Synthesis of cationic metalloporphyrin precursors related to the design of DNA cleavers

Abstract

The design of specific DNA cleavers is a growing field of research for several reasons: (i) DNA is the biological target of a large number of antitumor agents which are able to cleave double-stranded nucleic acids, bleomycin,* 1 neocarzinostatin,2 and enediyne molecules,3 (ii) transition metal complexes linked to a DNA recognizing molecule (intercalating agents,4 peptides,5 or oligonucleotides6) are also able to cleave selectively single-or double-stranded nucleic acids, and (iii) some of these hybrid molecules, "DNA cleaver-vector", might have a future as antiviral or antitumoral agents.7 Cationic manganese-porphyrin complexes are among the efficient DNA cleavers because of their affinity for nucleic acids and their capacity to oxidize the sugar carbon-hydrogen bonds of deoxyribose units.8 Mechanistic studies on DNA breaks mediated by cationic manganese-porphyrins strongly suggest that high-valent manganese-oxo species might be responsible for DNA cleavage instead of diffusible oxygen species like hydroxyl radicals.8•9 Such metal-oxo species were also proposed for "activated bleomycin", an antitumoral antibiotic able to cleave DNA.la'cl°DNA cleavage selectivity can be modulated by linking the tris(methylpyridiniumyl)porphyrinatomanganese motif to different vectors: an intercalating agent like 9-methoxyellipticine11 or an oligonucleotide.12 This DNA cleaver exhibits also an anti-HIV activity alone or linked to 9-methoxyellipticine.13 For these different reasons, we decided to undergo the preparation of a series of water-soluble, cationic porphyrin ligands based on the tris(methylpyridiniumyl)porphyrin motif (Table I). All these unsymmetric porphyrins contain a * Author to whom correspondence should be addressed.(1) (a) Hecht, S.

Spectroscopic Studies on Binding of Porphyrin-Phenazine Conjugate to Four-Stranded Poly(G)

“…Then, in the range of P/D from 4.5 to 9, it somewhat quenches, and further polymer addition again induces the gradual rise of the dye fluorescence, which at P/D=115 reaches value of I/I o ≈2. 35. Fluorescence polarization degree, p, measured for both conjugate moieties also increases during the binding process (see inset of Fig.…”

“…1) were synthesized and purified by the procedures described in [25]. Briefly, tris(4-pyridyl)phenylporphine containing a carboxybutyl function [35] was conjugated to N 1 -aminoalkyl derivative of imidazo [4,5-b]phenazine in the presence of BOP-HOBT coupling reagent, followed by N-methylation of pyridine residues by methyl iodide. Imidazo [4,5-b]phenazine dye and its aminoalkyl derivatives were obtained in accordance with methods reported in [36].…”

Thermodynamic investigation of a new water-soluble porphyrin with calf thymus DNA

“…Porphyrins were prepared and purified according to literature methods [43,44]. 5,10,15,20-tetrapyridyl porphyrin (TPyP) (Fluka), 5-bromopentanoate, methyl iodide (Acros chemicals) were used as received.…”

Binding of Metallated Porphyrin-Imidazophenazine Conjugate to Tetramolecular Quadruplex Formed by Poly(G): a Spectroscopic Investigation

“…1) were synthesized and purified by the procedures described in [33]. In brief, tris(4-pyridyl)phenylporphine containing a carboxybutyl function [40] was conjugated to N 1 -aminoalkyl derivative of imidazo [4,5-b]phenazine in the presence of BOP-HOBT coupling reagent, followed by Nmethylation of pyridine residues by methyl iodide. Porphyrin ring was then metalated by heating with zinc acetate in demethylformamide-collidine mixture [41].…”