Comparative computer graphics and solution studies of the DNA interaction of substituted anthraquinones based on doxorubicin and mitoxantrone

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Abstract
1-[[(Diethylamino)ethyl]amino]- and 1,4-, 1,5- and 1,8-bis[[(diethylamino)ethyl]amino]anthraquinones intercalate into DNA. Computer graphics modeling of their intercalation into the self-complementary deoxydinucleoside d(CpG) showed differences in binding properties. While the 1-substituted compound can bind from either groove, the 1,8-disubstituted compound binds with both substituents in the major groove. In the low-energy state of the complex with the 1,5-disubstituted compound, this ligand straddles the site with a substituent in each groove: to do this, the compound must bind to a non-base-paired region, so inducing base pairing. The 1,4-compound binds from the major groove; straddling is also possible if full minimization of deoxydinucleoside geometry is performed. The differences in binding mode and interaction energies are reflected in the affinities of interaction (1,5- > 1,4- .mchgt. 1,8- > 1-); also the antiproliferative effects in vitro [mouse P388 leukemia] are in general agreement with this ranking.