Bioreductive agents

M.V. Papadopoulou, R. Pouremad, M.K. Rao, M. Ji, W.D. Bloomer, In v/fraevaluation of 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-trifluoromethylquinoline hydrochloride (NLTQ-1), a new bioreductive agent as a hypoxia marker by F-19-magnetic resonance spectroscopy (F-19-MRS), In Vivo 15 (2001) 365-371. 

Smitskamp-Wilms E, Giaccone G, Pinedo HM, van der Laan BF, Peters GJ. DT-diaphorase activity in normal and neoplastic human tissues an indicator for sensitivity to bioreductive agents . Br J Cancer 1995 72 917-921. 

Keywords Antibacterial properties Bioreductive agents Mutagenic effects ... 

The reducible organic functional groups employed for these reductases include quinones, iV-oxides, aromatic or heteroaromatic nitro groups, and sulfoxides. These compounds are also termed bioreductive agents. ... 

DMXAA has been found to potentiate the response of two bioreductive agents, again at 10-fold lower doses than those used with FAA (61), and thus represents one of the most promising low mol-wt tumor blood flow inhibitors available. Results from the current clinical trial may indicate whether DMXAA will also have potential as an inhibitor of tumor blood flow in humans. 

Novel bioreductive anticancer agents based on indolequinones 97F271. 

A few interesting organic molecules may possess the ability to release hydroxyl radical under physiological conditions. The most extensively studied of these is 3-amino-l,2,4-benzotriazine 1,4-dioxide (tirapazamine, 95, Scheme 8.32). Tirapazamine is a bioreductively activated DNA-damaging agent that selectively kills the oxygen-poor (hypoxic) cells found in solid tumors. The biological activity of... 

SCHEME 7.2 Examples of potential bioreductive alkylating agents reported by Lin et al.17. 

The bioreductive alkylating agents developed in this laboratory did not afford observable quinone methide species upon quinone reduction and leaving group... 

The UV-Vis spectral detection of an intermediate in the catalytic reductive alkylation reaction provides only circumstantial evidence of the quinone methide species. If the bioreductive alkylating agent has a 13C label at the methide center, then a 13C-NMR could provide chemical shift evidence of the methide intermediate. Although this concept is simple, the synthesis of such 13C-labeled materials may not be trivial. We carried out the synthesis of the 13C-labeled prekinamycin shown in Scheme 7.5 and prepared its quinone methide by catalytic reduction in an N2 glove box. An enriched 13C-NMR spectrum of this reaction mixture was obtained within 100 min of the catalytic reduction (the time of the peak intermediate concentration in Fig. 7.2). This spectrum clearly shows the chemical shift associated with the quinone methide along with those of decomposition products (Fig. 7.3). 

The design of a bioreductive alkylating agent possessing antitumor activity described above validates our approach to rational drug design. Namely, the putative... 

Moore, H. W. Czemiak, R. Naturally occurring quinones as potential bioreductive alkylating agents. Med. Res. Rev. 1981, 1, 249-280. 

Workman, P. Enzyme-directed bioreductive drug development revisted a commentary on recent progress and future prospects with emphasis on quinone anticancer agents and quinone metabolizing enzymes, particularly DT-diaphorase. Oncol. Res. 1994, 6, 461 175. 

Lin, A. J. Shansky, C. W. Sartorelli, A. C. Potential bioreductive alkylating agents. 3. Synthesis and antineoplastic activity of acetoxymethyl and corresponding ethyl carbamate derivatives of benzoquinones. J. Med. Chem. 1974, 17, 558-561. 

Tomasz, M. Palom, Y. The mitomycin bioreductive antitumor agents cross-linking and alkylation of DNA as the molecular basis of their activity. Pharmacol. Ther. 1997, 76, 73-87. 

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