NMR and molecular modeling study of active and inactive taxol analogues in aqueous and nonaqueous solution

1994 ◽  
Vol 72 (1) ◽  
pp. 252-260 ◽  
Author(s):  
Howard J. Williams ◽  
A. Ian Scott ◽  
Reiner A. Dieden ◽  
Charles S. Swindell ◽  
Lisa E. Chirlian ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Water Solution ◽  
Biologically Active ◽  
Side Chain ◽  
Coupling Constant ◽  
Solution Conformation ◽  
Solution Structures ◽  
H Nmr ◽  
Chain Conformations ◽  
Inactive Analog

The conformations of the biologically active taxol analogs Taxotere®, 3R, 4R, and 4S, and the biologically inactive analog 3S were evaluated in CDCl3 and DMSO–water solution using 1H NMR coupling constant and NOESY data and molecular modeling. The solution structures of Taxotere® were very similar to those detected previously for taxol. The A-ring side chain conformations of analogs 3 and 4 could not be defined with the same precision as had been possible for taxol, but the conformational possibilities could be significantly limited by the data. Analogs 3R, 4R, and 4S (but not 3S) can mimic the dominant conformation of taxol in chloroform, but no logical relationship between biological activity and aqueous solution conformation could be detected.

The solution structures of chiral Ti4+ alkoxides. II. The roles of diolate basicity and side-chain binding group polarity

1992 ◽  
Vol 70 (8) ◽  
pp. 2256-2265 ◽  
Author(s):  
Stephen Bianchet ◽  
Pierre G. Potvin
Keyword(s):  
Side Chain ◽  
Resonance Spectroscopy ◽  
Side Chains ◽  
Metal Chelation ◽  
Coupling Constant ◽  
Additional Indication ◽  
Solution Structures ◽  
H Nmr ◽  
Spectral Asymmetry ◽  
Sugar Derivatives

With a view to reproduce the structure in solution of the Katsuki–Sharpless catalyst (the dimeric complex formed by homochiral diisopropyl tartrate with Ti(OiPr)4), five C2-symmetric chiral 2,3-butanediols, related to L-threitol but bearing N-, S-, and P-containing groups at the 1- and 4-positions, were prepared and their reactions with Ti(OiPr)4 were examined by nuclear magnetic resonance spectroscopy. The 1,4-dithioether formed a non-fluxional 2:2 tricyclic complex entirely analogous to those formed by alkylated sugar derivatives. The related disulfone formed a similar complex, but only at low temperatures, probably because of oligomerization at higher temperatures. A symmetric 2:1 complex also formed with excess Ti(OiPr)4, but incompletely and in equilibrium with the 2:2 species. No well-defined complexes were formed with pyrazole or phosphine oxide functionalities. However, in the presence of trifluoroacetic acid (TFA), a 1:2:2 L:Ti:TFA complex was identified with the dimethylpyrazole-containing diol and this resembled the 2:3 complexes formed by tartramides. Generally, the degree of spectral asymmetry and the coupling constant between diolate protons were instrumental in assigning structures and were used to classify all chiral diolate complexes into two groups according to whether or not they exhibited metal chelation and diolate bridging. By comparison of the effects of complexation on the diolate nuclei, a correlation was found between 13C and 1H nmr signal positions and between the pairs of signals in the spectra of asymmetric complexes, except in four cases where metal-bound side-chain groups induced a shielding of the bridging diolate proton. This could serve as an additional indication of metal chelation and diolate bridging and confirmed that nuclei at bridging positions appeared upfield of terminal ones. Noting that all the diols that readily chelated and bridged possessed electron-releasing side chains, while tartrates and tartramides that did not chelate possessed electron-withdrawing side chains, the basicity of the diolate oxygens is considered the most important determinant of structure. Side-chain polarity was instead found to influence whether or not a well-defined complex could form.

