title: Synthesis and Biological Evaluation of Iodoglucoazomycin (I-GAZ), an Azomycin-Glucose Adduct with Putative Applications in Diagnostic Imaging and Radiotherapy of Hypoxic Tumors.
abstract: 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 mm, 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 mm 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.
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, University Ave., Edmonton, AB, T6G 1Z2, Canada. pkumar@ualberta.ca.
authors.forename: Piyush
authors.identifier: 0000-0003-3113-3933
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, University Ave., Edmonton, AB, T6G 1Z2, Canada.|Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, El Sultan Hussein St. Azarita, Alexandria, Egypt.
authors.forename: Hassan R H
authors.initials: HR
authors.lastname: Elsaidi
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, University Ave., Edmonton, AB, T6G 1Z2, Canada.
authors.forename: Bohdarianna
authors.initials: B
authors.lastname: Zorniak
authors.affiliation: Clinical Imaging Research Centre, 14 Medical Drive, #B1-01, Singapore, 117599, Singapore.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Laurens
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, University Ave., Edmonton, AB, T6G 1Z2, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, University Ave., Edmonton, AB, T6G 1Z2, Canada.
authors.forename: Veena
authors.initials: V
authors.lastname: Bacchu
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, University Ave., Edmonton, AB, T6G 1Z2, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, University Ave., Edmonton, AB, T6G 1Z2, Canada.
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Wiebe
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005947:Glucose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D051272:Glucose Transporter Type 1 / Q000737:chemistry; D005960:Glucosides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D064593:Heterografts; D006801:Humans; D007457:Iodine Radioisotopes; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology / Q000532:radiotherapy*; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D047368:Tumor Burden; D000072258:Tumor Hypoxia
chemical_list: D051272:Glucose Transporter Type 1; D005960:Glucosides; D007457:Iodine Radioisotopes; C000622624:Iodoglucoazomycin; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; C495678:Slc2a1 protein, mouse; D005947:Glucose
keywords: antitumor agents; azomycin; glycoconjugates; iodination; tumor hypoxia