Nucleic acid binding drugs--XIV. The crystal structure of 1-methyl amsacrine hydrochloride; relationships to DNA-binding ability and anti-tumour activity.
The crystal structure of the 1-methyl derivative of the anticancer drug amsacrine [4'-(acridin-9-ylamino)-3'-methoxy-methanesulphonanilide+ ++] as its hydrochloride salt has been determined. The compound crystallizes in the monoclinic space group P21/n with cell dimensions a = 15.302(3), b = 8.035(2), c = 18.258(4) A and beta = 102.68(2) degrees, and has been refined to a final R of 0.055. The acridine chromophore is significantly non-planar, with a butterfly conformation about the C(9)-N(11) bond. The bonding geometry about the C(9) atom has been significantly altered compared to non-distorted amsacrine structures, as a result of this non-planarity. Energy calculations have been used to examine the flexibility of the molecule with respect to rotations about the C(9)-N(11) and N(11)-C(12) bonds, and with respect to intercalation into a dinucleoside duplex model for DNA. The latter calculations have been compared with solution DNA-binding and in vitro activity data for 1-methyl-amsacrine hydrochloride. The molecular modelling studies find that the energy of interaction between 1-methyl-amsacrine and a DNA intercalation fragment is significantly higher than for amsacrine itself, in accord with the biological data.
D000677:Amsacrine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D003460:Crystallization; D004247:DNA / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D000677:Amsacrine; C050734:1-methylamsacrine; D004247:DNA