Solution conformation on bovine growth hormone releasing factor by 1 H NMR and molecular modeling

FEBS Letters ◽  
1999 ◽  
Vol 456 (2) ◽  
pp. 343-348 ◽  
Author(s):  
Jeehye Kweon ◽  
Ho-Jin Lee ◽  
Young-Man Kim ◽  
Young-Sang Choi ◽  
Kang-Bong Lee
Keyword(s):  
Growth Hormone ◽  
Molecular Modeling ◽  
Bovine Growth Hormone ◽  
Solution Conformation ◽  
Growth Hormone Releasing Factor ◽  
H Nmr

scholarly journals Rotamer libraries for the high-resolution design of beta-amino acid foldamers

2016 ◽  
Author(s):  
Andrew W Watkins ◽  
P. Douglas Renfrew ◽  
Timothy W Craven ◽  
Paramjit S Arora ◽  
Richard Bonneau
Keyword(s):  
Amino Acids ◽  
High Resolution ◽  
State Of The Art ◽  
Biologically Active ◽  
Side Chain ◽  
Model Refinement ◽  
Nonnatural Amino Acids ◽  
Conformational Preferences ◽  
Chain Conformations ◽  
Macromolecular Modeling

β-amino acids offer attractive opportunities to develop biologically active peptidomimetics, either employed alone or in conjunction with natural α-amino acids. Owing to their potential for unique conformational preferences that deviate considerably from α-peptide geometries, β-amino acids greatly expand the possible chemistries and physical properties available to polyamide foldamers. Complete in silico support for designing new molecules incorporating nonnatural amino acids typically requires representing their side chain conformations as sets of discrete rotamers for model refinement and sequence optimization. Such rotamer libraries are key components of several state of the art design frameworks. Here we report the development, incorporation in to the Rosetta macromolecular modeling suite, and validation of rotamer libraries for β3-amino acids.

1H and 13C nuclear magnetic resonance and molecular orbital studies of the internal rotational potential and of spin–spin coupling transmission in phenylallene

1995 ◽  
Vol 73 (9) ◽  
pp. 1478-1487 ◽  
Author(s):  
Ted Schaefer ◽  
Scott Kroeker ◽  
David M. McKinnon
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Molecular Orbital ◽  
Coupling Constants ◽  
Spin Coupling ◽  
Side Chain ◽  
Coupling Constant ◽  
H Nmr ◽  
Spin Coupling Constants ◽  
Spin Spin Coupling ◽  
Coupling Mechanisms

The 1H nuclear magnetic resonance spectra of phenylallene, diluted in acetone-d6 and benzene-d6, yield long-range coupling constants over as many as eight formal bonds between the ring and side-chain protons. These are discussed in terms of σ- and π-electron spin–spin coupling mechanisms, which are sensitive to the torsion angle between the allenyl and phenyl fragments. The torsion angle is assessed by means of molecular orbital computations of the internal rotational potential, whose height is calculated as 16.0 kJ/mol at the MP2/6-31G* level of correlation-gradient theory. Comparison with experimental and theoretical internal rotational potentials for styrene suggests that steric repulsions in the planar form of styrene amount to about 4 kJ/mol. In a field of 7.0 T, phenylallene is partially aligned, entailing a positive dipolar coupling constant between the methylene protons, from which absolute signs of the spin–spin coupling constants involving these protons can be inferred. Such coupling constants over seven and eight bonds, to the meta and para protons, are taken as being mediated by the extended π-electron system, providing a measure of π-electron contributions to coupling constants between meta protons and those in side chains (spin correlation). Some coupling constants between protons and 13C nuclei in the side chain, as well as between ring protons and these 13C nuclei, are also discussed in terms of spin coupling mechanisms. Solvent perturbations of one-bond proton–carbon coupling constants in the allenyl group do not follow the usual pattern in which an increase in polarity of the solvent is associated with an increase in the magnitude of the coupling constant. Keywords: 1H NMR, phenylallene; 1H NMR, long-range spin–spin coupling constants in phenylallene; phenylallene, internal rotational potential, molecular orbital computations; molecular orbital calculations, an internal rotational potential in phenylallene.

The conformations of prostacyclin and related prostaglandins

1985 ◽  
Vol 63 (5) ◽  
pp. 1143-1149 ◽  
Author(s):  
Helmut Beierbeck ◽  
George Kotovych ◽  
Makiko Sugiura
Keyword(s):  
Nmr Spectroscopy ◽  
High Field ◽  
Coupling Constants ◽  
Side Chain ◽  
Spectroscopic Parameters ◽  
H Nmr ◽  
Vicinal Coupling Constants ◽  
Nuclear Overhauser ◽  
Chain Conformations ◽  
Ring Conformations

The conformations of prostacyclin, PGI2, and three of its analogues, 6R- and 6S-PGI1 and carbacyclin, were studied by high field 1H nmr spectroscopy. The cis-bicyclo- and cis-oxabicyclo[3.3.0]octane ring conformations were completely assigned. The minima for the pseudorotational conformations are observed at 7E/12E for PGI2, [Formula: see text] for 6R-PGI1, and 6E/11E for 6S-PGI1, and carbacyclin. The data indicate that each molecule adopts a narrow pseudolibrational range, if not a single conformation. The α- and ω-side chain conformations were characterized, but not unambiguously. Vicinal coupling constants and nuclear Overhauser enhancements proved to be the most useful spectroscopic parameters in this study.

