Kinetic and equilibrium binding studies of amsacrine-4-carboxamides: a class of asymmetrical DNA-intercalating agents which bind by threading through the DNA helix.
Detailed equilibrium and kinetic studies of the DNA interaction of the amsacrine-4-carboxamide class of compounds suggest that they bind by intercalating the acridine chromophore at near-maximal overlap with the base pairs, locating their two dissimilar side chains in specific grooves of the double helix. The first step is a fast bimolecular association to form an outside-bound complex (probably in the major groove). Insertion of the less bulky carboxamide side chain then occurs in a process governed largely by the rate of transient opening of the double helix by natural "breathing" motions and is followed by further monomolecular rearrangements to allow the carboxamide side chain to find its highest affinity binding sites in the minor groove. Dissociation of the complexes are much more ligand structure dependent, but also involve opening of the double helix to allow disengagement. Compounds of this type, which locate their two distinguishable side chains one in each DNA groove, form a unique class of DNA-binding ligand, with considerable potential for regiospecific delivery of reactive functionality to DNA. Although natural products which also have such specific binding modes are known (e.g. nogalamycin), the amsacrine-4-carboxamides discussed here are the first class of readily modified synthetic compounds with this property.
Wakelin
L P
LP
Molecular Sciences Group, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
Chetcuti
P
P
Denny
W A
WA
D000577:Amides / Q000138:chemical synthesis / Q000378:metabolism; D000677:Amsacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D004247:DNA / Q000378:metabolism*; D007202:Indicators and Reagents; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000378:metabolism; D007700:Kinetics; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides; D013329:Structure-Activity Relationship
D000577:Amides; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D000677:Amsacrine; D004247:DNA