Prekinamycin quinone methide

SCHEME 7.5 Generation of the prekinamycin quinone methide. The 13C label is designated with an asterisk ( ). 

SCHEME 7.24 Hydrolysis mechanism of the prekinamycin quinone methide. 

FIGURE 7.25 pH-rate profile for prekinamycin quinone methide hydrolysis. 

The results of AE calculations shown in Scheme 7.26 show that internal hydrogen bonds can influence the thermodynamics of quinone methide tautomerization in some instances. For the prekinamycin quinone methide without internal hydrogen bonds... 

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). 

Our studies of quinone methides and related species using 13C labeling and spectral global fitting started in the late 1990s and have continued to the present with two papers on prekinamycins slated for publication in 2009. In this section, we summarize what we learned from both our published and unpublished studies. 

Table 7.3 shows the concentrations of 1-5 that result in 50% growth inhibition (GI50) of five human cancer cell lines. Inspection of these data reveals that cytostatic activity of 1 and 3-5 depends on the thermodynamic favorability of the quinone methide species compared to the corresponding keto form. The most cytostatic prekinamycins 1 and 5 are associated with the thermodynamically stable quinone methides. In contrast, the inactive prekinamycins 3 and 4 are associated with thermodynamically stable keto tautomers. The exception is prekinamycin 2, which is cytostatic and possesses a relatively stable keto tautomer 3 compared to its quinone methide. Although the AE value for quinone methide tautomerization can predict cytostatic properties, prekinamycin 2 shows that there must be other factors determining biological activity. 

Feldman and Eastman have suggested that the kinamycins may by reductively activated to form reactive vinyl radical (25) and orf/to-quinone methide (26) intermediates (Scheme 3.2c) [16]. The authors provided convincing evidence that the alkenyl radical 25 is generated when the model substrate dimethyl prekinamycin (24) is exposed to reducing conditions (tri-n-butyltin hydride, AIBN). Products that may arise from addition of this radical (25) to aromatic solvents (benzene, anisole, and benzonitrile) were isolated. The ort/io-quinone methide 26 was also formed,... 

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