Analogues of the cholecystokinin octapeptide modified in the central part of the molecule

1991 ◽  
Vol 56 (9) ◽  
pp. 1963-1970 ◽  
Author(s):  
Jan Hlaváček ◽  
Václav Čeřovský ◽  
Jana Pírková ◽  
Pavel Majer ◽  
Lenka Maletínská ◽  
...  
Keyword(s):  
Amino Acid ◽  
Biological Activities ◽  
Point Of View ◽  
Biologically Active ◽  
Side Chain ◽  
Amino Acid Residues ◽  
Cholecystokinin Octapeptide ◽  
Biological Tests ◽  
Biological Potency ◽  
Biologically Active Conformation

In a series of analogues of the cholecystokinin octapeptide (CCK-8) the amino acid residues were gradually modified by substituting Gly by Pro in position 4, Trp by His in position 5, Met by Cle in position 6, or the Gly residue was inserted between Tyr and Met in positions 2 and 3 of the peptide chain, and in the case of the cholecystokinin heptapeptide (CCK-7) the Met residues were substituted by Nle or Aib. These peptides were investigated from the point of view of their biological potency in the peripheral and central region. From the results of the biological tests it follows that the modifications carried out in these analogues and in their Nα-Boc derivatives mean a suppression of the investigated biological activities by 2-3 orders of magnitude (at a maximum dose of the tested substance of 2 . 10-2 mg per animal).This means that a disturbance of the assumed biologically active conformation of CCK-8, connected with a considerable decrease of the biological potency of the molecule, takes place not only after introduction of the side chain into its centre (substitution of Gly4), but also after the modification of the side chains of the amino acids or by extension of the backbone in further positions around this central amino acid.

scholarly journals Synthesis and antioxidant properties of 2-(3-(hydroxyimino)methyl)-1H-indol-1-yl)acetamide derivatives

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Chandravadivelu Gopi ◽  
Magharla Dasaratha Dhanaraju
Keyword(s):  
Antioxidant Activity ◽  
Condensation Reaction ◽  
Antioxidant Properties ◽  
Side Chain ◽  
Antioxidant Power ◽  
H Nmr ◽  
Antioxidant Agents ◽  
Phenyl Rings ◽  
Ferric Reducing Antioxidant Power ◽  
Ft Ir

Abstract Background The main aim of this work was to synthesise a novel N-(substituted phenyl)-2-(3-(hydroxyimino) methyl)-1H-indol-1-yl) acetamide derivatives and evaluate their antioxidant activity. These compounds were prepared by a condensation reaction between 1H-indole carbaldehyde oxime and 2-chloro acetamide derivatives. The newly synthesised compound structures were characterised by FT-IR, 1H-NMR, mass spectroscopy and elemental analysis. Furthermore, the above-mentioned compounds were screened for antioxidant activity by using ferric reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) methods. Result The antioxidant activity result reveals that most of the compounds were exhibiting considerable activity in both methods and the values are very closer to the standards. Among the synthesised compounds, compound 3j, 3a and 3k were shown remarkable activity at low concentration. Conclusion Compounds 3j, 3a and 3k were shown highest activity among the prepared analogues due to the attachment of halogens connected at the appropriate place in the phenyl ring. Hence, these substituted phenyl rings considered as a perfect side chain for the indole nucleus for the development of the new antioxidant agents.

