Comparative study by circular dichroism of the conformation of deazapurine nucleosides and that of common purine nucleosides.

Miles, Daniel W.; Townsend, Leroy B.; Redington, Patrick; Eyring, Henry

doi:10.1073/pnas.73.7.2384

Cited by 11 publications

(2 citation statements)

References 31 publications

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“…6A-C, empty squares) for the adenine bases at the micellar interface. 61,62 It is known that nucleotides can adopt two main orientation of the base with respect to the glycosidic bond (Fig. 7), namely syn and anti, defined in terms of the glycosidic torsion angle, c, (O4 0 -C1 0 -N9-C4 for purines and O4 0 -C1 0 -N1-C2 for pyrimidines): the syn conformations correspond to c ¼ 0 AE90 and the anti conformations correspond to c ¼ 180 AE 90.…”

Section: Spectroscopymentioning

confidence: 99%

Collective headgroup conformational transition in twisted micellar superstructures

Bombelli¹,

Berti²,

Milani³

et al. 2008

Soft Matter

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Predictions on amphiphilic self-assemblies traditionally rely on considerations on molecular shape and charge of the surfactant. In the case of functional surfactants a more sophisticated toolbox becomes necessary to design amphiphiles encoding chemical functionalities that provide additional responsive properties to their self-assemblies. Here we report on a comprehensive and combined structuralspectroscopic characterization of 1,2-dilauroyl-phosphatidyl-adenosine (DLPA) micelles in phosphate buffer. The temperature dependence, more precisely the thermal history of the sample, is explicitly taken into account. The experimental data, supplemented with MD simulations, indicate the presence of two possible states at room temperature, characterized by distinctly different structural properties that depend on the thermal history of the sample. The twisted superstructures, produced by aging DLPA micelles through intermicellar assembly of locally cylindrical aggregates at room temperature, collapse upon warming at 35 C, yielding aligned filaments and/or wormlike structures. The initial superstructures cannot be recovered by thermal inversion. The reason for this behaviour is that the thermal activation causes a redistribution of syn-anti conformations of adenosine headgroups, as indicated by spectroscopic results (NMR, CD, FTIR), which is then collectively frozen thanks to molecular constraints present in the aggregate.

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Section: Spectroscopymentioning

confidence: 99%

Collective headgroup conformational transition in twisted micellar superstructures

Bombelli¹,

Berti²,

Milani³

et al. 2008

Soft Matter

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“…Along with difficulties associated with treating the weak perturbation effects of the nonchromophoric sugar, this incomplete knowledge has hindered the development of theoretical models for calculating the rotatory parameters and extracting stereochemical information from them. In spite of these problems, CD studies of nucleosides have produced some useful rules and diagrams relating the sign of the first CD band to anomeric configuration and to conformation (10,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61).…”

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confidence: 99%

Optical activity and electronic absorption spectra of some simple nucleosides related to cytidine and uridine: all-valence-shell molecular orbital calculations.

Miles¹,

Redington²,

Miles³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

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The circular dichroism and electronic absorption of three simple model systems for cytidine and uridine have been measured to 190 nm. The molecular spectral properties (excitation wavelengths, oscillator strengths, rotational strengths, and polarization directions) and electronic transitional patterns were investigated by using wave functions of the entire nucleoside with the goal of establishing the reliability of the theoretical method. The computed electronic absorption quantities were shown to be in satisfactory agreement with experimental data. It was found that the computed optical rotatory strengths of the B2. and El.electronic transitions and lowest observed n-ir* transition are in good agreement with experimental values. Electronic transitions were characterized by their electronic transitional patterns derived from population analysis of the transition density matrix.The theoretical rotational strengths associated with the B2. and El. transitions stabilize after the use of just a few singly excited configurations in the configuration interaction basis and, hypothetically, are more reliable as indicators of conformation in pyrimidine nucleosides related to cytidine.Spectroscopic studies of the nucleic acid bases and their derivatives have appeared continuously over the past quarter century (1-40). Many of these studies were motivated by the prospect of obtaining stereochemical information from changes in the absorption and optical rotation spectra of the nucleic acids and their models (41-51). More recently, the increasing importance of slightly modified versions of the nucleic acid monomers as potential therapeutic agents has accentuated the importance of optical studies in this area, particularly circular dichroism (CD) studies, which indirectly give one stereochemical information (10-18, 31-41, 52-61). The biological significance of the conformational aspects ofnucleosides and nucleotides has been sufficiently documented (60-63).Of the two main aspects of CD studies, stereochemical and spectroscopic, the spectroscopic problem is currently the more fundamental because incomplete knowledge of the electronic transitions that give rise to the absorption of radiation and the rotatory power has limited attempts to determine optically the chirality of nucleosides. Along with difficulties associated with treating the weak perturbation effects of the nonchromophoric sugar, this incomplete knowledge has hindered the development of theoretical models for calculating the rotatory parameters and extracting stereochemical information from them. In spite of these problems, CD studies of nucleosides have produced some useful rules and diagrams relating the sign of the first CD band to anomeric configuration and to conformation (10, 31-41, 52-61).The major goal of this study is to use the experimental data on 3-deaza-4-deoxyuridine, 3-deazauridine, and 3-deazacytidine to evaluate a new theoretical method for calculating and interpreting the optical properties of nucleosides. The method uses wave functions of...

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Conformational effects of purine N3 electronic properties on drug design and cyclic nucleotide metabolism

Miles

Eyring

2009

Int. J. Quantum Chem.

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The conformational effect of variations in electronic properties at the N3 position of purines, purine analogs, and cyclic AMP analogs are related to their biological properties. The effect of glycosidic conformation is demonstrated for the adenosine analogs 2-azaadenosine and 2-fluoroadenosine by both theoretical calculations and T I relaxation measurements. For these two analogs there is increased preference for the high anti conformations. The high anti conformation is considered to be required of purine substrates by the enzymes adenosine kinase and deoxycytidine kinase as well as adenylate cyclase activating adenosine receptors. Protein kinase I1 is considered as requiring an anti conformation for activation by cyclic AMP analogs, and an anti conformation may also be required at adenylate cyclase inhibiting adenosine receptors. The selective activation approach for designing nucleoside analogs is described. Selective therapeutic potential as antiparasitic, antiviral, antibacterial, or anticancer agents can be achieved with nucleoside analogs. The successful implementation of the selective activation approach depends on a precise understanding of the conformation and electronic specificity of normal versus disease associated nucleoside kinases and deoxynucleoside kinases. The conformation specificity of normal adenosine kinase and deoxycytidine kinase enzymes appears to be established. Less specific or alternative pathways leading to the formation of toxic nucleotide analogs are known to exist in bacteria, parasites, virus infections, and cancer. If the conformational, electronic, and functional group requirements for normal enzyme activation are removed in a nucleoside analog, then it can be selectively activated to a toxic form by the enzyme mechanisms available to a target disease. The target disease, by converting a nucleoside analog to a toxic form, will destroy itself with little or no damage anticipated for the host.

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Comparative study by circular dichroism of the conformation of deazapurine nucleosides and that of common purine nucleosides.

Cited by 11 publications

References 31 publications

Collective headgroup conformational transition in twisted micellar superstructures

Collective headgroup conformational transition in twisted micellar superstructures

Optical activity and electronic absorption spectra of some simple nucleosides related to cytidine and uridine: all-valence-shell molecular orbital calculations.

Conformational effects of purine N3 electronic properties on drug design and cyclic nucleotide metabolism

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