Hypoxia-selective cytotoxins

The dinuclear dialkyldithiocarbamate precursor [Co2(dtc)5]+ reacted with diamine mustards N,N- and /V,/V -bis(2-chloroethyl)ethylenediamine (bee, dee) and their non-chlorinated analogs yield [Co(dtc)2(diamine)]+.1049 The bee and dee compounds were prepared and tested as potential hypoxia-selective cytotoxins, but did not prove of value as potential bioreductive anticancer drugs, partly due to their redox instability. 

Naylor MA, Stephens MA, Stratford IJ, Keohane A, O Neill P.Threadgill MD, Webb P, Fielden EM, Adams GE (1991) Aziridinyl nitropyrroles and nitropyrazoles as hypoxia-selective cytotoxins and radiosensitizers. Anti-Cancer Drug Design 6 151-167... 

Denny WA (1995) Hypoxia-selective cytotoxins. In Foye WO (ed) Cancer chemotherapeutic agents Ch 14. American Chemical Society, Washington... 

Papadopoulos MV et al., Reductive metabolism of the nitroimidazole-based hypoxia-selective cytotoxin NLCQ-1 (NSC 709257), Oncol. Res., 14, 21, 2003. 

M. Tercel, W.R. Wilson and W.A. Denny, Nitrobenzyl mustard quaternary salts a new class of hypoxia-selective cytotoxins showing very high in vitro selectivity, J. Med. Chem., 36 (1993) 2578. 

W.R. Wilson, M. Tercel, R.F. Anderson and W.A. Denny, Radiation-activated prodrugs as hypoxia-selective cytotoxins model studies with nitroarylmethyl quaternary salts, Anti-Cancer Drug Des., 13 (1998)663. 

We have described a two-step method for introduction of chloromethyl substituents into nitroarenes. This approach consists in the VNS of hydrogen with fert-butyl dichloroacetate anion [58] followed by one-pot hydrolysis and decarboxylation [101], This approach has been used for the synthesis of (chloromethyl) nitroimidazole, a precursor of (nitroheteroaryl)methyl mustard, which was tested as hypoxia-selective cytotoxins (Scheme 27) [102],... 

Quinoxaline 1,4-di-N-oxide derivatives were reported to exhibit hypoxia-selective cytotoxins [5,6] as well as myco-bacterium tuberculostatic activities [7,8]. From the spectrum of activities reported in the literature, combinations of the modifications at positions 2- and 5- of the molecule have provided the most active drugs. The ophmization of benzimidazole-based structures has resulted in various drugs that are prevalent in the market, such as omeprazole... 

K.M. Amin, M.M.F. Ismail, E. Noaman, D.H. SolLman, Y.A. Ammar, New quinoxahne 1,4-di-N-oxides. Part 1 hypoxia-selective cytotoxins and anticancer agents derived from quinoxahne 1,4-di-N-oxides, Bioorg. Med. Chem. 14 (2006) 6917-6923. 

Fig. 13 Top QDO with selective hypoxia cytotoxic activity. Bottom PDO, and Pz related derivative, described as selective hypoxia cytotoxins...

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