Nitroimidazoles radiosensitizers

Wardman P (1982) The kinetics of the reaction of,anomalous 4-nitroimidazole radiosensitizers with thiols. Int J Radiat Biol 41 231-235... 

One-electron reduction of misonidazole - 2-nitroimidazole radiosensitizer [891], (nitroimidazolyl)succinic esters [892] and nitroindazoles [893, 894] has been studied by ESR and polarography. Misonidazole is participated in the determination of potentiation degree of the anticancer agent cytotoxicity [891],... 

Misonidazole [27 l-methoxy-3-(2-nitroimidazol-l-yl)-2-propanol] and the model compound l-methyl-2-nitroimidazole have been used as radiosensitizers in the treatment of certain types of human tumors. One important property of these compounds is that they are more toxic to hypoxic cells than to aerobic cells, indicating that reductive metabolism of the drug is involved in the toxicity. Results of a number of studies suggest that intracellular thiols play a significant role in the hypoxic cell toxicity, and it was found that reduction products formed stable thio ethers with GSH (for literature see References 181-183). The reaction mechanism of thio ether formation has not been fully established. It has been suggested that the 4-electron reduction product was involved in thio ether formation181,184,185, and that the hydroxylamine rather than the nitroso derivative was the reactant. On the other hand, an intermediate nitroso derivative is expected to give a sulfenamide cation (see Scheme 1) which easily allows thio ether formation. 

Adams GE, Flockhart IR, Smithen CE, Stratford IJ, Wardman P, Watts ME (1976a) Electron-affinic sensitization. VII. A correlation between structures, one-electron reduction potentials, and efficiencies of nitroimidazoles as hypoxic cell radiosensitizers. Radiat Res 67 9-20... 

Adams GE, Fielden EM, Hardy C, Millar BC, Stratford IJ, Williamson C (1981) Radiosensitization of hypoxic mammalian cells in vitro by some 5-substituted-4-nitroimidazoles. Int J Radiat Biol 40 153-162... 

Michaels HB, Ling CC, Epp ER, Peterson EC (1981a) Interaction of nitroimidazole sensitizers and oxygen in the radiosensitization of mammalian cells at ultrahigh dose rates. Radiat Res 85 567-582... 

Stillman MJ, Shaw CF III, Suzuki KT (1992) Metallothioneins. Synthesis, structure, and properties of metallothioneins, phytochelatins and metal-thiolate complexes. VCH Publishers, New York Stratford IJ, Hoe S, Adams GE, Hardy C, Williamson C (1983) Abnormal radiosensitizing and cytotoxic properties of ortho-substituted nitroimidazoles. Int J Radiat Biol 43 31-43 Stubbe J, Kozarich JW (1987) Mechanisms of bleomycin-induced DNA degradation. Chem Rev 87 1107-1136... 

Whillans DW, Hunt JW (1978) Rapid-mixing studies of the mechanisms of chemical radiosensitization and protection in mammalian cells. Br J Cancer 37 38-41 Whillans DW, Hunt JW (1982) A rapid-mixing comparison of the mechanisms of radiosensitization by oxygen and misonidazole in CHO cells. Radiat Res 90 126-141 Whillans DW, Adams GE, Neta P (1975) Electron-affinic sensitization. VI. Pulse radiolysis and ESR comparison of some 2- and 5-nitroimidazoles. Radiat Res 62 407-421... 

A large series of 5-nitroimidazoles used for radiosensitization of hypoxic cells in cancer chemotherapy has been studied by II and 13C NMR spectroscopy (in Table 3.12 only 13C data are presented) [346, 348],... 

Aryl l-methyl-4-nitro-5-imidazolyl sulfones, a new class of radiosensitizing pharmaceuticals [356-359], an extensive series of nitro derivatives of methylthio-[109] and ethylsulfonylimidazoles [360, 361], 1-alkyl [362]-, 1-trialkylsilylalkyl)-2-methyl-4-nitroimidazoles [363], allylated 4-nitroimidazoles [364], 5-amino derivatives of 4-nitroimidazoles [365], 5-azido-4-nitroimidazole [366], 15N-labeled... 

