title: [Direct site-specific cleavage of double-stranded DNA by conjugates of bleomycin A5 with triplex-forming oligonucleotide].
abstract: Monofunctional conjugates of 15-mer triplex-forming oligonucleotide (TFO) with covalently attached bleomycin A5 residue at the 5'-end (Blm-p15) were synthesized. Bifunctional conjugates of TFO containing, in addition to Blm, the residues of intercalator 6-chloro-2-methoxy-9-aminoacridine (Acr) or (N-(2-hydroxyethyl)phenazinium (Phn) were obtained for the first time. The Acr and Phn residues were attached to the 3'-phosphate group of TFO through L1 and L2 linkers, respectively, resulting in the compounds Blm-p15pL1-Acr and Blm-p15pL2-Phn. The values of dissociation constants of the corresponding triplexes were evaluated using the gel retardation method. The Acr residue in Blm-p15pL1-Acr was shown to enhance the stability of the formed triplex by one order of magnitude. It was demonstrated that all synthesized conjugates are capable of specifically and nonspecifically damaging a target DNA, forming direct breaks and alkaline-labile sites. The extent of the specific cleavage of the target DNA was 15% in the case of a fivefold excess of the conjugates over the DNA duplex. The site-specific triplex-mediated cleavage of a target DNA was shown for the first time to occur predominantly (> 90%) with the formation of the direct breaks of both DNA strands. The results show the availability of bleomycin-containing oligonucleotides as antigene compounds.
authors.forename: A S
authors.initials: AS
authors.lastname: Pavlova
authors.forename: P E
authors.initials: PE
authors.lastname: Vorob'ev
authors.forename: V F
authors.initials: VF
authors.lastname: Zarytova
mesh_terms: D001761:Bleomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D053903:DNA Breaks, Double-Stranded; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D009841:Oligonucleotides; D001761:Bleomycin; C025703:bleomycetin; D004247:DNA