%0 Journal Article
%A Khdour, Omar
%A Skibo, Edward B.
%D 2007
%T Chemistry of Pyrrolo[1,2-a]indole- and Pyrido[1,2-a]indole-Based
Quinone Methides. Mechanistic Explanations for Differences in
Cytostatic/Cytotoxic Properties
%U https://acs.figshare.com/articles/journal_contribution/Chemistry_of_Pyrrolo_1_2_i_a_i_indole_and_Pyrido_1_2_i_a_i_indole_Based_Quinone_Methides_Mechanistic_Explanations_for_Differences_in_Cytostatic_Cytotoxic_Properties/2975668
%R 10.1021/jo070866o.s002
%2 https://ndownloader.figshare.com/files/4676146
%K vinyl quinone formation
%K quinone methide reactivity
%K pyrrolo ring
%K pyrido ring
%K protonated carbonyl pKa values
%K quinone methide
%K vinyl quinone species
%X In the present study we investigate pyrido[1,2-a]indole- and pyrrolo[1,2-a]indole-based quinones capable
of 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 fused
rings on quinone methide and vinyl quinone formation and fate as well as on cytostatic and cytotoxic
activity. We used the technique of Spectral Global Fitting to study the fleeting quinone methide intermediate
directly. Conclusions regarding quinone methide reactivity are that carbonyl O-protonation is required
for nucleophile trapping and that the pKa value of this protonated species is near neutrality. The abnormally
high protonated carbonyl pKa values are due to the formation of an aromatic carbocation species upon
protonation. The fused pyrido ring promotes quinone methide and vinyl quinone formation but slows
nucleophile trapping compared to the fused pyrrolo ring. These findings are explained by the presence
of axial hydrogen atoms in the fused pyrido ring resulting in more steric congestion compared to the
relatively flat fused pyrrolo ring. Consequently, pyrrolo[1,2-a]indole-based quinones exhibit more cytostatic
activity than the pyrido[1,2-a]indole analogues due to their greater nucleophile trapping capability.
%I ACS Publications