Comparative computer graphics and solution studies of the DNA interaction of substituted anthraquinones based on doxorubicin and mitoxantrone.
1-[[(Diethylamino)ethyl]amino]- and 1,4-, 1,5-, and 1,8-bis[[(diethylamino)ethyl]amino]anthraquinones are shown to intercalate into DNA. Computer graphics modelling 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- greater than 1,4- much greater than 1,8- greater than 1-); also the antiproliferative effects in vitro are in general agreement with this ranking.
D000818:Animals; D000880:Anthraquinones / Q000378:metabolism* / Q000627:therapeutic use; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D003201:Computers; D004247:DNA / Q000378:metabolism*; D004317:Doxorubicin / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008942:Mitoxantrone; D012996:Solutions; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000880:Anthraquinones; D012996:Solutions; D004317:Doxorubicin; D004247:DNA; D008942:Mitoxantrone