Structure/Nuclease Activity Relationships of DNA Cleavers Based on Cationic Metalloporphyrin−Oligonucleotide Conjugates

Abstract

The covalent attachment of a managanese-tris(methylpyridiniumyl)porphyrin entity to an antisense oligonucleotide allowed sequence-selective oxidative cleavage of DNA when the metalloporphyrin was activated by potassium monopersulfate (KHSO5). We prepared several structurally modified metallo-porphyrin-oligonucleotide conjugates in order to find out the most efficient compound for in vitro DNA cleavage. The nature and the length of the tether were modulated, the metalloporphyrin entity was modified (metal, ligand), and different ways of activation of the metalloporphyrin were assayed. We noticed that the location of the peptidic bond within the linker could greatly affect the cleavage efficiency of the different conjugates. We showed that the most efficient conjugate for oxidative DNA cleavage was a manganese tetracationic porphyrin-oligonucleotide compound. When the metalloporphyrin moiety was activated by a reducing agent in the presence of molecular oxygen, DNA cleavage was efficient at suitable concentrations of the reducing agent, in order to avoid the reduction of the activated DNA cleaver, a putative high-valent metal-oxo species, by the excess of reducing agent.

A DNA–porphyrin minor-groove complex at atomic resolution: The structural consequences of porphyrin ruffling

“…Significantly, the nickel ion is also close to one backbone and in particular to the C1Ј and O3Ј atoms of this backbone. This provides a plausible starting point for any subsequent photoinduced or oxygen-mediated strand cleavage (27). It is known that the latter occurs within the minor groove and involves oxidative or free-radical attack on deoxyribose sugars, especially at the C1Ј position.…”

Investigation on DNA Binding and Photo-Cleavage Properties of Water-Soluble Porphyrin and Metalloporphyrins

“…The color shade is highly linearly correlated with the quantity of living cells within a certain range. According to the OD values, the percent cytotoicity induced by various concentrations of the complexes can be calculated as Cytotoxicity (%) = [(OD cell control ) OD medium experiment )/OD cell control ] · 100% [9]. According to the survival ratio, the 50% cytotoxic concentrations (TC 50 ) of the complexes and the maximum non-cytotoxic concentrations (TC 0 ) can be calculated by the Reed-Muench method.…”

“…Secondly, the DNA binding mechanism is very dependent upon not only the sequence of the DNA strands but also the structure perturbation of the porphyrin molecules [7,8]. The ionic strength of a solution, in which the interaction takes place and the ratios of porphyrin to DNA, are also factors that influence the binding modes [9][10][11]. The interaction of porphyrins and metalloporphyrins with DNA has attracted considerable interest due to two main reasons.…”

Aggregation and DNA binding characteristics of tetrakis(N,N',N″,N‴-tetramethyltetra-3,4-pridino)porphyrazine cobalt(II)

“…The classical cationic porphyrin, meso-tetra-(N-methylpyridyl)porphyrin (TMPyP), first attracted attention as a water-soluble porphyrin that could be studied over a wide pH-range [1][2][3] later, TMPyP was recognized to interact with DNA through both outside binding and intercalation [4]. Since then, cationic porphyrins have been investigated as DNAbinding and cleavage reagents and sensitizers for photodynamic therapy [5][6][7], nuclease-resistant de-*Correspondence to: Abdol-Khalegh Bordbar, email: bordbar@chem.ui.ac.ir or khalegh_bordbar@yahoo.com, fax: +98 311-6689732 livery agents for anti-sense oligonucleotides and probes for nucleic acid structure. Cationic tetraazaporphyrins, or porphirazines, represent an alternative and highly under-developed class of cationic porphyrinic compounds.…”