title: Substituents on quinone methides strongly modulate formation and stability of their nucleophilic adducts.
abstract: Electronic perturbation of quinone methides (QM) greatly influences their stability and in turn alters the kinetics and product profile of QM reaction with deoxynucleosides. Consistent with the electron-deficient nature of this reactive intermediate, electron-donating substituents are stabilizing and electron-withdrawing substituents are destabilizing. For example, a dC N3-QM adduct is made stable over the course of observation (7 days) by the presence of an electron-withdrawing ester group that inhibits QM regeneration. Conversely, a related adduct with an electron-donating methyl group is very labile and regenerates its QM with a half-life of approximately 5 h. The generality of these effects is demonstrated with a series of alternative quinone methide precursors (QMP) containing a variety of substituents attached at different positions with respect to the exocyclic methylene. The rates of nucleophilic addition to substituted QMs measured by laser flash photolysis similarly span 5 orders of magnitude with electron-rich species reacting most slowly and electron-deficient species reacting most quickly. The reversibility of QM reaction can now be predictably adjusted for any desired application.
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Weinert
authors.forename: Ruggero
authors.initials: R
authors.lastname: Dondi
authors.forename: Stefano
authors.initials: S
authors.lastname: Colloredo-Melz
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Frankenfield
authors.forename: Charles H
authors.initials: CH
authors.lastname: Mitchell
authors.forename: Mauro
authors.initials: M
authors.lastname: Freccero
authors.forename: Steven E
authors.initials: SE
authors.lastname: Rokita
mesh_terms: D001667:Binding, Competitive; D004355:Drug Stability; D045563:Indolequinones / Q000737:chemistry*; D007700:Kinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D009705:Nucleosides / Q000737:chemistry; D010782:Photolysis; D013329:Structure-Activity Relationship
chemical_list: D045563:Indolequinones; D009705:Nucleosides; C068040:quinone methide