Quinone methides alkylation

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

An external nucleophile, mercaptoethanol, was added to determine whether inactivation of the enzyme was preventable by consuii tion of the electrophilic hydrolysis product of compound 1 before the electrophile (quinone methide) alkylated the enzyme. Protection by the thiol did not occur, indicating that the inhibiting electrophile was formed in and remained in the enzyme active site. 

DNA alkylation has the potential to yield a time-dependent spectrum of adducts, in which initially formed kinetically favored lesions give way to the thermodynamically favored adducts over time. Reversible alkylation has been observed at several of the nucleophilic sites in DNA, including N3A (CC-1065,7, Scheme 8.10, duocarmycin, 8)," " NIA (qui-none methide, 9)," N7G (leinamycin, Schane 8.11, aflatoxin Bj epoxide, 10 and quinone methide, 9),57.ii4.ii8 (quinone methide, 9)," and bPG (ecteinascidin 743,11)." The bidentate Nl/ISPG adduct of malondialdehyde also forms reversibly. ... 

Bolton, J. L. Turnipseed, S. B. Thompson, J. A. Influence of quinone methide reactivity on the alkylation of thiol and amino groups in proteins studies utilizing amino acid and peptide models. Chem.-Biol. Interact. 1997, 107, 185-200. 

Lewis, M. A. Graff Yoerg, D. Bolton, J. L. Thompson, J. A. Alkylation of 2 -deoxy-nucleosides and DNA by quinone methides derived from 2,6-di-tert-butyl-4-methyl-phenol. Chem. Res. Toxicol. 1996, 9, 1368-1374. 

Weinert, E. E. Rokita, S. E. Kinetic and trapping studies of 2 -deoxynucleoside alkylation by a quinone methide. Chem. Res. Toxicol. 2005, 18, 1970-1970. 

Thompson, D. C. Perera, K. London, R. Spontaneous hydrolysis of 4-trifluoromethyl-phenol to a quinone methide and subsequent protein alkylation. Chem.-Biol. Interact. 2000, 126, 1-14. 

Modica, E. Zanaletti, R. Freccero, M. Alkylation of amino acids and glutathione in water by o-quinone methide. Reactivity and selectivity. J. Org. Chem. 2001, 66, 41-52. 

Di Valentin, C. Freccero, M. Zanaletti, C. Sarzi-Amade, M. o-Quinone methide as alkylating agent of nitrogen, oxygen, and sulfur nucleophiles. The role of H-bonding and solvent effects on the reactivity through a DFT computational study, j. Am. Chem. Soc. 2001, 123, 8366-8377. 

Freccero, M. Gandolfi, R. Sarzi-Amade, M. Selectivity of purine alkylation by a quinone methide. Kinetic or thermodynamic control J. Org. Chem. 2003, 68, 6411-6423. 

K. Mizutani, T. Electronic and structural requirements for metabolic activation of butylated hydroxytoluene analogs to their quinone methides, intermediates responsible for lung toxicity in mice. Biol. Pharm. Bull. 1997, 20, 571-573. (c) McCracken, P. G. Bolton, J. L. Thatcher, G. R. J. Covalent modification of proteins and peptides by the quinone methide from 2-rm-butyl-4,6-dimethylphenol selectivity and reactivity with respect to competitive hydration. J. Org. Chem. 1997, 62, 1820-1825. (d) Reed, M. Thompson, D. C. Immunochemical visualization and identification of rat liver proteins adducted by 2,6-di- m-butyl-4-methylphenol (BHT). Chem. Res. Toxicol. 1997, 10, 1109-1117. (e) Lewis, M. A. Yoerg, D. G. Bolton, J. L. Thompson, J. Alkylation of 2 -deoxynucleosides and DNA by quinone methides derived from 2,6-di- m-butyl-4-methylphenol. Chem. Res. Toxicol. 1996, 9, 1368-1374. 

For over 35 years, the quinone methide species has been invoked as a reactive intermediate in bioreductive alkylation and in other biological processes.8 29 Generally, there is only circumstantial evidence that the quinone methide species forms in solution. Conceivably, the O-protonated quinone methide (i.e., the hydroquinone carbocation) could be the electrophilic species. If so, bioreductive alkylation may simply be an SN1 reaction. Also, there are questions concerning the mechanism of quinone methide... 

The bioreductive alkylating agents developed in this laboratory did not afford observable quinone methide species upon quinone reduction and leaving group... 

The UV-Vis spectral detection of an intermediate in the catalytic reductive alkylation reaction provides only circumstantial evidence of the quinone methide species. If the bioreductive alkylating agent has a 13C label at the methide center, then a 13C-NMR could provide chemical shift evidence of the methide intermediate. Although this concept is simple, the synthesis of such 13C-labeled materials may not be trivial. We carried out the synthesis of the 13C-labeled prekinamycin shown in Scheme 7.5 and prepared its quinone methide by catalytic reduction in an N2 glove box. An enriched 13C-NMR spectrum of this reaction mixture was obtained within 100 min of the catalytic reduction (the time of the peak intermediate concentration in Fig. 7.2). This spectrum clearly shows the chemical shift associated with the quinone methide along with those of decomposition products (Fig. 7.3). 

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. 

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... 

Ping, W. Yang, S. Lixia, Z. Hanping, H. Xiang, Z. Quinone methide derivatives important intermediates to DNA alkylating and DNA cross-linking actions. Curr. Med. Chem. 2005, 12, 2893-2913. 

Lemus, R. L. Skibo, E. B. Studies of extended quinone methides. Design of reductive alkylating agents based on the quinazoline ring system, j. Org. Chem. 1988, 53, 6099-6105. 

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