Bifunctional Metal – Nitroimidazole Complexes for Hypoxia Theranosis in Cancer

Abstract

Oxygen supply -demand imbalances can render proliferating cells acutely or chronically hypoxic. In cancer cells, hypoxia-induced pathophysiological changes give rise to genetic changes that lead to treatment-resistant, aggressive phenotypes. The reduced curability of hypoxic tumours by radiotherapy is one of consequent challenges, but their hypoxia also offers unique, exploitable properties. Nitroimidazoles, for example, capitalize on oxygen-sensitive reductive activation to achieve hypoxiaselective localization for theranostic consequence. The discovery of 2-nitroimidazole (azomycin) heralded the development of many drugs, including effective radiosensitizers of hypoxic cells. These electron-affinic, reductively bioactivated nitroheterocyclics undergo initial oxygen-reversible, enzymatic one-electron reductions that lead to the formation of molecular adducts that impair vital

99mTc Labelling Strategies for the Development of Potential Nitroimidazolic Hypoxia Imaging Agents

“…This mechanism is inhibited by oxygen, thereby conferring specificity for hypoxia. Five classes of bioreductive compounds have been described [11]: nitro(hetero)cyclic compounds, aromatic N-oxides, aliphatic N-oxides, quinones, and metal complexes, from which nitro(hetero)cyclic compounds, in particular nitroimidazoles are the ones usually being applied for radiopharmaceutical development [12].…”

Synthesis and Biological Evaluation of Iodoglucoazomycin (I‐GAZ), an Azomycin–Glucose Adduct with Putative Applications in Diagnostic Imaging and Radiotherapy of Hypoxic Tumors

“…Cellular molecular responses to focal tissue hypoxia are critical to the development and prognosis of several clinical pathologies, including cancer, liver disease, myocardial and peripheral vascular diseases, diabetes and arthritis . In cancer, electron‐affinic, bioreductively activated oxygen‐mimetics, particularly the 2‐nitroimidazoles (2‐NI; azomycin) have been investigated as radiosensitizer adjuncts for X‐ray radiotherapy of radioresistant hypoxic cells and as imaging diagnostics of hypoxic tumor . In general, these radiosensitizers have failed to perform effectively as neo‐adjuvants to radiation therapy.…”

“…[5] In cancer, electron-affinic, bioreductivelya ctivated oxygen-mimetics, particularlyt he 2-nitroimidazoles (2-NI;a zomycin) have been investigated as radiosensitizer adjuncts for X-ray radiotherapy of radioresistant hypoxicc ells [6][7][8] and as imaging diagnostics of hypoxict umor. [9][10][11][12][13][14] In general, these radiosensitizers have failed to perform effectively as neo-adjuvants to radiation therapy.I nt he case of nitroimidazoles, the narrow therapeutic window and related dose-limiting toxicities have contributed to their clinical ineffectiveness. [15] For imaging focal hypoxia, however,t he nitroimidazole-basedr adiotracers have been effective.…”

Editorial Review 2015 – Nuclear Medicine, Diagnostic Imaging and Therapy

“…The review article on, 'Bifunctional Metal -Nitroimidazole Complexes for Hypoxia Theranosis in Cancer', by Ricardo et al discusses the design, radiochemistry and hypoxia-selective properties of organometallic complexes including nitroimidazoles, towards bioactive targets [5]. Numerous drugs are based on the substrate 2-nitroimidazole and its ability to be effective radiosensitizers of hypoxic cells.…”