Nitroimidazoles as hypoxic cell radiosensitizers and hypoxia probes: misonidazole, myths and mistakes

Abstract

Nitroimidazoles have been extensively explored as hypoxic cell radiosensitizers but have had limited clinical success, with efficacy restricted by toxicity. However, they have proven clinically useful as probes for tumour hypoxia. Both applications, and probably much of the dose-limiting toxicities, reflect the dominant chemical property of electron affinity or ease of reduction, associated with the nitro substituent in an aromatic structure. This single dominant property affords unusual, indeed extraordinary flexibility in drug or probe design, suggesting further development is possible in spite of earlier limitations, in particular building on the benefit of hindsight and an appreciation of errors made in earlier studies. The most notable errors were: the delay in viewing cellular thiol depletion as a likely common artefact in testing in vitro; slow recognition of pH-driven concentration gradients when compounds were weak acids and bases; and a failure to explore the possible involvement of pH and ascorbate in influencing hypoxia probe binding. The experience points to the need to involve a wider range of expertise than that historically involved in many laboratories when studying the effects of chemicals on radiation response or using diagnostic probes.

NMR Chemical Shift and Methylation of 4-Nitroimidazole: Experiment and Theory

“…2. 4-NI displayed three 13 C signals at 136.4, 144.7, and 119.4 ppm, which are assigned to C (2) , C (4) , and C (5) of 4-NI, respectively, in good agreement with earlier results. [43,44] The 13 C chemical shifts for CH 3 -4NI were different for positions C (4) and C (5) , 147.5 (Dd of 1.7 ppm) and 121.3 ppm (Dd of 1.6 ppm), respectively, while C (2) at 137.6 ppm remained within 0.5 ppm ( Table 1).…”

“…Nitroimidazoles were first in the class of compounds reported to have antimycobacterial activity in the early 1970s [1] and more recently as radiosensitizers of hypoxic tumour cells. [2] Methylation is an important pathway in the metabolism of many drugs, such as neurotransmitters and xenobiotic compounds. Although methyl conjugation of pyridine (an N-methylation) was first described over a century ago, [3] only recently have we begun to understand factors responsible for individual variations in methylation, [4] One of the challenges of modern medicine is the understanding of the biological basis for individual variation in drug response and in the occurrence of adverse drug reactions.…”

2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche

“…Aldh3a1 protects cells by detoxifying lipid peroxidation-derived reactive aldehydes such as 4hydroxynonenal 45 . Aldh3a1 can also release antioxidant nitric oxide (NO) from S-nitrosothiols [45][46][47] . Upregulation of Aldh3a1 has been identified as a cause of resistance to ferroptosis induced by sulfasalazine 48 , an inhibitor of the cystine-glutamate transporter subunit xCT, and drug screening for synthetic lethality identified aldehyde dehydrogenase inhibitors that cooperatively enhance the effects of sulfasalazine on cell lines derived from several types of solid tumors as well as on subcutaneous tumors in animal models 48,49 .…”

Radio-Sensitizing Effects of CuII and ZnII Complexes of Ornidazole: Role of Nitro Radical Anion

“… 20 , 21 Nitroimidazoles being “electron-affinic” react with DNA free radicals having the potential for universal activity to combat hypoxia-associated radio-resistance. 18 , 23 , 24 Several members were found clinically effective at a tolerable dose. 18 , 23 , 25 However, most compounds had limited clinical success; their efficacy is restricted by dose-limiting toxicity, attributed to electron affinity, i.e., to the relative ease of reduction of −NO 2 in nitroimidazoles to nitroimidazole radical anion (RNO 2 •– ).…”

“… 18 , 23 , 24 Several members were found clinically effective at a tolerable dose. 18 , 23 , 25 However, most compounds had limited clinical success; their efficacy is restricted by dose-limiting toxicity, attributed to electron affinity, i.e., to the relative ease of reduction of −NO 2 in nitroimidazoles to nitroimidazole radical anion (RNO 2 •– ). 23 Such a reduction may be modulated by complex formation.…”