1,721,011 research outputs found
Dynamic aspects of the stereochemistry of phenothiazines in solution : Part 2. Segmental motion and conformational analysis of the side-chain in promazines
No full textSome promazines and the model compound NN-dimethyl-3-phenylpropylamine have been studied, as protonated and unprotonated species, by 1H and 13C n.m.r. spectroscopy. 13C T1 relaxation times have shown that the mobility of the dimethylaminopropyl chain in chloroform solution varies depending on whether the chain is protonated or unprotonated, and whether it is attached to a phenyl or to a tricyclic system. Segmental motions were also detected in two compounds. The conformation of the side-chain has been deduced for different solvents. Remarkably, for protonated promazines the preferred conformations are gauche for the Cα-Cβ fragment and trans for the Cβ-Cγ in chloroform as well as in water solution, whereas the model compound exists preferentially in the fully extended trans–trans-conformation. In dioxan and in DMSO the population of the αβ-gauche forms decreases. The presence and the nature of the 2-substituent do not appear to have any effect, whereas the tricyclic system is predominant in the stabilization of the αβ-gauche form. This has been related to the ability of these molecules to aggregate in solution with a vertical stacking-type association
Structure and dynamics of intercalation complexes of anthracyclines with d(CGATCG)2 and d(CGTACG)2. 2D-1H and 31P NMR investigations
No full textThe interaction of (2S )-2-methoxymorpholinodoxorubicin 4 and morpholinodoxorubicin 5 with the hexanucleotides d(CGATCG)2 and d(CGTACG)2 has been studied by a combined use of 2D-1H and 31P NMR techniques and molecular dynamics (MD) calculations, in comparison with doxorubicin 1, daunorubicin 2 and idarubicin 3. Both 1H and 31P chemical shifts of imino protons and phosphates respectively have been shown to be a sensitive probe for the intercalation sites (two anthracycline molecules at the CpG sites). A relevant number of NOE interactions allowed the structure of the complexes in solution to be derived through restrained MD calculations, which were compared with those obtained by X-ray analysis. In all the complexes the aglycone was shown to be located in the middle of the double helix, orthogonally oriented with respect to the base pairs, with ring D extending out of the helix on the major groove and ring A, with 9H8 conformation, between guanines G2 and G12. The daunosamine and morpholino moieties lie in the center of the minor groove, with slightly different positions than in the X-ray structures. In all the complexes the daunosamine ring is located at the A3 (T3) level, while the morpholino ring displays NOE interactions with the fourth unit T4 (A4). The deformations of the double helix are revealed by an increased distance between protons of the C5 and G6 units and by conformational changes at the level of the α, ζ, Îμ and δ angles of the phosphoribose backbone. The variation of the 31P chemical shifts is interpreted in terms of conformational equilibria leading to different populations of conformers. This is clearly shown from the values of the α and ζ torsion angles, monitored during the MD, which indicate a relevant population of trans forms for ζ and also for α angles of C5pG6 and G2pT3 (G2pA3) units, while the other phosphates exist entirely in the α, ζ, gauche,gauche conformation. The dissociation rate constants were measured by 2D 31P NOESY-exchange experiments for 1 and 4. The decrease of koff for 4, corresponding to a ten-fold increase of the residence time of the drug in the intercalation sites, is in line with the higher activity found for methoxymorpholinodoxorubicin 4
Conformational analysis of N-acetyldaunomycin in solution. A transient 1H nuclear Overhauser effect study of the glycosidic linkage geometry
No full textThe conformational properties of daunomycin (1) and several analogues (2)–(16) have been investigated by 1H n.m.r. in different solvents, CDCI3, D2O, DMSO, dioxane, and pyridine. From H,H three-bond and long-range coupling constants, the geometry of ring A in each solvent has been determined, through a Karplus–Altona equation, which includes a correction for the substiuent electronegativity. Conformers 9H8, 8H9, 9S, S9, and S8 have been found in solution, and in several cases, especially in DMSO, more than one conformer is present at equilibrium. The equilibrium is always fast compared with n.m.r. times and the relative populations of each conformer have been calculated from experimental and model coupling constants by using a least-squares procedure. Two factors have been recognized to be responsible for the shape of ring A: the intramolecular hydrogen-bond 9–OH O(7) and steric interactions between peri substituents on the A and B rings. Evidence for this hydrogen-bonding has been obtained by dilution experiments, and, for the peri interactions, by evaluating the substituent effects on the conformational preference. Other intramolecular hydrogen bonds have been proved not to exist in solution. The influence of the solvents on the shape of ring A has also been studied. All the results are discussed and compared with those obtained in the solid phase. Daunosamine moiety has also been analysed, and the conformation of the sugar ring is always 1′C4. (L) in all the solvents examined
A Quantitative Approach in Conformational Analysis by 2D-Inversion Recovery Difference Spectroscopy
No full textConformational analysis of 9-deoxydaunorubicin in solution : The application of a quantitative transient 1H nuclear Overhauser effect
