Cytotoxicity of quinones

In light of the results we discussed in previous sections, which indicate that the cytotoxicity of quinones is due to generation of free radicals and DNA damage, it seems that these compormds would be potent triggers of apoptosis. 

The first examples of macrocyclization by enyne RCM were used in Shair s impressive biomimetic total synthesis of the cytotoxic marine natural product longithorone A (429) [180]. This unique compound features an unusual hep-tacyclic structure which, in addition to the stereogenic centers in rings A-E, is also chiral by atropisomerism arising from hindered rotation of quinone ring G through macrocycle F (Scheme 85). It was assumed that biosynthesis of 429 could occur via an intermolecular Diels-Alder reaction between [12]paracy-... 

Like for benzene, the cytotoxicity of naphthalene is not due to the epoxide but to the quinone metabolites, namely 1,2-naphthoquinone and 1,4-naphthoquinone [85], As shown in Table 10.1, naphthalene 1,2-oxide (10.2) is a better substrate than benzene oxide for epoxide hydrolase. Its rapid isomerization to naphthalen-l-ol, facile enzymatic hydration to the dihydrodiol and lack of reactivity toward nucleophiles such as glutathione may explain its absence of direct toxicity [85],... 

Although all quinones have the same functional group, their physicochemical behavior and mechanisms of toxicity vary due to the presence of different substituents. Thus, the cellular aspects of quinone metabolism are diverse, and a single mechanism explaining these actions has not yet been identified. Furthermore, it is noteworthy that the cytotoxicity of some xenobiotic compomids, such as benzene, benzo[a]pyrene, and 1-naphthol, may partly be caused by metabolic conversion of these compoimds to quinones (Snyder et al, 1987 Zheng et al, 1997). 

Wislocki, P., A. Wood, R. Chang, W. Levin, H. Yagi, O. Hernandez, P. Dansette, D. Jerina, and A. Conney, Mutagenicity and Cytotoxicity of Benzo[u]pyrene, Arene Oxides, Phenols, Quinones, and Dihydrodiols in Bacterial and Mammalian Cells, Cancer Res., 36, 3350-3357 (1976). 

The cytotoxicity of several benzo-annulated iso-a-carbolines (369-372, 377, 378, 380) has been studied in vitro on human tumor KB cells (Table X) 136). The linear ellipticine analog 371 is 10 times more active than ellipticine (1) in this screen. As was mentioned earlier, this derivative also displays significant in vivo activity against P388, L1210, and B16 implanted mouse tumors TIC values 190, 175, and 224%, respectively). The resemblance of the imine grouping of these iso-a-carbolines to ellipticine quinone imine 6 is obvious. It will be of interest to see how the electrophilic behavior of these compounds compares to that of the quinone imines. 

Quinone exists in the atmosphere in the gas phase. The dominant atmospheric loss process for quinone is expected to be by reaction with the hydroxyl (OH) radical (reaction with ozone is expected to be slow because of the >C(0) substituent groups). The estimated half-life and lifetime of quinone in the atmosphere due to reaction with the OH radical are 3 and 4 h, respectively. Bolton JL, Trush MA, Penning TM, Dryhurst G, and Monks TJ (2000) Role of quinones in toxicology. Chemical Research in Toxicology 13 135-160. Monks TJ and Jones DC (2002) The metabolism and toxicity of quinones, quinoimines, quinone methides, and quinone-thioethers. Current Drug Metabolism 3 425 38. O Brien PJ (1991) Molecular mechanisms of quinone cytotoxicity. Chemico-Biological Interactions 80 1-14. 

Blackstaffe, L., Shelley, M. D., and Fish, R. G. (1997). Cytotoxicity of gossypol enantiomers and its quinone metabolite gossypolone in melanoma cell lines. Melanoma Res. 7,364-372. 

