Bioreductive activation

The mitomycins do not react directly with DNA, but require prior activation by reduction of the quinone. This property of bioreductive activation has inspired the design and development of synthetic anticancer drugs that are also activated by reduction, as this is expected to confer a degree of tumor selectivity [45, 46]. Many solid tumors are short of oxygen relative to normal tissue, so reductive activation of the mitomycins and other bioreductive drugs can proceed in tumors, while it is inhibited by the oxidizing environments in normal tissues. 

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... 

The bioreductively-activated, hypoxia-selective DNA-damaging properties found in tirapazamine are not uniqne to this nitrogen heterocycle. Analogous properties have been observed for quinoxaline di-A-oxides snch as 99 and In addi-... 

Tumor hypoxia and bioreductive activation of anticancer prodrugs... 

Tumor Hypoxia and Bioreductive Activation of Anticancer Prodrugs... 

Scheme 6. Bioreductive activation through reduction of a nitro group followed by 1,6-elimination and representative related prodrugs. The nitrogen is part of the carbamate structure.

Scheme 8. Bioreductive activation of prodrug 20 to active drug 20a.

Scheme 12. Bioreductive activation of sulfoxide-containing nitrogen mustard prodrugs.

Shair, M.D. Yoon, T. Chou, T.-C. Danishefsky, S. J. Enediyne quinone imines truncated biologically active dynemicin congeners. Angew. Chem., Int. Ed. Engl. 1994, 33, 2477-2479 Shair, M.D. Yoon, T.Y. Mosny, K.K. Chou, T.C. Danishefsky, S.J. The total synthesis of dynemicin A leading to development of a fully contained bioreductively activated enediyne prodrug. J. Am. Chem. Soc. 1996. 118, 9509-9525. 

The indolequinone moiety is of interest (i) as the activating nucleus of aziridine alkylating substituents and/or alkylating functionality through an iminium derivative produced in a C-3 elimination process [115-118], and (ii) as a vehicle for oxygen-sensitive, bioreductively-activated drug delivery [119,120] (see below). 

Figure 7. Basis for selectivity of action towards hypoxic cells of bioreductively-activated drugs which involve oxygen-reactive intermediates.

M.A. Naylor, M. Jaffar, J. Nolan, M.A. Stevens, S. Butler, K.B. Patel, S.A. Everett, G.E. Adams and I.J. Stratford, 2-CycIopropylindoloquinones and their analogues as bioreductively activated antitumor agents structure-activity in vitro and efficacy in vivo, J. Med. Chem., 40 (1997) 2335. 

S.A. Everett, M.A. Naylor, K.B. Patel, M.R.L. Stratford and P. Wardman, Bioreductively-activated prodmgs for targeting hypoxic tissues elimination of aspirin... 

P. Wardman, Bioreductive activation of quinones redox properties and thiol reactivity. Free Radical Res. Commun., 8 (1990) 219. 

The ester 246 has been prepared as a potential bioreductively-activated prodrug of 5-fluoro-2 -deoxyuridine (FUDR). It was resistant to human serum esterases due to the steric hindrance of the a-methyl groups, but chemical reduction led to rapid release of FUDR by intramolecular aminolysis. ... 

Damen EWP, Nevalainen TJ, van den Bergh TJM, de Groot FMH, Scheeren HW (2002) Synthesis of Novel Paclitaxel Prodrugs Designed for Bioreductive Activation in Hypoxic Tumour Tissue. Bioorg Med Chem 10 71... 

Mitomycin C is used extensively to treat various neoplasms and has led to the discovery of two aminoethylene disulfides KW-2149 (124) and BMS-181174 (125). These new compounds differ from mitomycin C only in the C(7) substituent. Novel mechanisms for BMS-181174 and KW-2149 differ from the bioreductive activation pathway commonly accepted for mitomycin C, in that the C(7) aminoethylene disulfide unit undergoes thiol-mediated disulfide exchange to give a mitomycin C thiol derivatives [131]. 

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