Cryptands and related tripodal ligands: interaction with nucleic acids and nuclease activity of their Eu(III) complexes
TL;DR: Three tripodal ligands, three macrobicyclic cryptands, and corresponding Eu(III) complexes were probed for their influence on double-stranded nucleic acids, showing higher affinity to DNA as compared to RNA and another one even slightly destabilizes RNA.
Abstract: Three tripodal ligands ( 1 – 3 ), three macrobicyclic cryptands ( 4 – 5 ), the [222] and [221] cryptands 7 and 8 , and corresponding Eu(III) complexes were probed for their influence on double-stranded nucleic acids. One ligand ( 2 ) shows higher affinity to DNA as compared to RNA and another one ( 4 ) even slightly destabilizes RNA. Cryptands 7 and 8 show no detectable melting point effects; addition of the [222] cryptand 7 to Eu(III) salts has no significant effect on the nuclease activity of the free metal ion. Only the [221] cryptand 8 forms a stable complex with Eu(III) in water, leading to almost no rate decrease with the phosphodiester BNPP, in striking contrast to DNA. The histidine-containing ligand 2 exhibits an increased hydrolytic activity against BNPP and against plasmid DNA.
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TL;DR: The lanthanide ion based macrocyclic complexes 1La, 1Eu and 1Yb were synthesised by the alkylation of L-alanine derived α-chloroamide, giving a tetrasubstituted GlyAla conjugated azamacrocycle using a 1,4,7,10-tetraazacyclododecane, followed by a complexation with either La(III), Eu(III) or Yb(III)) triflate.
Abstract: The lanthanide ion based macrocyclic complexes 1La, 1Eu and 1Yb, were synthesised by the alkylation of L-alanine derived α-chloroamide, giving a tetrasubstituted GlyAla conjugated azamacrocycle using a 1,4,7,10-tetraazacyclododecane, followed by a complexation with either La(III), Eu(III) or Yb(III) triflate. Each complex gave rise to enhancements in the rate of hydrolysis of the phosphodiester of HPNP, an RNA mimic compound, at pH 7.4 and 37°C. For 1La, the hydrolysis was shown to give dual pH behaviour, where within a narrow pH window the hydrolysis of HPNP was greatly enhanced between 6.5 and 7.0, whereas it decreased between 7.2 and 7.4. At higher pH, above 8, the rate was again greatly enhanced. We conclude that these enhancements are due to the formation of a hydrophobic cavity in 1 upon lanthanide ion complexation, in conjunction with the Lewis acid activation of the phosphate diester by the metal ion. These complexes thus mimic the nature of the active site of many ribonucleases.
40 citations
TL;DR: Laterally non-symmetric cryptands are defined as cryptands where the two bridgehead atoms like N or C or benzene units are connected by three bridges such that the donor atoms about the bridgeheads are different as mentioned in this paper.
Abstract: Cryptands where the two bridgehead atoms like N or C or benzene units are connected by three bridges such that the donor atoms about the bridgeheads are different can be called laterally non-symmetric cryptands These cryptands constitute a class which can be useful in several contemporary areas of research The present article describes the synthesis of the cryptands and the use of metal cryptates in homogeneous catalysis, in the photochemical splitting of water to generate H 2 , in the cleavage of nucleic acids as chemical nucleases These cryptands can be derivatized to have new receptors which might be useful as well
35 citations
TL;DR: In this article, the authors showed that 2Tb has a typical monocapped square antiprism geometry, where the Tb(III) ion is central, coordinating to the four amino moieties of the cyclen ring and four of the oxygens of amide carbonyl groups of the four pendant arms, with the ninth coordinated site being occupied by a water molecule.
Abstract: The glycine–alanine conjugated ligands of cyclen (1,4,7,10,-tetraazacyclododecane) 1 and 2, possessing methyl and benzyl alanine esters respectively, and the corresponding lanthanide complexes 1La, 1Eu, 1Tb, 1Yb, 2La, 2Eu, and 2Tb were designed with the aim of mimicking the nature of the hydrophobic cavity of ribonucleases. X-ray crystallographic investigations showed that 2Tb has a typical monocapped square antiprism geometry, where the Tb(III) ion is central, coordinating to the four amino moieties of the cyclen ring and four of the oxygens of amide carbonyl groups of the glycine residues of the four pendant arms, with the ninth coordinated site being occupied by a water molecule. All the complexes were shown to promote the hydrolysis of the phosphodiester bond of 2-hydroxypropyl p-nitrophenyl phosphate (HPNP, τ1/2=5.78×103 h) with 1Tb being the most efficient in promoting such hydrolysis at pH 7.4 and at 37 °C for the 1Ln family with τ1/2=4.9 h. For the 2Ln family, 2La was most effective in promoting hydrolysis of HPNP, with τ1/2=3.7 h. The rate of hydrolysis was also investigated for 1La and 2La as function of pH, with both complexes displaying bell-shaped pH dependence within the physiological pH range. For 1Ln the highest activity was observed at pH 7.0, with τ1/2=4.6 h, whereas for 2La it occurred at pH 7.4. Beyond pH 8, the rate of both complexes was shown to be almost linearly increased. The ability of 1Eu and 2Eu to cleave a 23-mer sequence from the mRNA of the GAG–HIV gene was also investigated. It was found that both gave rise to cleavage of the sequence at every nucleotide residue after 4 h of incubations at pH 7.4 and 37 °C.
