A bioreduction

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

In the route to BO-2727 (18), a broad-spectrum P-methyl carbapenem being developed by Merck, a bioreduction catalyzed by the fungus Mortierella alpina MF 5534 is used to form a precursor (7 )-P-hydroxy ester 19 (Scheme 19.12).102 This fungal culture was a result of screening approximately 260 strains of microorganisms and resulted in the production of gram quantities of product with a de of >98%. 

What are the bottelnecks for bioreduction The drawbacks of a bioreduction process involving whole cells of microoganisms can be summarized i) Microbial strains possessing both carbonyl reductase activity and cofactor (NAD(P)H)-regenerating activity are necessary to obtain a highmolar yield, because a stoichiometric amount of cofactor is required for substrate reduc-... 

A bioreduction system might be applied to many NAD(P)H-dependent enzyme reactions other than carbonyl reduction. Recently, two novel old yellow enzymes (OYEs) catalyzing the asymmetric hydrogenation of C=C bonds were found and applied to a bioreduction system for the production of double chiral compounds. 

Although reductases play an important role in the in vivo synthesis of many chemicals (see flavour example in Fig. 7.11), little attention has been paid to this type of biocatalyst. In most cases whole microbial or plant cells are used to perform a bioreductive reaction due to the requirement for (expensive) cofactors. Typical examples include the reduction of certain double bonds in terpenes by plant cells [27,41], the reduction of Massoi lactone to R(+)-8-decalactone by Basidiomycetes and S. cerevisiae [28], and the baker s yeast-catalyzed reduction of ketones to (chiral) alcohols [42]. 

Scheme 10) serves as a bioreductive prodrug of a nitrogen mustard.44,45 NADPH-dependent cytochrome P450 reductase has been shown to catalyze the reduction of nitromin to its active nitrogen mustard (22a).45... 

The lactonization step is highly favored because of the steric pressure created by the three methyl groups ( trimethyl lock concept). An alternative to the hydrolytic first step involves a bioreductive generation of the intermediate phenolic amide (Figure 36.23). 

Solid tumors display a reductive environment because of hypoxia and the overproduction of bioreductive enzymes. To take advantage of the characteristics of the environment provided by the solid tumor, a bioreductive, tumor-targeted drug delivery system was designed. The system would undergo... 

Such compounds can also be considered as carrier prodrugs, in so far as the thiolate is linked to an n-propylthio (a) or a tetrahydrofuranylmethylenethio (b) transport moiety, or as bioprecursors, in so far as a bioreductive... 

Cu]-ATSM is a bioreductive molecule also being proposed for tumor hypoxia imaging. In a trial including 14 patients with NSCLC treated with radiation and/ or chemotherapy it was shown that the mean tumor-to-muscle activity ratio before treatment was significantly... 

Inside cells, 2-nitroimidazole acts as a bioreductive molecule. It undergoes a single electron reduction in hypoxic environments, forming reactive radicals that bind to intracellular protein thiols and become trapped (96). Because nitro-imidazole uptake requires intact nitroreductase enzymes, 2-nitroimidazole, in principle, could be exploited to distinguish between normoxic, hypoxic (but viable), and necrotic tissues (90). 

Aromatic A -Oxides. - Tirapazamine is a bioreductive anticancer agent that is particularly toxic to hypoxic cells. The protection afforded from such drugs by oxygen is believed to indicate that oxygen radicals are not primarily responsible for their cytotoxicity, which probably results from DNA damage induced directly by reactive metabolites. Patterson and Taiwo have observed DMPO adducts of-OH, 02 and a carbon-centred radical upon the incubation... 

A bioreductive alkylation-based mechanism involving reactions of quinone methides or other electrophilic side chains with vital cell compounds such as DNA, ribonucleic acid, and proteins. 

Scheme4.18 One-pot synthesis of interesting allylic alcohols by combining a Wittig reaction and a bioreduction.

Scheme4.20 Combination of an aldol-catalyzed reaction with a bioreduction to obtain chiral 1,3-diols.

An important message from the scientific literature is that ISPR alone will not solve all the challenges to be met in scaling-up a bioreduction. In common with other complex biocatalytic reactions such as the transaminase-catalyzed synthesis of optically pure amines [65,66] or the cyclohexanone monooxygenase-catalyzed... 

Janssens, M.Y., Verovski, V.N., Van den Berge, D.L., Monsaert, C., and Storme, G.A. (1999). Radiosensitization of hypoxic tumom cells by 5-nitroso-V-acetylpenicillaniine implicates a bioreductive mechanism of nitric oxide generation. Br. J. Cancer 79. 1085-1089. 

Denny, W.A., and Wilson, WR. (2000). Tirapazamine a bioreductive anticancer drug that exploits tumour hypoxia. Expert Opin. Investig. Drugs 9, 2889-2901. 

Numerous methods have been applied for the synthesis of nanorods, starting historically with electrochemical deposition within nanoporous alumina membranes [19], followed by photochemical reduction in the presence of a cationic surfactant [20,21] (cetyltrimethylammonium chloride, CigTAC), electrochanical reduction in the presence of a cationic surfactant [22] (cetyltrimethylammonium bromide, CigTAB), a bioreduction method [23], and finally the most widely used synthesis seed-mediated wet-chemical reduction in the presence of Cj TAB [24] (sometimes also with the cosurfactant benzyldimethylammonium chloride, BDAC [8]). The most noteworthy advancements of the nanorod syntheses have been the surfactant-mediated control of shape, use of QgTAB in place of CigTAC, and the recognition of the useful effect of Ag ions. Currently almost aU rods are made by batch processes, but there have also been reports of successful rod growth in a continuous reactor [25]. 

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