Bioreductions

It may also be possible to stimulate bioreductions in soils, such as Cr(VI) to Cr(III), more effectively by growing plants than by adding bacteria or nutrients to stimulate the microbial process. 

Novel bioreductive anticancer agents based on indolequinones 97F271. 

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. 

Such isolated enzyme approaches for deracemization have a clear disadvantage in that they require two operational manipulations with an intermediate recovery step. A one-pot strategy is offered by employing whole-cell biotransformations with strains containing set(s) of complementary dehydrogenases operating in both biooxidative and bioreductive modes. Trace amounts of the intermediate ketone species can be isolated in several cases. In order to lead to an efficient deracemization... 

Renshaw JC, LJC Butchins, FR Livens, I May, JR Lloyd (2005) Bioreduction of uranium environmental implications of a pentavalent intermediate. Environ Sci Technol 39 5657-5660. 

V. Armendariz, Bioreduction of Gold(III) to Gold(O) and Nanoparticle Formation by Oat and Wheat Biomasses The Use of Plants in Nanobiotechnology. Master Thesis, the University of Texas at El Paso, Chemistry Department, El Paso, TX, 2005, p. 107. 

Crocq et al. (1997) have synthesized trimegestone through Bakers yeast mediated reduction of a ketone (this material is a new progestomimetic molecule for the treatment of postmenopausal diseases). The key step of the multistep synthesis is the chemo-, regio- and almost stereospecific bioreduction of a triketone to the desired alcohol. 

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-... 

Suzuki Y, Kelly SD, Kenrner KM, Banfield JF (2002) Nanometre-size products of uranium bioreduction. Nature 419 134... 

The continuing interest in bioreductive alkylation is largely due to the clinical success of mitomycin C and the low reduction potentials observed in many tumors.9 The low reduction potentials favor the quinone to hydroquinone conversion necessary for bioreductive alkylation. Hypoxia due to low blood flow3 and/or the unusually high expression of the quinone two-electron reducing enzyme DT-diaphorase in some histological cancer types10-14 contribute to the tumor s tendency to reduce quinones. 

Selective bioreductive alkylation in high DT-diaphorase cancer types (melanoma renal and nonsmall-cell lung cancers)15 would exhibit maximal antitumor activity with minimal side effects. 

For over 35 years, the quinone methide species has been invoked as a reactive intermediate in bioreductive alkylation and in other biological processes.8 29 Generally, there is only circumstantial evidence that the quinone methide species forms in solution. Conceivably, the O-protonated quinone methide (i.e., the hydroquinone carbocation) could be the electrophilic species. If so, bioreductive alkylation may simply be an SN1 reaction. Also, there are questions concerning the mechanism of quinone methide... 

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

SCHEME 7.3 Examples potential bioreductive alkylating purines reported by Skibo... 

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. 

Moore, H. W. Bioactivation as a model for drug design bioreductive alkylation. Science 1977, 197, 527-532. 

Stratford, I. J. Workman, P. Bioreductive drugs into the next millennium. Anti-Cancer Drug Des. 1998, 13, 519-528. 

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. 

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