29 citations
TL;DR: The cyclen-based pyridine complexes 1Ln 3Ln (Ln = La(III) and Eu(III)) were synthesised as metallo-ribonuclease mimics and their ability to hydrolytically cleave the phosphodiester of HPNP at 37°C was investigated using UV-vis spectroscopy, whereas the binding of the substrate was evaluated using 31 P NMR and EU(III)-luminescent measurements.
Abstract: The cyclen based pyridine complexes 1Ln – 3Ln (Ln = La(III) and Eu(III)) were synthesised as metallo-ribonuclease mimics and their ability to hydrolytically cleave the phosphodiester of HPNP at 37 °C was investigated using UV–vis spectroscopy, whereas the binding of the substrate was evaluated using 31 P NMR and Eu(III)-luminescent measurements. In contrast 2La gave rise to fast pH dependent hydrolysis of HPNP, with maximum efficiency at ca. pH 8.2, and with a half-lifetime of ∼1 h, the 1Ln and 3Ln complexes were found to be inactive, emphasizing the importance of the nature of the pyridine isomer as a cofactor in the hydrolytic process.
26 citations
TL;DR: The affinities of polyamines consisting of ethylenediamine units equipped with either one or two terminal naphthyl-, anthryl-, or acridyl units towards PolyA are screened by measuring the melting point changes of the double strands, and also by a fluorimetric binding assay using ethidium bromide.
Abstract: The affinities of polyamines consisting of ethylenediamine units equipped with either one or two terminal naphthyl-, anthryl-, or acridyl units towards PolyA.PolyU as an RNA model, and Poly(dA).Poly(dT) as a DNA model are screened by measuring the melting point changes (ΔTm) of the double strands, and also partially by a fluorimetric binding assay using ethidium bromide. The larger aromatic moieties with long spacers between them allow bisintercalation; this leads to an increased preference for DNA in comparison to RNA, where ion pairing of the ammonium centers with the major RNA groove phosphates dominates. Allosteric affinity control by metalation is achieved e.g. with Cu2+ ions, which induce conformational distortions within the chains. With anthryl- in contrast to naphthyl derivatives intercalation can be so strong that distortion of the ethylenediamine chain by metalation is not powerful enough. A particularly high concentration of positive charges is accessible with tripodal derivatives built up from ethylenediamine and propylenediamine units; in the absence of aryl parts, which interfere with the RNA groove preference, one observes the highest affinity difference known until today, reflected in a melting point ratio of ΔTm(RNA)/ΔTm(DNA) = 40, whereas other synthetic ligands reach only a ΔTm(RNA)/ΔTm(DNA) ratio of about 3.
23 citations
References
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TL;DR: Recently, there has been a great interest in designing small metal complexes which are capable of catalytically hydrolyzing deoxyribonucleic acid (DNA), ribonuclear acid (RNA), and protein this article.
Abstract: Recently there has been great interest in designing small metal complexes which are capable of catalytically hydrolyzing deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein. In this review, we attempt to justify this goal, as well as discuss some of the strategies currently being pursued. In addition, because much of the work is based on a few well-studied enzymatic hydrolases and exchange-inert metal complexes, the mechanisms proposed for these systems will also be briefly discussed, with special attention being paid to the relevance of these systems to the design of synthetic metallohydrolases. However, since the ultimate goal is not only to design an efficient hydrolase, but also to completely understand the mechanism, this review will generally be limited to labile metal complexes for which the coordination geometry is known and detailed kinetic and/or mechanistic information is available.
542 citations
TL;DR: A new tris(ZnII−cyclen) (Zn3L3) as discussed by the authors, which has three ZnII+macrocyclic tetraamine complexes connected through a 1,3,5-trimethylbenzene spacer, has been synthesized as a novel receptor for organ organs.
Abstract: A new tris(ZnII−cyclen) (Zn3L3), which has three ZnII−macrocyclic tetraamine (cyclen) complexes connected through a 1,3,5-trimethylbenzene spacer, has been synthesized as a novel receptor for organ...
252 citations
TL;DR: Complexes between cobalt(III) and eight different 1,4,7,10-tetraazacyclododecane (cyclen) as well as two tris(3-aminopropyl)amine (trpn) derivatives are reported with varying numbers and structures of peralkylammonium groups in side chains of the ligands.
Abstract: Complexes between cobalt(III) and eight different 1,4,7,10-tetraazacyclododecane (cyclen) as well as two tris(3-aminopropyl)amine (trpn) derivatives are reported with varying numbers and structures of peralkylammonium groups in side chains of the ligands. The presence of additional positive charges has small effects on hydrolysis rates of nitrophenyl- and bis(nitrophenyl)phosphate esters but leads to substantially enhanced cleavage of plasmid DNA. Increasing the number of the charged side groups and/or their distance to the metal ion center provides for better binding to the DNA groove, as shown also by affinity measurements with calf-thymus DNA. In line with this, saturation kinetics of plasmid DNA cleavage yield a corresponding increase of efficiency in Michaelis−Menten-type KM values, with rather constant kcat parameters. A binuclear cobalt complex with two cyclen centers separated by a −(CH2)6-N+(CH3)2-(CH2)6-N+(CH3)2-(CH2)6− spacer shows, with only 5 × 10-5 M catalyst concentration, the largest known...
224 citations