‐GAZ followed by deprotection afforded I‐GAZ in 74 % overall yield. I‐GAZ was radioiodinated via ‘exchange’ labeling using [ 123/131 I]iodide (50–70 % RCY) and then purified by Sep‐Pak™ (>96 % RCP). [ 131 I]I‐GAZ was stable in 2 % ethanolic solution in sterile water for 14 days when stored at 5 °C. In cell culture, I‐GAZ was found to be nontoxic to EMT‐6 cells at concentrations <0.5 m m , and weakly radiosensitizing (SER 1.1 at 10 % survival of EMT‐6 cells; 1.2 at 0.1 % survival in MCF‐7 cells). The hypoxic/normoxic uptake ratio of [ 123 I]I‐GAZ in EMT‐6 cells was 1.46 at 2 h, and under normoxic conditions the uptake of [ 123 I]I‐GAZ by EMT‐6 cells was unaltered in the presence of 5 m m glucose. The biodistribution of [ 131 I]I‐GAZ in EMT‐6 tumor‐bearing Balb/c mice demonstrated rapid clearance from blood and extensive renal and hepatic excretion. Tumor/blood and tumor/muscle ratios reached ∼3 and 8, respectively, at 4 h post‐injection. Regression analysis of the first order polynomial plots of the blood and tumor radioactivity concentrations supported a perfusion–excretion model with low hypoxia‐dependent binding. [ 131 I]I‐GAZ was found to be stable in vivo, and did not deiodinate.