DESIGN OF PYRIMIDO[4,5-G]QUINAZOLINE-BASED ANTHRAQUINONE MIMICS - STRUCTURE ACTIVITY RELATIONSHIP FOR QUINONE METHIDE FORMATION AND THE INFLUENCE OF INTERNAL HYDROGEN-BONDS ON QUINONE METHIDE FATE

Pyrimido[4,5-g]quinazolinequinone derivatives were synthesized as a anthraquinone-like reductive alkylating agents. Like many naturally-occurring antibiotics, these quinone derivatives are designed to afford an alkylating quinone methide species upon reduction and leaving-group elimination. Kinetic studies of pyrimido[4,5-g]quinazoline hydroquinones provided evidence of quinone methide intermediate able to trap nucleophiles (alkylation) and protons (ketonization). The rate of quinone methide formation is determined by the hydroquinone free energy. Thus, a linear free energy relationship for quinone methide formation was obtained by plotting rates of quinone methide formation as the log versus the quinone reduction potential. The pyrimido[4,5-g]quinazoline quinone methides fall on this free energy plot, showing that these species are formed by the same mechanism as the other structurally-diverse quinone methides previously studied in this research group. Internal hydrogen bonds present in pyrimido[4,5-g]quinazoline derivatives influence the fate of the quinone methide species as well as the rate of hydroquinone oxidation in the presence of oxygen Such hydrogen bonds stabilize the hydroquinone species, thereby resulting in slow rates of hydroquinone oxidation to quinone in alkaline aerobic buffer. Stabilization of the hydroquinone also results in substantial nucleophile trapping by the quinone methide. Without internal hydrogen bonds, hydroquinone oxidations are rapid and the quinone methide traps only electrophiles.