Pyrido indole quinone methide

FIGURE 7.16 Trapping of the phosphate of 5 -dGMP by the pyrido [1,2-a] indole quinone methide. The 13C-NMR shows most trapping with ring retention, labeled pyrido, with trace amounts of ring expansion, labeled azepino. ... 

FIGURE 7.19 pH-rate profile for the disappearance pyrido[l,2-a]indole quinone methide. 

SCHEME 7.17 Electrostatic potential map of the protonated pyrido[l,2-<2]indole-based cyclopropyl quinone methide. The two possible nucleophile-trapping paths with the respective products are shown. 

In a recent study, we showed that the more flexible pyrido[l,2-a]indole-based cyclopropyl quinone methide is not subject to the stereoelectronic effect.47 Scheme 7.17 shows an electrostatic potential map of the protonated cyclopropyl quinone methide with arrows indicating the two possible nucleophilic attack sites on the electron-deficient (blue-colored) cyclopropyl ring. The 13C label allows both nucleophile attack products, the pyrido[l,2-a]indole and azepino [l,2-a]indole, to be distinguished without isolation. The site of nucleophilic is under steric control with pyrido [1,2-a]indole ring formation favored by large nucleophiles. 

The results of the methanolic solvolysis study shown in Fig. 7.15 reveals that nucleophilic attack on the cyclopropyl quinone methide by methanol affords the pyrido[1,2-a]indole (73 ppm) and azepino[l,2-a]indole (29ppm) trapping products. Initially, nucleophilic attack on the cyclopropane ring affords the hydroquinone derivatives (see Scheme 7.17) that oxidizes to the quinones upon aerobic workup. 

FIGURE 7.15 Enriched 13C-NMR of the methanolic solvolysis pyrido [l,2-a]indole-based cyclopropyl quinone methide. 

To assess the trapping of biological nucleophiles, the pyrido[l,2-a]indole cyclopropyl quinone methide was generated in the presence of 5 -dGMP. The reaction afforded a mixture of phosphate adducts that could not be separated by reverse-phase chromatography (Fig. 7.16). The 13C-NMR spectrum of the purified mixture shown in Fig. 7.16 reveals that the pyrido [1,2-a] indole was the major product with trace amounts of azepino[l,2-a] indole present. Since the stereoelec-tronic effect favors either product, steric effects must dictate nucleophilic attack at the least hindered cyclopropane carbon to afford the pyrido[l,2-a]indole product. Both adducts were stable with elimination and aromatization not observed. In fact, the pyrido [1,2-a] indole precursor (structure shown in Scheme 7.14) to the pyrido [l,2-a]indole cyclopropyl quinone methide possesses cytotoxic and cytostatic properties not observed with the pyrrolo [1,2-a] indole precursor.47... 

SCHEME 7.18 Formation and fate of the pyrrolo[l,2-a]indole (w — 0) and the pyrido[l,2-a] indole-based ( = 1) quinone methides. 

The rate constants associated with the acid-catalyzed conversion of the pyrido[ 1,2- ]indole hydroquinone to its quinone methide were too large to measure. We did manage to measure two rate constants at pH 7 and 8, both with a value of 0.36 min-1. Based on the pH-rate profile obtained the pyrrolo 1,2-a indole hydroquinone, these... 

Khdour O, Skibo EB (2007) Chemistry of pyrrolo[l,2-a]indole- and pyrido[l,2-a]indole-based quinone methides. Mechanistic explanations for differences in cytostatic/cytotoxic properties. J Org Chem 72 8636-8647... 

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