Recognition of DNA bulges by dinuclear iron(II) metallosupramolecular helicates

Abstract

Bulged DNA structures are of general biological significance because of their important roles in a number of biochemical processes. Compounds capable of targeting bulged DNA sequences can be used as probes for studying their role in nucleic acid function, or could even have significant therapeutic potential. The interaction of [Fe 2 L 3 ] 4+ metallosupramolecular helicates (L = C 25 H 20 N 4 ) with DNA duplexes containing bulges has been studied by measurement of the DNA melting temperature and gel electrophoresis. This study was aimed at exploring binding affinities of the helicates for DNA bulges of various sizes and nucleotide sequences. The studies reported herein reveal that both enantiomers of [Fe 2 L 3 ] 4+ bind to DNA bulges containing at least two unpaired nucleotides. In addition, these helicates show considerably enhanced affinity for duplexes containing unpaired pyrimidines in the bulge and/or pyrimidines flanking the bulge on both sides. We suggest that the bulge creates the structural motif, such as the triangular prismatic pocket formed by the unpaired bulge bases, to accommodate the [Fe 2 L 3 ] 4+ helicate molecule, and is probably responsible for the affinity for duplexes with a varying number of bulge bases. Our results reveal that DNA bulges represent another example of unusual DNA structures recognized by dinuclear iron(II) ([Fe 2 L 3 ] 4+ ) supramolecular helicates.

Recognition of DNA/RNA bulges by antimicrobial and antitumor metallohelices

“…1D) and various combinations of bases flanking the bulge (X 1 = C, T, A, T, A; X 2 = C, T, A, A, T; Y 1 = G, A, T, A, T; Y 2 = G, A, T, T, A for the two-adenine bulge and X 1 = X 2 = C, T, A; Y 1 = Y 2 = G, A, T for the three-adenine bulge; Inspired by the results that we obtained in the previous experiments (Tables 1-3), we decided to explore the effect of the flexicates on the DNA bulges containing loops composed of pyrimidines (thymine) and flanked on both the 5′-side and 3′-side of the bulge by pyrimidines (cytosine) (B = T, n = 2, 3; X 1 = X 2 = C, Y 1 = Y 2 = G; Fig. Similarly to our previous report 16 we used an electrophoretic mobility shift assay to explore whether the stability of the flexicate-DNA bulge complex is sufficient to withstand migration through a polyacrylamide gel. Indeed, the results listed in Table 4 confirm that the combination of the bulge loop composed of pyrimidines with pyrimidines as bases flanking the bulge, as in C-T2-C and C-T3-C, gave the highest increase of the T m of DNA duplexes containing a two-or three-nucleotide bulge in the presence of flexicates.…”

“…1D) in the presence of flexicates was recorded. 16 The Λ-enantiomer was more efficient in stabilizing DNA bulges than the Δ-enantiomer, except for G-T3-G, where the stabilizing effect of both enantiomers was identical. 1D).…”

“…The most promising bulge binding agents discovered to date are: those based on NCS-chrom, a wedge-shaped enediyne antitumor antibiotic neocarzinostatin chromophore, 2-acylamino-1,8-naphthyridine, rhodium intercalators or the zinc(II) complex of 1-(4-quinoylyl)methyl-1,4,7,10-tetraazacyclododecane, and dinuclear ruthenium complexes. 16 These molecules can also recognize other unusual DNA structures, such as Y-shaped three-way junctions, 17,18 three-way junctions containing unpaired nucleotides, the so-called T-shaped three-way junctions 19 and human telomeric G-quadruplex DNA. S1 †).…”

Enhancement of the physicochemical properties of [Pt(dien)(nucleobase)]2+ for HIVNCp7 targeting

“…2 Metallohelicates are a further example of use of “non-covalent” recognition of discrete DNA sequences with consequences for protein recognition. 3 Use of formally substitution-inert compounds is attractive as it may allow greater control of the biologically relevant reactions as well as improving pharmacokinetics through elimination of wasteful non-specific biomolecule covalent bond formation.…”

Iron(II) Supramolecular Helicates Condense Plasmid DNA and Inhibit Vital DNA‐Related Enzymatic Activities

“…It has been described that helicates recognize and stabilizeY -shaped DNA and RNA three-way junctions( 3WJ), [7] otherY -shaped junctions(i.e.,areplication fork), and DNA 3WJs containing unpairednucleotides( i.e.,t he so-called T-shaped3 WJs). [8] Recently,i th as been demonstratedt hat helicates selectivelyr ecognize DNA bulges containing more than two unpaired nucleotides [9] and bind human telomeric G-quadruplex DNA. [10] The relatively high positive charge (4 +)a nd high affinity for DNA make iron(II) supramolecular helicates good candidates for DNA-condensing agents.…”