84-53-7Relevant academic research and scientific papers
Guanidine-based polymer brushes grafted onto silica nanoparticles as efficient artificial phosphodiesterases
Savelli, Claudia,Salvio, Riccardo
, p. 5856 - 5863 (2015/03/31)
Polymer brushes grafted to the surface of silica nanoparticles were fabricated by atom-transfer radical polymerization (ATRP) and investigated as catalysts in the cleavage of phosphodiesters. The surfaces of silica nanoparticles were functionalized with an ATRP initiator. Surface-initiated ATRP reactions, in varying proportions, of a methacrylate moiety functionalized with a phenylguanidine moiety and an inert hydrophilic methacrylate species afforded hybrid nanoparticles that were characterized with potentiometric titrations, thermogravimetric analysis, and SEM. The activity of the hybrid nanoparticles was tested in the transesterification of the RNA model compound 2-hydroxypropyl para-nitrophenylphosphate (HPNP) and diribonucleoside monophosphates. A high catalytic efficiency and a remarkable effective molarity, thus overcoming the effective molarities previously observed for comparable systems, indicate the existence of an effective cooperation of the guanidine/guanidinium units and a high level of preorganization in the nanostructure. The investigated system also exhibits a marked and unprecedented selectivity for the diribonucleoside sequence CpA. The results presented open up the way for a novel and straightforward strategy for the preparation of supramolecular catalysts.
Buffer catalyzed cleavage of uridylyl-3′,5′-uridine in aqueous DMSO: Comparison to its activated analog, 2-hydroxypropyl 4-nitrophenyl phosphate
Lain,L?nnberg,L?nnberg
, p. 3484 - 3492 (2015/03/18)
Buffer catalysis of the cleavage and isomerization of uridylyl-3′,5′-uridine (UpU) has been studied over a wide pH range in 80% aq. DMSO. The diminished hydroxide ion concentration in this solvent system made catalysis by amine buffers (morpholine, 4-hydroxypiperidine and piperidine) visible even at relatively low buffer concentrations (10-200 mmol L-1). The observed catalysis was, however, much weaker than what has been previously reported for the activated RNA model 2-hydroxypropyl 4-nitrophenyl phosphate (HPNP) in the same solvent system. In the case of morpholine, contribution of both the acidic and the basic buffer constituent was significant, whereas with 4-hydroxypiperidine and piperidine participation of the acidic constituent could not be established unambiguously. The results underline the importance of using realistic model compounds, along with activated ones, in the study of the general acid/base catalysis of RNA cleavage.
An RNA modification with remarkable resistance to RNase A
Ghidini, Alice,Ander, Charlotte,Winqvist, Anna,Stroemberg, Roger
supporting information, p. 9036 - 9038 (2013/09/24)
A 3′-deoxy-3′-C-methylenephosphonate modified diribonucleotide is highly resistant to degradation by spleen phosphodiesterase and not cleaved at all by snake venom phosphodiesterase. The most remarkable finding is that, despite the fact that both the vicinal 2-hydroxy nucleophile and the 5′-oxyanion leaving group are intact, the 3′-methylenephosponate RNA modification is also highly resistant towards the action of RNase A.
Synthesis of oligoribonucleotides with phosphonate-modified linkages
Pav, Ondej,Koiova, Ivana,Barvik, Ivan,Pohl, Radek,Budinsky, Milo,Rosenberg, Ivan
supporting information; experimental part, p. 6120 - 6126 (2011/10/10)
Solid phase synthesis of phosphonate-modified oligoribonucleotides using 2′-O-benzoyloxymethoxymethyl protected monomers is presented in both 3′→5′ and 5′→3′ directions. Hybridisation properties and enzymatic stability of oligoribonucleotides modified by regioisomeric 3′- and 5′-phosphonate linkages are evaluated. The introduction of the 5′-phosphonate units resulted in moderate destabilisation of the RNA/RNA duplexes (ΔTm -1.8 °C/mod.), whereas the introduction of the 3′-phosphonate units resulted in considerable destabilisation of the duplexes (ΔTm -5.7 °C/mod.). Molecular dynamics simulations have been used to explain this behaviour. Both types of phosphonate linkages exhibited remarkable resistance in the presence of ribonuclease A, phosphodiesterase I and phosphodiesterase II.
