Quinone methides alkylating agents

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

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. 

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. 

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. 

Ouyang, A. Skibo, E. B. Design of a cyclopropyl quinone methide reductive alkylating agent. J. Org. Chem. 1998, 63, 1893-1900. 

Freccero, M. Quinones methides as alkylating and cross-linking agents. Mini-Reviews Org. Chem. 2004, 1, 403 415. 

One successful approach to suicide inhibitors for serine proteases is outlined in Figure 8. The dihydrocoumarin reacts with chymotrypsin to form an acyl enzyme and uncover a p-hydroxybenzyl chloride functional group. This is an extremely reactive alkylating agent due to formation of the quinone methide and the enzyme is rapidly inactivated (44). It is likely that suicide substrates will be applied to other proteases in the future. 

Incorporation of a benzylic halide into the structure of the alternate-substrate lactone (12-4) led to the bifunctional lactones (13-1, Table 2.13), and (13-2), which showed rapid and irreversible inactivation of a-chymotrypsin and PPE [178]. It was postulated that the intermediate acyl-enzyme formed from attack of Ser-195 on the lactone carbonyl dehydrohalogenated to form a reactive quinone methide that coupled with His-57. If this mechanism were followed, then lactone (13-2) would be an example of a mechanism-activated inhibitor. However, lactone (13-2) is sufficiently reactive as an alkylating agent to directly couple with imidazole while the lactone ring is intact. Because of this, it is not clear, from the published data, whether acylation of Ser-195 precedes alkylation, a prerequisite for this compound to be confirmed as a mechanism-activated inhibitor. Interestingly, the corresponding coumarin (13-3) was both less potent and only provided partial inactivation of a-chymotrypsin [179, 180]. It was shown that the lactone linkage in this coumarin was stable in the presence of a-chymotrypsin and that the modified enzyme retained its intact active-site. These facts led to the postulate that, like the action of phenacyl bromides or benzyl bromides on a-chymotrypsin, the partial inactivation by (13-3) involves alkylation of Met-192 [179]. 

Dimethyl-5-methoxyindole prepared via the VNS cyanomethylation of 3-methyl-4-methoxynitrobenzene has been used as starting material for the synthesis of cyclopropano-annelated quinone methide, a reductive alkylating agent for in vitro studies of its interactions with deoxyguanosine-5 -monophosphate (Scheme 67) [185]. 

Figure 7 Proposed mechanism for formation of free radicals and porential alkylating agents by anchracyclines in the presence of redox enzymes (flavc oteins IF]), which reduce die anihracy-dine in a one-electron step to the semiquinone. The Cj-quinone methide, a potential alkylating agent, is a tautomer of the deoxyaglycone produced from this reaction. (Redrawn and modified from Ref. 206.)...

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