Antitumor agents quinone

Bisantrene (56), also known as orange crush", is a broad spectrum intercalating antitumor agent competing with doxorubicin and the somewhat more closely related quinone mitoxantrone (51)... 

The rationale for the cyclopent[Z>]indole design discussed above was that the quinone methide would build up in solution and intercalate/alkylate DNA. Enriched 13C-NMR studies indicate that the quinone methide builds up in solution and persists for hours, even under aerobic conditions (Fig. 7.21). In contrast, the quinone methide species formed by known antitumor agents (mitomycin C) are short lived and highly reactive. The spectrum shown in Fig. 7.21 also shows the N to O acyl transfer product that we isolated and identified. However, we could not determine if the quinone methide structure actually has the acetyl group on the N or O centers. 

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. 

Xing, C. Skibo, E. B. Dorr, R. T. Aziridinyl quinone antitumor agents based on indoles and cyclopent[6]indoles structure-activity relationships for cytotoxicity and antitumor activity. J. Med. Chem. 2001, 44, 3545-3562. 

Transformation of o-methoxyphenol (135) into o-quinone monoacetal (136) using PIDA was used for the initial step of the synthesis of the enediyne aglycone, ( )-calicheamicinone (10), of the potent antitumor agent calicheamicin [93] (Scheme 10). 

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... 

Quinone derivatives such as quinone methides (the monomethylene analogues of quinones) have also been extensively studied ([183] and references cited therein) because they possess biological activity, particularly as antitumor agents. The first thermally stable quinone methide having no substituents in the methylene group ( simple quinone methide ) was crystallographically characterized [183a], It was shown that stabilization of the quinone methide can be achieved by complexation to a transition metal center (5.25) ... 

Ellipticine quinones have an intrinsic interest as antitumor agents <04JME4958> and are also known intermediates in the synthesis of ellipticines <02CRV4303>. For instance, ellipticine quinones 53b and 53c have been transformed into the alkaloid ellipticine <80JA1457 90J(P1)1319 98H(48)1593>. Hence, these homolytic pyridine acylations by 2-indolylacyl radicals also constitute formal syntheses of the natural product. 

Compounds whose structures include a quinone moiety have been intensively investigated as potential antitumor agents. At least two quinones, mitomycin C and diaziquone, that have found their way to the clinic. These compounds in addition include a reactive aziridine ring. A recent entry that incorporates both those features, apaziquone (135), also known as E09, may be viewed as an oxidized indole. In the key reaction of a succinct synthesis to this agent, quinone 129 is allowed to react with... 

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].

To date, only two purely NRPS biosynthetic machineries have been reported from myxobacteria. The first NRPS pathway to be characterized (and the first myxobacterial gene cluster to be identified) directs the biosynthesis of the DNA-binding antibiotic and antitumor agent saframycin Mxl 30 in M. xanthus Its heterocyclic quinone structure originates from a linear peptide intermediate 27 (Ala-Gly-Tyr-Tyr), which is synthesized by a tetramodular assembly line composed of two multifunctional NRPSs, SafA and SafB (Figure 10). It is likely that the tyrosine precursor is modified to 3-hydroxy-5-methyl-0-methyltyrosine through hydroxylation as well as O- and C-methylation reactions, before the monomer is loaded onto the NRPS complex. Once the tetrapeptide structure (27) is constructed, chain release by the last module of the assembly line should occur. However, in SafA, the typical C-terminal TE domain is substituted with a putative... 

Finally, quinones from the benzoquinone group have also been reported to be antitumor agents against several tumoral cell lines, such as prostatic cancer [84] and human leukaemia K 562 cells [85],... 

The related pyranoindolo-2,4-dione (314), prepared from the indole diester (313), also undergoes reaction with a quinone to give a cycloadduct (315), which presumably arises from the intermediacy of a quinodiketene the adduct is a precursor of the antitumor agent daunomycin (Scheme 96) <90CPB585>. 

Fryatt, T., Pettersson, H.I., Gardipee, W.T., Bray, K.C., Green, S.J., Slawin, A.M.Z., Beall, H.D. and Moody, C.J. 2004. Novel quinolinequinone antitumor agents Structure-metabolism studies with NAD(P)H quinone oxidoreductase (NQOl). Bio. Med. Chem. 12 1667-1687. 

ELECTROCHEMISTRY IN CANCER APPLICATIONS TO PHARMACOLOGICAL STUDIES OF QUINONE-CONTAINING ANTITUMOR AGENTS... 

Electrochemistry in Cancer Applications to Pharmacological Studies and Quinone-Containing Antitumor Agents... 

Churcher, I., Hallett, D. and Magnus, P. (1998) Synthesis of the antitumor agent aglycon ( )-calicheamicinone using an o-quinone monoketal strategy. Journal of the American Chemical Society, 120(40), 10350-10358. 

Quinone methides have been shown to be important intermediates in chemical synthesis,1 2 in lignin biosynthesis,3 and in the activity of antitumor and antibiotic agents.4 They react with many biologically relevant nucleophiles including alcohols,1 thiols,5-7 nucleic acids,8-10 proteins,6 11 and phosphodiesters.12 The reaction of nucleophiles with ortho- and /iara-quinone methides is pH dependent and can occur via either acid-catalyzed or uncatalyzed pathways.13-17 The electron transfer chemistry that is typical of the related quinones does not appear to play a role in the nucleophilic reactivity of QMs.18... 

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