Cleavage and isomerization of UpU promoted by dinuclear metal ion complexes
Linjalahti, Heidi,Feng, Guoqiang,Mareque-Rivas, Juan C.,Mikkola, Satu,Williams, Nicholas H.
, p. 4232 - 4233 (2008/10/09)
The catalysis of phosphoryl transfer by metal ions has been intensively studied in both biological and artificial systems, but the status of the transient pentacoordinate phosphoryl species (as transition state or intermediate) is the subject of considerable debate. We report that dinuclear metal ion complexes that incorporate second sphere hydrogen bond donors not only promote the cleavage of RNA fragments just as efficiently as the activated analogue HPNPP but also provide the first examples of metal ion catalyzed phosphate diester isomerization close to neutral pH. This observation implies that the reaction catalyzed by these complexes involves the formation of a phosphorane intermediate that is sufficiently long-lived to pseudorotate. Copyright
Tethered dinuclear europium(III) macrocyclic catalysts for the cleavage of RNA
Nwe, Kido,Andolina, Christopher M.,Morrow, Janet R.
body text, p. 14861 - 14871 (2009/02/08)
Dinuclear europium(III) complexes of the macrocycles 1,3-bis[1-(4,7,10- tris(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane]-m-xylene (1), 1,4-bis[1-(4,7,10-tris(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane] -p-xylene (2), and mononuclear europium(III) complexes of macrocycles 1-methyl-,4,7,10-tris(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (3), 1-[3′-(N,N-diethylaminomethyl)benzyl]-4,7,10-tris(carbamoylmethyl)-1,4,7, 10-tetraazacyclododecane (4), and 1,4,7-tris(carbamoylmethyl)-1,4,7,10- tetraazacyclododecane (5) were prepared. Studies using direct excitation ( 7F0 → 5D0) europium(III) luminescence spectroscopy show that each Eu(III) center in the mononuclear and dinuclear complexes has two water ligands at pH 7.0, I = 0.10 M (NaNO 3) and that there are no water ligand ionizations over the pH range of 7-9. All complexes promote cleavage of the RNA analogue 2-hydroxypropyl-4- nitrophenyl phosphate (HpPNP) at 25°C (I = 0.10 M (NaNO3), 20 mM buffer). Second-order rate constants for the cleavage of HpPNP by the catalysts increase linearly with pH in the pH range of 7-9. The second-order rate constant for HpPNP cleavage by the dinuclear Eu(III) complex (Eu2(1)) at pH 7 is 200 and 23-fold higher than that of Eu(5) and Eu(3), respectively, but only 7-fold higher than the mononuclear complex with an aryl pendent group, Eu(4). This shows that the macrocycle substituent modulates the efficiency of the Eu(III) catalysts. Eu2(1) promotes cleavage of a dinucleoside, uridylyl-3′,5′-uridine (UpU) with a second-order rate constant at pH 7.6 (0.021 M-1 s-1) that is 46-fold higher than that of the mononuclear Eu(5) complex. Methyl phosphate binding to the Eu(III) complexes is energetically most favorable for the best catalysts, and this supports an important role for the catalyst in stabilization of the developing negative charge on the phosphorane transition state. Despite the formation of a bridging phosphate ester between the two Eu(III) centers in Eu2(1) as shown by luminescence spectroscopy, the two metal ion centers are only weakly cooperative in cleavage of RNA and RNA analogues.
