Conjugation of a hairpin pyrrole-imidazole polyamide to a quinone methide for control of DNA cross-linking.
A series of quinone methide precursors designed for DNA cross-linking were prepared and conjugated to a pyrrole-imidazole polyamide for selective association to the minor groove. Although reaction was only observed for DNA containing the predicted recognition sequence, yields of strand alkylation were low. Interstrand cross-linking was more efficient than alkylation but still quite modest and equivalent to that generated by a comparable conjugate containing the N-mustard chlorambucil. Varying the length of the linker connecting the polyamide and quinone methide derivative did not greatly affect the yield of DNA cross-linking. Instead, intramolecular trapping of the quinone methide intermediate by nucleophiles of the attached polyamide appears to be the major determinant that limits its reaction with DNA. Self-adducts of the quinone methide conjugate form readily and irreversibly as detected by a combination of chromatography and mass spectroscopy. This result is unlike comparable self-adducts observed for oligonucleotide conjugates that form more slowly and remain reversible. Equivalent intramolecular alkylation of a polyamide by its attached chlorambucil mustard was not observed under similar condition. The presence of DNA, however, did facilitate hydrolysis of this mustard conjugate.
Kumar
Dalip
D
Department of Chemistry and Biochemistry, University of Maryland, College Park 20742, USA.
Veldhuyzen
Willem F
WF
Zhou
Qibing
Q
Rokita
Steven E
SE
D000478:Alkylation; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry*; D045563:Indolequinones / Q000138:chemical synthesis / Q000737:chemistry*; D015394:Molecular Structure; D009150:Mustard Compounds / Q000737:chemistry; D009757:Nylons / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*
D003432:Cross-Linking Reagents; D007093:Imidazoles; D045563:Indolequinones; D009150:Mustard Compounds; D009757:Nylons; D011758:Pyrroles; C068040:quinone methide; C029899:imidazole; D004247:DNA