Quinones anticancer

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. 

Quinone anticancer agents Daunomycin Q , Oj Cardiotoxicity Anti-cancer [33-35]... 

Bachur, N.R., S.L. Gordon, M.V Gee, and H. Kon (1979). NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals. Proc. Natl. Acad. Sci. USA 76, 954-957. 

Quinones of various degrees of complexity have antibiotic, antimicrobial, and anticancer activities, eg, a2iddinornitosene [80954-63-8] (36), (-)-2-methyl-l,4-naphthoquinone 2,3-epoxide [61840-91 -3] (37), and doxombicin [23214-92-8] (adriamycin) (38) (see Antibiotics Chemotherapeutics, anticancer), ah of these natural and synthetic materials have stimulated extensive research in synthetic chemistry. 

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. 

There are various pathways for free radical-mediated processes in microsomes. Microsomes can stimulate free radical oxidation of various substrates through the formation of superoxide and hydroxyl radicals (the latter in the presence of iron) or by the direct interaction of chain electron carriers with these compounds. One-electron reduction of numerous electron acceptors has been extensively studied in connection with the conversion of quinone drugs and xenobiotics in microsomes into reactive semiquinones, capable of inducing damaging effects in humans. (In 1980s, the microsomal reduction of anticancer anthracycline antibiotics and related compounds were studied in detail due to possible mechanism of their cardiotoxic activity and was discussed by us earlier [37], It has been shown that semiquinones of... 

Many organic and inorganic compounds, fibers, and particles are capable of damaging nucleic acids by generating reactive oxygen species via the reduction of dioxygen. These stimuli include different classes of organic compounds, classic prooxidants (anticancer antibiotics, various quinones, asbestos fibers, and so on), and even antioxidants, which can be oxidized in the presence of transition metal ions. 

Although reduction of quinones is usually a detoxication pathway, there are examples such as mitomycin C in which the hydroquinone is more toxic than the quinone as shown in Figure 5.12 and this may increase the susceptibility of cancers that express high levels of NQO. In this case, the reduction of the quinone leads to the loss of methanol, which is the first step in the activation of this anticancer agent (20). 

Komiyama, T., Kikuchi, T., and Sugiura, Y., 1986, Interactions of anticancer quinone dmgs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C, with NADPH-cytochrome P-450 reductase, xanthine oxidase and oxygen, J. Pharmacobiodyru 9 651-664. 

Tertiary amine oxides and hydroxy la mines are also reduced by cytochromes P-450. Hydroxylamines, as well as being reduced by cytochromes P-450, are also reduced by a flavoprotein, which is part of a system, which requires NADH and includes NADH cytochrome b5 reductase and cytochrome b5. Quinones, such as the anticancer drug adriamycin (doxorubicin) and menadione, can undergo one-electron reduction catalyzed by NADPH cytochrome P-450 reductase. The semiquinone product may be oxidized back to the quinone with the concomitant production of superoxide anion radical, giving rise to redox cycling and potential cytotoxicity. This underlies the cardiac toxicity of adriamycin (see chap. 6). 

This anthracydine type anticancer drug has a quinone moiety so can easily accept an electron and undergo redox cycling. As a result, it interferes with the mitochondrial electron transport chain, damages mitochondrial DNA, and leads to ATP depletion. The result is a dose-dependent cardiomyopathy. 

The sulfur compound sulfuraphane, extracted from fresh broccoli, has received attention in recent years because of its strong action in inducing synthesis of quinone reductase and glutathione S-transferases that help detoxify xenobiotics and may have significant anticancer activity/... 

Quinones of various degrees of complexity have antibiotic, antimicrobial. and anticancer activities. 

Quinones are a diverse group of substances generally soluble in organic solvents and not saponified by alkali. They are yellow to red pigments, often constituents of wood tissues, and have toxic and antimicrobial properties. Plants containing quinines with anticancer properties include the following ... 

Lau, D.H. et al. (1989) Association of DNA cross-linking with potentiation of the morpholino derivative of doxorubicin by human liver microsomes, J. Nat. Cancer Inst. 81, 1034-1038. Rumyantseva, G.V. et al. (1989) Hydroxyl radical generation and DNA strand scission mediated by natural anticancer and synthetic quinones, FEBS letters 242, 397-400. 

The anticancer activity and host toxicity of compounds with a quinone group was investigated. There is considerable death of tumour cells, together with the induction of breaks in DNA single and double strands, although a low binding value for the semiubiquinone with DNA was found [132]. 

Calphostin C] (perylene quinone) Cladosporium cladosporioides (fungus) PKC [anticancer, antiviral]... 

Antibiotic-683 (210) [152] reveals an unusual OH residue at C-4 and is therefore related to elmycin E and X-14881 D [3]. The nearly completely saturated ring C is probably a result of biosynthetic redox reactions leading to an epoxide ring between C-6 a and C-12 a and a reduced quinone system (see also elmycin C). Structure 210 is produced by Streptomyces sp. strain Y-83,30683 and shows antibacterial and extraordinary anticancer (mouse leukemia l-1210, ICjq 3 g ml ) activities. Another recent relative of 210 and elmycin C is angucyclinone D 211,... 

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