Quinone, bioactive

Gutierrez, P. L. The role of NAD(P)H oxidoreductase (DT-diaphorase) in the bioactivation of quinone-containing antitumor agents a review. Free Radio. Biol. Med. 2000, 29, 263-275. 

Bolton, J. L. Acay, N. M. Vukomanovic, V. Evidence that 4-ally 1-o-quinones spontaneously rearrange to their more electrophilic quinone methides potential bioactivation mechanism for the hepatocarcinogen safrole. Chem. Res. Toxicol. 1994, 7, 443 450. 

FIGURE 5.12 Bioactivation of mitomycin C, the first step of which involves reduction of the quinone. 

The groups of Liebeskind and Moore independently explored the ring expansion of allenyl-substituted cyclobutenol derivatives. This allows either the preparation of 5-alkylidene-2-cyclopentenones, which are substructures of naturally occurring bioactive compounds [59], or the generation of o-quinone methides, which are very attractive intermediates in the synthesis of hexahydrocannabinols [109]. As shown in Scheme 8.42, the ring expansion of the tetrasubstituted methoxyallene derivative 170 furnished the vinylhydroquinone 172 in high yield [109]. 

Covalent protein adducts of quinones are formed through Mchael-type addihon reachon with protein sulfhydryl groups or glutathione. Metabolic activahon of several toxins (e.g., naphthalene, pentachlorophenol, and benzene) into quinones has been shown to result in protein quinone adducts (Lin et al, 1997 Rappaport et al, 1996 Zheng et al., 1997). Conversion of substituted hydroquinones such as p-aminophenol-hydroquinone and 2-bromo-hydroquinone to their respective glutathione S-conjugates must occur to allow bioactivation into nephrotoxic metabolites (Dekant, 1993). Western blot analysis of proteins from the kidneys of rats treated with 2-bromo-hydroquinone has revealed three distinct protein adducts conjugated to quinone-thioethers (Kleiner et al, 1998). 

Stoka, V., Turk, B., Schendd, S.L., Kim, T.-H., Cirman, T, Srripas, SJ., EUerby, L.M., Bredesen, L., Freeze, H, Abrahamson, M., Bromme, D., Krajewski, S., Reed, J.C., Yin, X.-M., Turk, V., and Salvesen G.S., 2001, Lysosomal Protease Pathways to Apoptosis. Cleavage of Bid, not pro-caspases, is the most likely route. J. Biol. Chem. 276 3149-3157 Srm, X. and Ross, D., 1996, Quinone-induced apoptosis in human colon adenocarcinoma ceUs via DT-diaphorase mediated bioactivation. Chem. Biol. Interact. 100 267-76 Taatjes, D.J. and Koch, T.H., 2001, Nuclear targeting and retention of anthracycUne antitumor dmgs in sensitive and resistant tumor ceUs. Curr. Med Chem. 8 15-29 Tarr, M. and van Helden, PT)., 1990, Inhibition of transcription by adriamycin is a... 

Catechol may be oxidized by peroxidases to the reactive intennediate benzo-1,2-quinone, which readily binds to proteins (Bhat et al., 1988) this process, catalysed by rat or human bone-marrow cells in the presence of H2O2 (0.1 mM), is stimulated by phenol (0.1-10 mM), and decreased by hydroquinone and by glutathione, which conjugates with benzo-l,2-quinone. These phenols (phenol, catechol and hydroquinone) may play a role in benzene toxicity to bone marrow all three are formed as benzene metabolites (Smith et al., 1989) and they interact in several ways as far as their bioactivation by (myelo)peroxidases is concerned (Smith et al., 1989 Subrahmanyam et al., 1990). 

Kalgutkar, A. S., et al. (2005). Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4. Drug Metab. Dispos. 33 243-253. 

Reactive metabolites include such diverse groups as epoxides, quinones, free radicals, reactive oxygen species, and unstable conjugates. Figure 8.2 gives some examples of activation reactions, the reactive metabolites formed, and the enzymes catalyzing their bioactivation. 

Similar types of nucleophilic substitutions have also been carried out when PIFA is activated by two equivalents of Lewis acids such as trimethylsilyl triflu-oromethanesulfonate (TMSOTf) and BF3 Et20 or heteropolyacid in standard solvents such as CH2C12 and MeCN. These reactions were applied to intramolecular reactions by the same authors leading to biaryls (49) [54-57], quinone imine derivatives (50) [58], and dihydrobenzothiophens (51) [59], which are important structures of bioactive natural products [Eqs. (7)-(9)]. Dominguez and co-workers have expanded the above biaryl coupling reaction to the syntheses of benzo[c]phenanthridine system (52) [60] and heterobiaryl compounds (53) [61] [Eqs. (10,11)]. 

Fan, P. W., Bolton, J. L. Bioactivation of Tamoxifen to Metabolite E Quinone Methide Reaction with Glutathione and DNA. Drug Metab. Disp. 2001, 29, 891-896. 

Recently, it has been found that, in addition to its detoxification function and its function as a biomarker for up-regulation of other phase II enzymes, up-regulation of quinone reductase by monofunctional inducers may play a role in the stabilization of p53, the protein product of a tumor suppressor gene, which induces growth arrest and apoptosis. Sulforaphane has also been shown to mediate growth arrest and induce cell cycle arrest and apoptosis in many cancer cell lines, including those of human prostate, colon, and T-cell leukemia origin. - The exact mechanisms, and whether all the bioactivities of sulforaphane involve the ARE, are not yet understood. 

Mushrooms and various fungi and lichens are rich in enol metabolites and many exhibit significant bioactivities , such as usnic acid (14) which serves as a regulator for plant growth and shows antitumor and antibiotic activities " . The widely distributed quinone polyporic acid (15a, PPA) from the Purple-Dye Polypore mushroom (Hapalopilus nidu-lans) and other sources is a weak inhibitor (IC50 = 0.1 to >1.5 mM " ) of dihydroorotate... 

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