F. Charmantray et al., Synthesis and study of 4-hydroxymethyl-3-(alkylamino) acridines as models of a new class of DNA-intercalating-alkylating agents, J CHEM S P1, (22), 2001, pp. 2962-2968
The synthesis, and the reactions with nucleophiles, of 4-hydroxymethyl-3-(d
imethylamino)- and -3-(methylamino)- acridines are presented. The reactivit
y of both compounds in methanol and propan-2-ol is studied. The correspondi
ng 4-methoxy- and 4-isopropoxymethyl-3-(alkylamino) acridines are obtained
quantitatively. Kinetics data indicate that protonation of the acridine rin
g nitrogen greatly increases reaction rates, and results are in favour of a
very efficient intramolecular acid-base catalysis generating quinone-imine
-methide intermediates. Transetherification reactions (i.e., transformation
of methyl ethers into isopropyl ethers) are also observed. The reactivity
with DNA is studied. Covalent binding to calf-thymus DNA is evidenced by UV
-visible analysis of the modi ed DNA pellets. Ratios of 1 drug bound per 14
base pairs for the 3-methylamino analogue and 1 drug per 16 base pairs for
the dimethyl analogue are calculated, and correspond to 50% of the drugs b
ound to the macromolecule.