No full textThe preferred conformation of 9-deoxy-N-trifluoroacetyldaunorubicin has been determined by 1H and 13C n.m.r. in CDCl3 solution. The conformation of ring A was easily defined as a pure half-chair 9H8, from the values of proton coupling constants, and on the basis of a preceding study of daunomycin derivatives. The orientation of the sugar with respect to the aglycone moiety has been obtained by quantitative transient nuclear Overhauser experiments (n.O.e.). The interproton distances have been deduced from the cross-relaxation rates determined by measuring the time development of n.O.e.s, after selective inversion of single resonances. The experimental points were fitted to the theoretical curves through a non-linear least-squares procedure. The overall isotropic motion was proved by 13C T1 measurements of all protonated carbons; the interproton reference distance r4′–5′, deduced from the correlation time value, is in satisfactory agreement with those measured by X-ray analyses of daunomycin and carminomycin. The glycoside linkage geometry has also been expressed in terms of the rotational angles φ= H(1′)–C(1′)–O(7)–C(7) and ψ= C(1′)–O(7)–C(7)–H(7). The results have been compared with those obtained through molecular mechanics calculations, performed with the Allinger MMP2 program
Mode of binding of camptothecins to double helix oligonucleotides
No full textWe report an NMR study on the interaction of topotecan (Tpt) and other camptothecins (Cpts) with several double helix and single strand oligonucleotides. The results obtained by (31)P NMR spectroscopy, nuclear Overhauser experiments (NOE) and molecular dynamics (MD) simulations show that Cpt drugs do not intercalate into the double helix, as suggested by many authors. Phosphorus NMR spectra indicated that no deformation occurs at any level of the phosphodiester backbone, while 2D NOESY experiments allowed the detection of several contacts between the aromatic protons of Cpts and those of the double helix. Models of the drug/oligonucleotide complexes, built on the basis of NOE data, show that the drug is located at the end of the double helix, by stacking the A and B rings with the guanine or cytidine of the terminal CG base pairs, with a preference for the 3[prime or minute]-terminal end sites. Cpts interact with double strand, as well as with single strand oligomers, as can be seen from the NMR shift variation observed on the drug protons; but this shielding effect cannot be an evidence of intercalation, as it is largely due to external non-specific interactions of the positively charged drug with the negatively charged ionic surface of the oligonucleotide. The molecular weight of one of the complexes was obtained from the correlation time value. The conformational behaviour of the DNA fragment d(CGTACG)(2) was studied by MD simulations on a ns time scale in the presence of water molecules and Na(+) ions. Different models were examined and the deformations induced on the phosphodiester backbone by molecules that are known to intercalate, were monitored by MD simulations
Interaction between double helix DNA fragments and the new antitumor agent sabarubicin, Men10755
No full textAmongthe disaccharide derivatives of the antitumor anthracycline doxorubicin, sabarubicin (Men10755) is
more active and less cytotoxic than doxorubicin. It showed a strong in vivo antitumor activity in all preclinical
models examined, in conjunction with a better tolerability, and is now in phase II clinical trials.
The interaction of sabarubicin andMen10749(a similar disaccharidewith a different configuration at C-40 of
the proximal sugar) with the hexanucleotides d(CGTACG)2 and d(CGATCG)2 was studied by a combined use
of 2D-1Hand 31PNMRtechniques. Both 1Hand 31P chemical shifts of imino protons and phosphates allowed
to established the intercalation sites between the CG base pairs, as it occurs for other anthracyclines of the
series. The dissociation rate constants (koff) of the slow step of the intercalation process were measured for
Men10755 and Men10749, by NMR NOE-exchange experiments. The increase of koff , with respect of doxorubicin,
showed that the intercalation process is significantly faster for both drugs, leading to an average residence
time for sabarubicin into d(CGTACG)2 sixfold shorter than for doxorubicin. This could give account of
both higher cytoplasmic/nuclear ratio and lower cellular uptake of sabarubicin in comparison with doxorubicin
and accordingly of the lower cytotoxicity of these disaccharide analogues.
A relevant number of NOE interactions allowed the structure of the complexes in solution to be derived
through restrained MD calculations. NMR-DOSY experiments were performed with several drug/oligonucleotide
mixtures in order to determine the structure and the dimension of the aggregates
Conformational-analysis of doxorubicin and analogs in aqueous-solution - determination of the glycosidic linkage geometry by h-1 2D-inversion recovery difference noe spectroscopy
No full textNuclear magnetic resonance conformational study of daunomycin and related antitumour antibiotics in solution. The conformation of ring A
No full textThe conformational properties of daunomycin (1) and several analogues (2)–(16) have been investigated by 1H n.m.r. in different solvents, CDCI3, D2O, DMSO, dioxane, and pyridine. From H,H three-bond and long-range coupling constants, the geometry of ring A in each solvent has been determined, through a Karplus–Altona equation, which includes a correction for the substiuent electronegativity. Conformers 9H8, 8H9, 9S, S9, and S8 have been found in solution, and in several cases, especially in DMSO, more than one conformer is present at equilibrium. The equilibrium is always fast compared with n.m.r. times and the relative populations of each conformer have been calculated from experimental and model coupling constants by using a least-squares procedure. Two factors have been recognized to be responsible for the shape of ring A: the intramolecular hydrogen-bond 9–OH O(7) and steric interactions between peri substituents on the A and B rings. Evidence for this hydrogen-bonding has been obtained by dilution experiments, and, for the peri interactions, by evaluating the substituent effects on the conformational preference. Other intramolecular hydrogen bonds have been proved not to exist in solution. The influence of the solvents on the shape of ring A has also been studied. All the results are discussed and compared with those obtained in the solid phase. Daunosamine moiety has also been analysed, and the conformation of the sugar ring is always 1′C4. (L) in all the solvents examined
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