Tirapazamine is inactivated by two-electron reduction steps catalyzed by quinone reductase, yielding first the mono-N-oxide (reaction a and compound 18). In contrast, it is activated to a cytotoxic nitroxide (16) by a one-electron reduction catalyzed by NADPH-cytochrome P450 reductase (reaction b). This delocalized radical loses one molecule of water to yield a reactive radical (reaction c and compound 17). Radical 17 can then abstract one hydrogen radical from DNA (reaction d and compound 18), leading to DNA breaks and cytotoxicity. In summary, both inactivation and activation involve reduction reactions, but cytotoxicity will depend on the relative levels of quinone reductase and CYP reductase in hypoxic cells. 

The role of xenobiotic metabolism in the cytotoxicity of an ecotoxicant to fish cell lines has been best studied with BaP, but even with this PAH the story is incomplete (Table 3). Two types of cytotoxic responses to BaP have been documented. One has been a transitory decline in metabolism, but not in cell viability, after BaP exposures of 24-48 h. This was observed in the rainbow trout liver cell lines, RTL-W1 and Rl174. Metabolism appeared necessary for this effect as the response was blocked in RTL-W1 and Rl by, respectively, the CYP1A inhibitor, a-naphthoflavone (ANF) and the prostaglandin-H-synthase inhibitor, indomethacin. BaP quinones were thought to be the BaP metabolites responsible for this effect. 

O Brien, P.J. (1991) Molecular mechanisms of quinone cytotoxicity. Chem.-Biol. Interact. 80 1-41. 

Brunmark and Cadenas (27A15) reviewed the major mechanisms that are involved in quinone-induced cytotoxicity in 1989. The redox chemistry of quinoid compounds was surveyed in terms of (1) reactions involving only electron transfers, such as those accomplished during the enzymatic reduction of quinones and nonenzymatic interaction with redox couples generating semiquinones, and (2) nucleophilic addition reactions. In their explanation of the mechanisms involved, quinone is reduced to the hydroquinone or semiqui-none radical by cellular reductase. The semiquinone radical then undergoes rapid autooxidation with the generation of the parent quinone and concomitant formation of superoxide. The hydroquinone reacts rapidly with superoxide to form H2O2 and the semiquinone. 

Ellipticine (E) 1 is an indolic alkaloid with antitumor activity. Some of its phenolic derivatives as N-methyl-9-hydroxyellipticine (Celiptinium), obtained from 9-hydroxy ellipticine (9-OH E), exhibit high cytotoxicity. 38 Syntheses of 9-OH E are not satisfactory considering yields and cost, justifying the attempts at the direct conversion of E to 9-OH E via 9-oxoellipticine (9-0X0 E). Potassium nitrosodisulfonate (Fremy s salt), a valuable oxidant for the synthesis of quinone-imine from heterocyclic amines,139 was used. Under these conditions the conversion of E to 9-0X0 E was observed for the first time. Its reduction to 9-OH E is then easily achieved with ascorbic acid. The radical nature of Fremy s salt [ 0-N(S03K)2] led us to carry out the oxidation reaction under sonication in order to increase the yields via an easier electron transfer.1 1... 

By analogy to the results obtained with the phenol ferrocifen derivatives, the cytotoxicity of compounds 10 and 11 may be ascribed to the intermediate formation of imino methides (Fig. 47.12). Actually, imino methides have been implicated in cytotoxic processes [35-40]. However, while acetylated quinone imines are important toxic compounds, namely, identified in the metabolism of Parkinson s disease drug tolcapone [41] and the analgesic acetaminophen [42], acetylated imine methides... 

Rodriguez. J.. Quinoa. E.. Riguera, R.. Peters. B.M.. Abrell. L.M.. and Crews, P. (1992) The structure and stereochemistry of cytotoxic sesquiterpenes quinones from Dactylospongia elegans. Tetrahedron, 48, 6667-6680. 

Park, A. and Schmitz, F.J. (1993) Synthesis of perfragilin B, a cytotoxic isoquinoline quinone isolated from the bryozoan Membranipora peifragilis. Tetrahedron Lett., 34, 3983-3984. 

---