Stereospecific Association of C-20 Epimers of 3β-Hydroxy-16-oxo-24-nor-17-azachol-5-eno-23-nitryle

1997 ◽  
Vol 52 (6) ◽  
pp. 749-756
Author(s):  
Zofia Plesnar ◽  
Stanisław Malanowski ◽  
Zenon Lotowski ◽  
Jacek W. Morzycki ◽  
Jadwiga Frelek ◽  
...  
Keyword(s):  
Proton Nuclear Magnetic Resonance ◽  
Side Chain ◽  
Water Molecules ◽  
Carbonyl Groups ◽  
Nmr Data ◽  
Molecular Modelling Studies ◽  
Modelling Studies ◽  
Lactam Carbonyl ◽  
Self Association ◽  
Chain Conformations

Abstract The cryoscopic measurements show that title compounds are strongly associated in CHCl3 solutions. The association of the 20 R epimer is distinctly less pronounced than that of the 20 S epipmer. Self-association of the 20 S epimer leads to the formation of very large com­plexes. The 20 R epimer forms associates via water molecules. The dissimilarity may be ex­plained in terms of different accessibility of the lactam carbonyl groups in the two epimers for the association. It is proposed that the association process is controlled by the configura­tion at the carbon atom C(20) and conformation around the C(20)-C(22) bond. Populations of side chain conformations of both epimers were determined by means of proton nuclear magnetic resonance. It was found for the 20 R epimer that the t and the -g rotamers are almost equally populated, and the rotamer +g is excluded. For the 20 S epimer the +g rotamer predominates over the t one, and the -g rotamer is excluded. The NMR data are fully consistent with the results of the molecular modelling studies.

scholarly journals Design and synthesis of a novel 5-(aminomethylene)thiazolidine-2,4-dione derivatives as potent hepatitis-B virus polymerase inhibitors

2015 ◽  
Vol 10 (2) ◽  
pp. 271
Author(s):  
Wei-Guo Li ◽  
He-Qun Wang
Keyword(s):  
Hbv Dna ◽  
Biologically Active ◽  
Secondary Amines ◽  
Design And Synthesis ◽  
H Nmr ◽  
Viral Antigens ◽  
Polymerase Inhibitors ◽  
Potent Inhibition ◽  
B Virus ◽  
C Nmr

<p>A series of novel thiazolidinedione analogues (TZD) were designed and synthesized potent inhibitors of HBV capsid assembly. The synthesis of thiazolidine-2,4-dione derivatives (4a–4o), starting from the condensation of 5-(ethoxymethylene)thiazolidine-2,4-dione (1) with various secondary amines (3) derived from biologically active compounds. The newly synthesized TZD analogues 4a-4o were characterized by <sup>1</sup>H NMR, <sup>13</sup>C NMR, and MS and evaluated for their anti-HBV activity. Most of the compounds inhibited the expression of viral antigens at low concentration. Six compounds, 4g, 4h, 4l, 4m, 4n, and 4o, demonstrated potent inhibition of HBV DNA replication at submicromolar range. Of these five initial hits, compound 4o was the most active when compared with lamivudine.</p><p> </p><p> </p>

The solution conformation of prostacyclin as determined by high field proton magnetic resonance techniques

1980 ◽  
Vol 58 (10) ◽  
pp. 974-983 ◽  
Author(s):  
George Kotovych ◽  
Gerdy H. M. Aarts ◽  
Tom T. Nakashima ◽  
Glen Bigam
Keyword(s):  
Magnetic Resonance ◽  
Correlation Time ◽  
Proton Magnetic Resonance ◽  
Double Resonance ◽  
Relaxation Times ◽  
Segmental Motion ◽  
Solution Conformation ◽  
Nmr Spectrum ◽  
H Nmr ◽  
The Difference

The proton magnetic resonance (1H nmr) spectrum at 400 MHz of prostacyclin at pH 10.4 in glycine buffer has been completely analyzed utilizing homonuclear double resonance, inversion recovery, and difference nOe experiments. The spectral analysis shows that the two protons at C-4 are non-equivalent even though they are removed from the asymmetric centres at C-8 and C-9 by five bonds. The difference nOe measurements verify the configuration at C-5.Proton longitudinal relaxation times (T1) were measured at 400 and 200 MHz. From the T1 frequency dependence, effective rotational correlation times ranging from 2.3 × 10−10 to 3.0 × 10−10 s were calculated for H-5, H-9, H-11, and H-15. This indicates that the portion of the molecule encompassed by these protons has a longer correlation time than is observed for the C-2 and the C-17 to C-19 protons, for which the average correlation time is 1.2 × 10−10 s. Hence the aliphatic side chains have more segmental motion.

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