Reductive activation

The error reduction activities that were begun in the pre-launch phase should be completed at this stage. 

Number of inadequately controlled risks identified and corrected, along with the appropriate allocation of capital to risk reduction activities... 

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. 

The requirement for reduction prior to DNA alkylation and crosslinking was first demonstrated by Iyer and Szybalski in 1964 [29], and can be induced both by chemical reducing agents such as sodium dithionite and thiols in vitro and by various reductive enzymes such as DT-diaphorase (NAD(P)H-quinone oxidoreduc-tase) in vitro and in vivo [47]. Much work to characterize the mechanism of reductive activation and alkylation has been carried out, principally by the Tomasz and Kohn groups, and Figure 11.1 illustrates a generally accepted pathway for mitomycin C [16, 48-50] based on these experiments, which is very similar to the mechanism originally proposed by Iyer and Szybalski [29]. 

Figure 11.1 Proposed nrechanisur for reductive activation of and DNA alkylation/crosslmkmg by mitomyci... 

Like the mitomycins, FR900482 (6), FR66979 (7), FK973 (8), and FK317 (9) have also been shown to crosslink DNA both in vivo [68-70], and in vitro after reductive activation [71-76] with selectivity for the 5 -CpG-3 sequence [77]. The mechanism outlined in Figure 11.2 was originally proposed by Goto and Fukuyama [78] and has been verified by the experimental work of Williams and Hopkins [71-77, 79]. Reduction of the N-O bond produces intermediate 27, which can lose a molecule of water to form 28, which reacts with DNA by a mechanism similar to that found... 

Some of the reactions in this chapter operate by still other mechanisms, among them an addition-elimination mechanism (see 13-15). A new mechanism has been reported in aromatic chemistry, a reductively activated polar nucleophilic aromatic substitution. The reaction of phenoxide with p-dinitrobenzene in DMF shows radical features that cannot be attributed to a radical anion, and it is not Srn2. The new designation was proposed to account for these results. 

These data confirm the sequence similarity of the three nitrogenases and indicate that cofactor exchange experiments are relatively straightforward. However, the environment of the cofactor clearly affects the substrate reduction activity, as observed with mutations in... 

We have already referred to the Mo/Ru/S Chevrel phases and related catalysts which have long been under investigation for their oxygen reduction properties. Reeve et al. [19] evaluated the methanol tolerance, along with oxygen reduction activity, of a range of transition metal sulfide electrocatalysts, in a liquid-feed solid-polymer-electrolyte DMFC. The catalysts were prepared in high surface area by direct synthesis onto various surface-functionalized carbon blacks. The intrinsic... 

Fox B, CT Walsh (1982) Mercuric reductase. Purification and characterization of a transposon-encoded flavoprotein containing an oxidation-reduction active disulfide. J Biol Chem 257 2498-2503. 

Ramalho PA, MH Cardoso, A Cavaco-Paulo, MT Ramalho (2004) Characterization of azo reduction activity in a novel ascomycete yeast strain. Appl Environ Microbiol 70 2279-2288. 

From these results, a sequence for the NO reduction activity can be given ... 

Stamenkovic V, Fowler B, Mun BS, Wang G, Ross PN, Lucas CA, Markovic NM. 2007a. Improved oxygen reduction activity on Pt3Ni(lll) via increased surface site availabihty. Science 315 493-497. 

Higuchi E, Uchida H, Watanahe M. 2005. Effect of loading level in platinum-dispersed carbon black electrocatalysts on oxygen reduction activity evaluated by rotating disk electrode. J Electroanal Chem 583 69-76. 

Wakabayashi N, Takeichi M, Itagaki M, Uchida M, Watanabe M. 2(X)5a. Temperature-dependence of oxygen reduction activity at a platinum electrode in an acidic electrolyte solution investigated with a channel flow double electrode. J Electroanal Chem 574 339-346. 

Yano H, Higuchi E, Uchida H, Watanabe M. 2006a. Temperature dependence of oxygen reduction activity at Nafion-coated bulk Pt and Pt/carbon black catalysts. J Phys Chem B 110 16544-16549. 

Yano H, Kataoka M, Yamashita H, Uchida H, Watanabe M. 2007. Oxygen reduction activity of carbon supported Pt-M (M = V, Ni, Cr, Co and Fe) alloys prepared by nanocapsule method. Langmuir 23 6438-6445. 

Hwang JT, Chung JS. 1993. The morphological and surface properties and their relationship with oxygen reduction activity for platinum-iron electrocatalysts. Electrochim Acta 38 2715-2723. 

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