Design, Synthesis, and Preliminary Biological Evaluation of 6-O-Glucose–Azomycin Adducts for Diagnosis and Therapy of Hypoxic Tumors

Abstract

Several 2-nitroimidazole-based molecules (NIs) are used as clinical hypoxic tumor radiodiagnostics, but they are not effective as radiosensitizers/radiochemotherapeutics. These NIs permeate tumor cells nonselectively via diffusion, and in therapy, where high doses are required, their dose limiting toxicities preclude success. The synthesis and preliminary in vitro evaluations of three glucoazomycins, members of a novel class of C6-O-glucose-linked-azomycin conjugates that are putative substrates of glucose transport proteins (GLUTs) and possess hypoxia-selective radiosensitization features, are now reported. The hypoxia-dependent upregulation of several GLUTs provides a rational basis to develop these glucoazomycins because more selective uptake in hypoxic cells would decrease systemic toxicities at effective doses. Calculated partition coefficients (ClogP, -1.70 to -2.99) predict rapid in vivo clearance for low systemic toxicity. In vitro experimental data show that glucoazomycins are radiosensitizers and that they competitively inhibit glucose uptake.

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

“…Several glucose-linked drugs designed to deliver attached therapeutics to tumours that overexpress a glucose transporter are also undergoing clinical evaluation or late preclinical development [171][172][173] . Most notably, glufosfamide -a glucose conjugate of iphosphoramide -has advanced to Phase III clinical trials (NCT01954992) 174 , in which it is being assessed for treatment of metastatic pancreatic cancer.…”

Glucose conjugation for the specific targeting and treatment of cancer

“…The synthesis and preliminary biological evaluation of a series of glucose-azomycin adducts were recently reported in 2012 by Kumar and coworkers [63]. 2-nitroimidazole compounds have been studied in clinical trials as radiosensitizers.…”

“…To assess whether the uptake of these glucose conjugates was partially GLUT receptor-mediated, glycoconjugates were tested at concentrations ranging from 100 μM to 10 mM for the ability to compete with 14 C glucose uptake in Xenopus oocytes, which express GLUT-1. The compound depicted in Figure 8b, a diastereomeric mixture of α and β glucose conjugated at the 6 position to 3-carbon linker, off of which emerges a fluorine diagnostic arm and azomycin, was shown to be the strongest competitor for glucose uptake [63], suggesting that its cellular transport is at least partially GLUT-1 mediated. In vivo studies using glucoconjugated azomycins were not reported.…”

Anticancer agents interacting with membrane glucose transporters

“…This compound also proved to be an effective radiosensitizer in multiple cancer cell lines using radiation doses up to 18 Gy. 96 …”