Bifunctional rhodium intercalator conjugates as mismatch-directing DNA alkylating agents.
A conjugate of a DNA mismatch-specific rhodium intercalator, containing the bulky chrysenediimine ligand, and an aniline mustard has been prepared, and targeting of mismatches in DNA by this conjugate has been examined. The preferential alkylation of mismatched over fully matched DNA is found by a mobility shift assay at concentrations where untethered organic mustards show little reaction. The binding site of the Rh intercalator was determined by DNA photocleavage, and the position of covalent modification was established on the basis of the enhanced depurination associated with N-alkylation. The site-selective alkylation at mismatched DNA renders these conjugates useful tools for the covalent tagging of DNA base pair mismatches and new chemotherapeutic design.
Schatzschneider
Ulrich
U
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Barton
Jacqueline K
JK
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives / Q000737:chemistry; D000477:Alkylating Agents / Q000737:chemistry; D000478:Alkylation; D020137:Base Pair Mismatch; D001665:Binding Sites; D002911:Chrysenes / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D007364:Intercalating Agents / Q000737:chemistry*; D008024:Ligands; D046911:Macromolecular Substances; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D010618:Phenanthrolines / Q000737:chemistry; D012238:Rhodium / Q000737:chemistry*; D013379:Substrate Specificity
D000477:Alkylating Agents; D002911:Chrysenes; D007364:Intercalating Agents; D008024:Ligands; D046911:Macromolecular Substances; D009942:Organometallic Compounds; D010618:Phenanthrolines; D015082:2,2'-Dipyridyl; D004247:DNA; D012238:Rhodium