Substrate specificity of an active dinuclear Zn(II) catalyst for cleavage of RNA analogues and a dinucleoside
O'Donoghue, Annmarie,Pyun, Sang Yong,Yang, Meng-Yin,Morrow, Janet R.,Richard, John P.
, p. 1615 - 1621 (2007/10/03)
The cleavage of the diribonucleoside UpU (uridylyl-3′-5′- uridine) to form uridine and uridine (2′,3′)-cyclic phosphate catalyzed by the dinuclear Zn(II) complex of 1,3-bis(1,4,7-triazacyclonon-1-yl)- 2-hydroxypropane (Zn2(1)(H2O)) has been studied at pH 7-10 and 25 °C. The kinetic data are consistent with the accumulation of a complex between catalyst and substrate and were analyzed to give values of kc (S-1), Kd (M), and kc/K d (M-1 s-1) for the Zn2(1)(H 2O)-catalyzed reaction. The pH rate profile of values for log k C/Kd for Zn2(1)(H2O)-catalyzed cleavage of UpU shows the same downward break centered at pH 7.8 as was observed in studies of catalysis of cleavage of 2-hydroxypropyl-4-nitrophenyl phosphate (HpPNP) and uridine-3′-4-nitrophenyl phosphate (UpPNP). At low pH, where the rate acceleration for the catalyzed reaction is largest, the stabilizing interaction between Zn2(1)(H2O) and the bound transition states is 9.3, 7.2, and 9.6 kcal/mol for the catalyzed reactions of UpU, UpPNP, and HpPNP, respectively. The larger transition-state stabilization for Zn 2(1)(H2O)-catalyzed cleavage of UpU (9.3 kcal/mol) compared with UpPNP (7.2 kcal/mol) provides evidence that the transition state for the former reaction is stabilized by interactions between the catalyst and the C-5′-oxyanion of the basic alkoxy leaving group.
Dinuclear Zn2+ complexes in the hydrolysis of the phosphodiester linkage in a diribonucleoside monophosphate diester.
Yashiro, Morio,Kaneiwa, Hideki,Onaka, Kenichi,Komiyama, Makoto
, p. 605 - 610 (2007/10/03)
Dizinc complexes that were formed from 2:1 mixtures of Zn(NO3)2 and dinucleating ligands TPHP (1), TPmX (2) or TPpX (3) in aqueous solutions efficiently hydrolyzed diribonucleoside monophosphate diesters (NpN) under mild conditions. The dinucleating ligand affected the structure of the aquo-hydroxo-dizinc core, resulting in different characteristics in the catalytic activities towards NpN cleavage. The pH-rate profile of ApA cleavage in the presence of (Zn2+)(2)-1 was sigmoidal, whereas those of (Zn2+)(2)-2 and (Zn2+)(2)-3 were bell-shaped. The pH titration study indicated that (Zn2+)(2)-1 dissociates only one aquo proton (up to pH 12), whereas (Zn2+)(2)-2 dissociates three aquo protons (up to pH 10.7). The observed differences in the pH-rate profile are attributable to the various distributions of the monohydroxo-dizinc species, which are responsible for NpN cleavage. As compared to that using (Zn2+)(2)-1, the NpN cleavage using (Zn2+)(2)-2 showed a greater rate constant, with a higher product ratio of 3'-NMP/2'-NMP. The saturation behaviors of the rate, with regard to the concentration of NpN, were analyzed by Michaelis-Menten type kinetics. Although the binding of (Zn2+)(2)-2 to ApA was weaker than that of (Zn2+)(2)-1, (Zn2+)(2)-2 showed a greater kcat value than (Zn2+)(2)-1, resulting in higher ApA cleavage activity of the former.
