Quinones, reductive 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. 

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]. 

Reductive activation of the quinone shown in Scheme 7.9 and incubation in methanol afforded a complex mixture of products consisting mainly of head-to-tail coupling at C-5 or C-7 (Scheme 7.10). Minor reactions involve transfer of H2 from the hydroquinone to the ene-imine (internal redox reaction) and methanol trapping. The structures of the dimers and trimers in Scheme 7.10 were derived from H-NMR,... 

SCHEME 7.14 Cyclopropyl quinone methide formation upon reductive activation. The CC-1065 A-ring is shown in the inset. 

The most important conclusion of this research program is that quinone methide O-protonation is required for alkylation to occur. The quinone methide species is often referred to in the literature as an electrophilic species. Actually, the quinone methides obtained from reductive activation possess a slightly electron-rich methide center. There is electron release to the methide center by the hydroxyl, which is balanced by electron... 

Feldman and Eastman have suggested that the kinamycins may by reductively activated to form reactive vinyl radical (25) and orf/to-quinone methide (26) intermediates (Scheme 3.2c) [16]. The authors provided convincing evidence that the alkenyl radical 25 is generated when the model substrate dimethyl prekinamycin (24) is exposed to reducing conditions (tri-n-butyltin hydride, AIBN). Products that may arise from addition of this radical (25) to aromatic solvents (benzene, anisole, and benzonitrile) were isolated. The ort/io-quinone methide 26 was also formed,... 

Figure 4.2. Monophenolase and diphenolase activities of polyphenoloxidase and stabilization of the formed quinones. (A) Quinone reduction. (B) Descarboxylation. (C) Modification by an exomolecular nucleophile. (D) Modification by an endomolecular nucleophile.

In this scheme veratryl alcohol was viewed to be metabolized by the combined action of oxidative systems (the lignin peroxidase and possibly other active oxygen species) and reductive conversions (aldehyde and quinone reductions). A possible route via veratric acid was discounted because both veratraldehyde and veratric acid were not substrates for the lignin peroxidase under the condition studied. However, both veratraldehyde and veratric acid were rapidly and quantitatively reduced by ligninolytic cultures of P. chrysosporium (21). 

Antitumor agents mitomycin A (61 A) and mitomycin C (61C) contain a latent quinone functionality, which is exposed by reductive activation and elimination of a glycoside or an alcohol followed by opening of the aziridine ring. These quinone methides then react with nucleic acids to form bis-adducts.103 The reductive activation of mitomycins provides selectivity in targeting solid tumors, because this is favored in the oxygen-deprived environment of tumor cells, and inhibited by the oxygen-rich environment of healthy tissues.107... 

The reductive activation of mitomycins in the cell is thought to be an enzymatic process.108 Reduction of mitomycins A and C in vitro by H2/Pt02 or by Na2S204 gives 62, which then breaks down to the quinone methide 63A.109 This quinone methide reacts with DNA to give a complex mixture of alkylated DNA and cross-linked oligonucleotides. Mitomycin A is both more easily reduced and more toxic than mitomycin C, and there is some evidence that the toxicity of... 

Reductive activation of quinones 65112 and 66113 affords the novel cyclopropyl quinone methide alkylating agents 67 and 68 (Scheme 30C). These... 

Pan, S., Andrews, P.A., Glover, C.J., and Bachur, N.R., 1984, Reductive activation of mitomycin C and mitomycin C metabolites catalysed by NADPH-cytochorome P-450 reductase and xantine oxidase. J. Biol. Chem. 259 959-962 Pollakis, G., Goormaghtigh, E., and Ruysschaert, J.-M., 1983, Role of quinone structure in the mitochondrial damage induced by antitumor anthracyclines. FEBS Lett. 155 267-272 Rappaport, S.M., McDonald, T.A., and Yeowell-O Connell, K., 1996, The use ofprotein adducts to investigate the disposition of reactive metabolites of benzene. Environ. Health Perspect. 104Suppl6 1235-1237... 

The redox-sensitive linker 1.34 (91), obtained in several steps from Merrifield resin and a lactone precursor, was charged with a N-protected aminoacid, treated with NBS to debenzylate and oxidize the linker to quinone, and submitted to SPS. The quinone linker was reductively activated to dihydroquinone with NaBH4 in THF/MeOH for 30 min at rt, then cleaved by treatment with anhydrous TBAF in THF for 20 h at rt to provide the free acidic peptide via intramolecular cyclization of the linker moiety. 

Gardill SL and Suttie JW (1990) Vitamin K epoxide and quinone reductase activities. Evidence for reduction by a common enzyme. Biochemical Pharmacology 1055-61. 

By co-immobilizing tyrosinase with a serine esterase on a gold electrode, it is possible to establish a multistep reaction pathway that allows the activity of the esterase to be determined indirectly via measurement of o-quinone reduction at the electrode. The molecular architecture of a bi-enzyme sensor interface is shown schematically in Figure 57.13. 

Figure 20.6 The hypoxia-selective antitumor agent tirapazamine 15. Reaction a reductive inactivation by two-electron steps catalyzed by quinone reductase (the first two-electron step being shown here). Reaction b reductive activation (one-electron step catalyzed by cytochrome P450 reductase). Reaction c dehydration to yield the reactive radical 17, which abstracts a hydrogen radical from DNA [37, 38].

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