The ESR spectra of radical ions of known radiosensitizers metronidazole, misonidazole, omidazole, and other nitroimidazoles have been investigated in the conditions of photolysis [856, 857], pulse radiolysis [849, 856, 858-865], and in the presence of other donors of free electrons [866-872], Radical anions of 2-nitroimi-dazole [849] and 4(5)-nitroimidazole [860] depending on medium pH can exist in three forms (Scheme 3.21) ... 

This dependence may be useful in search of potential radiosensitizers. Determined with the help of pulse radiolysis, the thermodynamic potentials of one-electron reduction of 2-, 4-, and 5-nitroimidazoles (pH 7) have a higher negative values than those obtained by classical polarography (pH 7.4) [946], Probably, it is generated by the fact that the process of electrochemical reduction involves irreversible stages of the decomposition of nitroimidazole anion radicals. The correlation of E (and E1/2) of nitroimidazoles and their radiosensitizing properties is discussed. With E7 values the correlation is found to be better [946],... 

Pulse radiolysis has been used to measure the bimolecular rate constants of the electron transfer reaction for substituted 2- and 5-nitroimidazoles of interest as antiprotozoal drugs and radiosensitizers [951], The mechanism of inhibition of... 

Table 3.47 One-electron redox potentials and radiosensitizing properties of nitroimidazoles [941]...

High-performance liquid chromatography (HPLC) has been used to analyze metronidazole [1435-1437], misonidazole [1309,1438], and other nitroimidazoles [1435, 1439] in body fluids or pharmaceutical dosage forms. HPLC analysis of effect of hypoxic-cell radiosensitizer misonidazole on the radiation-induced reduction of DNA bases (thymine, cytosine, and adenine) has been carried out [1440, 1441], HPLC was employed to characterize different nitroimidazoles [327, 366, 388,409, 450, 1442-1444], nitropyrazoles [246, 301], nitrothiazoles [366], l-aryl(hetaryl)-4-nitro-l,2,3-triazoles [601], nitrobenzimidazoles [707], nitrobenzofurazans [774, 1445-1449], nitrobenzotriazoles [1450],... 

Properties 2-Nitroimidazole hypoxic cell radiosensitizer mf C8H12N404. 

Reactions of nitroarenes with both sugar and base radicals have been studied in some depth by several groups, summarized in earlier reviews [77-79,93,100]. Thus a radical that clearly forms adducts, such as that derived from an ether, reacted with nitroimidazoles with a redox relationship three times shallower than observed for radiosensitization of mammalian cells [100] ... 

G.E. Adams, I. Ahmed, E.D. Clarke, P. O Neill, J. Parrick, I.J. Stratford, R.G. Wallace, P. Wardman and M.E. Watts, Structure-activity relationships in the development of hypoxic cell radiosensitizers, in. Effects of basic substituents in nitroimidazole side-chains, Int. J. Radiat. Biol., 38 (1980) 613. 

Salgado-Zamora and co-workers"" prepared a series of imidazo[5,l-h]oxazoles as potential radiosensitizers or antiprotozoal agents (Scheme 1.59). Alkylation of 4-bromo-2-methyl-5-nitroimidazole 208 with a series of phenacyl halides gave a 1 3 mixture of the regioisomeric imidazoles 209 and 210. These were separated, and 210 was cyclized to the desired 2-aryl-5-methyl-7-nitroimidazo[5,l-h]oxazoles 211. This reaction tolerates a wide variety of phenacyl halides. Selected examples are presented in Table 1.17. 

Nitroaromatic compounds (e.g. nitroimidazoles and nitro-furans) are useful against anaerobic microbial infections (1). They are also differentially toxic towards anaerobic or hypoxic mammalian cells (2) and selectively radiosensitize hypoxic cells, offering a potential new use for nitro compounds in cancer radiotherapy (3,4). The selective toxicity, i.e. the protection by O2, may arise via the one-electron transfer reaction (T), since the nitro radicals, RNO2 have been observed in anaerobic microsomal incubations (5) and the anaerobic reduction products such as hydroxylamines probably lead to cytotoxicity by binding to DNA and RNA (6) ... 

Fig. 8.3. Structures of some nitroimidazoles with radiosensitizing properties of current...

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