The pKa of the internucleotidic 2′-hydroxyl group in diribonucleoside (3′→5′) monophosphates
Acharya,Foeldesi,Chattopadhyaya
, p. 1906 - 1910 (2007/10/03)
Ionization of the internucleotidic 2′-hydroxyl group in RNA facilitates transesterification reactions in Group I and II introns (splicing), hammerhead and hairpin ribozymes, self-cleavage in lariatRNA, and leadzymes and tRNA processing by RNase P RNA, as well as in some RNA cleavage reactions promoted by ribonucleases. Earlier, the pKa of 2′-OH in mono- and diribonucleoside (3′-5′) monophosphates had been measured under various nonuniform conditions, which make their comparison difficult. This work overcomes this limitation by measuring the pKa values for internucleotidic 2′-OH of eight different diribonucleoside (3′-5′) monophosphates under a set of uniform noninvasive conditions by 1H NMR. Thus the pKa is 12.31 (±0.02) for ApG and 12.41 (±0.04) for ApA, 12.73 (±0.04) for GpG and 12.71 (±0.08) for GpA, 12.77 (±0.03) for CpG and 12.88 (±0.02) for CpA, and 12.76 (±0.03) for UpG and 12.70 (±0.03) for UpA. By comparing the pKas of the respective 2′-OH of monomeric nucleoside 3′-ethyl phosphates with that of internucleotidic 2′-OH in corresponding diribonucleoside (3′→5′) monophosphates, it has been confirmed that the aglycons have no significant effect on the pKa values of their 2′-OH under our measurement condition, except for the internucleotidic 2′-OH of 9-adeninyl nucleotide at the 5′-end (ApA and ApG), which is more acidic by 0.3-0.4 pKα units.
Phosphodiester Cleavage of Ribonucleoside Monophosphates and Polyribonucleotides by Homo- and Heterodinuclear Metal Complexes of a Cyclohexane-Based Polyamino-Polyol Ligand
Jancso, Attila,Mikkola, Satu,Loennberg, Harri,Hegetschweiler, Kaspar,Gajda, Tamas
, p. 5404 - 5415 (2007/10/03)
The ability of the dinuclear complexes of tdci [1,3,5-trideoxy-1,3,5-tris(dimethylamino)-cis-inositol] to promote the cleavage of the phosphodiester bonds of nucleoside 2′,3′-cyclic monophosphates, dinucleoside monophosphates and polyribonucleotides has been studied. The homodinuclear copper(II) and zinc(II) complexes efficiently promote the hydrolysis of cyclic nucleotides. The second-order rate constant (k2≈0.44M-1S-1) estimated for the cleavage of 2′,3′-cAMP induced by dinuclear copper(II) complexes is about 107 times greater than that for the hydroxide-ion-catalysed reaction. The complex selectively cleaves the 2′O-P bond of 2′,3′-cUMP and forms the 3′-product in 91% yield. An equimolar mixture of copper(II), zinc(II) and tdci proved to be more efficient than either of the binary systems: a 7-20-fold rate enhancement was observed for the cleavage of 2′,3′-cNMP substrates. The half-life for the hydrolysis of 2′,3′-cAMP decreased from 300 days to five minutes at 25°C when the concentration of each of the three components was 2.5mM. In contrast to the copper(II) or zinc(II) complexes of tdci, the heterodinuclear species promoted the hydrolysis of several dinucleoside monophosphates. For two ApA isomers, cleavage of the 3′,5′-bond was about 6.5 times faster than cleavage of the 2′,5′-bond. On the basis of the kinetic data, a trifunctional mechanism is suggested for the heterodinuclear-complex-promoted cleavage of the phosphodiester bond. Double Lewis acid activation occurs when the metal ions bind to the phosphate oxygen atoms. In particular, a metal-bound hydroxide ion serves as a general base or a nucleophilic catalyst, and, presumably, a zinc(II)-bound aqua ligand behaves as a general acid and facilitates the departure of the leaving alkoxide group. The effect of the complexes on the hydrolysis of poly(U), poly(A) and type III native RNA was also investigated, and, for the first time, kinetic data on the cleavage of the phosphodiester bonds of polyribonucleotides by a dinuclear complex was obtained.
