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| - Chemistry of Pyrrolo[1,2-a]indole- and Pyrido[1,2-a]indole-BasedQuinone Methides. Mechanistic Explanations for Differences inCytostatic/Cytotoxic Properties
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| - In the present study we investigate pyrido[1,2-a]indole- and pyrrolo[1,2-a]indole-based quinones capableof forming quinone methide and vinyl quinone species upon reduction and leaving group elimination.Our goals were to determine the influence of the 6-membered pyrido and the 5-membered pyrrolo fusedrings on quinone methide and vinyl quinone formation and fate as well as on cytostatic and cytotoxicactivity. We used the technique of Spectral Global Fitting to study the fleeting quinone methide intermediatedirectly. Conclusions regarding quinone methide reactivity are that carbonyl O-protonation is requiredfor nucleophile trapping and that the pKa value of this protonated species is near neutrality. The abnormallyhigh protonated carbonyl pKa values are due to the formation of an aromatic carbocation species uponprotonation. The fused pyrido ring promotes quinone methide and vinyl quinone formation but slowsnucleophile trapping compared to the fused pyrrolo ring. These findings are explained by the presenceof axial hydrogen atoms in the fused pyrido ring resulting in more steric congestion compared to therelatively flat fused pyrrolo ring. Consequently, pyrrolo[1,2-a]indole-based quinones exhibit more cytostaticactivity than the pyrido[1,2-a]indole analogues due to their greater nucleophile trapping capability.
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