QSAR and Multivariate Data Analysis of Amphiphilic Benzylamines and their Interaction with Various Phospholipids Determined by Different Methods

Seydel, Joachim K.; Cordes, H. P.; Wiese, Michael; Chi, Han-Lin; Croes, N.; Hanpft, R.; Lüllmann, Heinz; Mohr, Klaus; Patten, Marsha; Padberg, Y.; Lüllmann‐Rauch, Renate; Vellguth, S; Meindl, Wolfgang; Schönenberger, Helmut

doi:10.1002/qsar.19890080403

Cited by 17 publications

(9 citation statements)

References 19 publications

(1 reference statement)

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“…[9,10] A direct measurable relaxation rate parameter is the line width at half peak height (Dn 1/2 ) of a given proton signal, which is proportional to T 2 À1 according to Equation (1). Changes in proton relaxation rates are related to a change (decrease) in the motional freedom of the solute in the presence of macromolecules, and therefore can be used to quantify the degree of interaction of the molecule with liposomes.…”

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confidence: 99%

Amphiphilic NO‐Donor Antioxidants

et al. 2007

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Models of amphiphilic NO-donor antioxidants 24-26 were designed and synthesized. The products were obtained by linking a lipophilic tail (C(6), C(8), C(10)) with a polar head constituted by the 2,6-dimethoxyphenol antioxidant joined to the NO-donor 3-furoxancarboxamide substructure through a bridge containing a quaternary ammonium group. Compound 23, containing the shortest C(2)-alkyl chain, was also studied as a reference. The antioxidant properties (TBARS and LDL oxidation assays) and the vasodilator properties of the compounds were studied in vitro. The ability of these products to interact with phospholipid vesicles was also investigated by NMR techniques. The results indicate that both activities are modulated by the ability of the compounds to accumulate on phospholipid layers.

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confidence: 99%

Amphiphilic NO‐Donor Antioxidants

et al. 2007

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“…Indeed good correlations have been found between NMR slopes and log D lip as well as other lipophilicity descriptors obtained using artificial membranes. 7,45,50 The NMR method can also afford information on the interaction of distinct molecular fragments with phospholipids, by comparing, within the same solute, the NMR slopes of different signals corresponding to distinct molecular fragments. In this case, since different molecular portions may interact differently with liposomes, the relationship between log D lip and the NMR slope is not univocal, but may vary according to the signal being monitored.…”

Section: Principle Of 1 H-nmr Studies To Obtain Relaxation Rates As Mmentioning

confidence: 99%

“…8,15,[50][51][52][53][54] One can distinguish between two classes of NMR techniques, namely wide-line and highresolution experiments. Wide-line techniques are carried out on crystals, unsonicated phospholipid bilayers or large lipid vesicles in the gel or liquid-crystalline phase, and rely mainly on the analysis of 31 P chemical shift anisotropy and 2 H quadrupolar splitting.…”

Section: H-nmr Spectroscopymentioning

confidence: 99%

Liposome/water lipophilicity: Methods, information content, and pharmaceutical applications

Balen

Martinet

Caron

et al. 2004

Medicinal Research Reviews

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This review discusses liposome/water lipophilicity in terms of the structure of liposomes, experimental methods, and information content. In a first part, the structural properties of the hydrophobic core and polar surface of liposomes are examined in the light of potential interactions with solute molecules. Particular emphasis is placed on the physicochemical properties of polar headgroups of lipids in liposomes. A second part is dedicated to three useful methods to study liposome/water partitioning, namely potentiometry, equilibrium dialysis, and (1)H-NMR relaxation rates. In each case, the principle and limitations of the method are discussed. The next part presents the structural information encoded in liposome/water lipophilicity, in other words the solutes' structural and physicochemical properties that determine their behavior and hence their partitioning in such systems. This presentation is based on a comparison between isotropic (i.e., solvent/water) and anisotropic (e.g., liposome/water) systems. An important factor to be considered is whether the anisotropic lipid phase is ionized or not. Three examples taken from the authors' laboratories are discussed to illustrate the factors or combinations thereof that govern liposome/water lipophilicity, namely (a) hydrophobic interactions alone, (b) hydrophobic and polar interactions, and (c) conformational effects plus hydrophobic and ionic interactions. The next part presents two studies taken from the field of QSAR to exemplify the use of liposome/water lipophilicity in structure-disposition and structure-activity relationships. In the conclusion, we summarize the interests and limitations of this technology and point to promising developments.

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“…However, a drawback of applying selected therapeutics as test compounds is their heterogeneity in molecular structure and physicochemical properties. Only very few structure−activity studies for explicit membrane-interaction endpoints have been reported to date . A possible reason for this situation may be the lack of appropriate training datasets.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Pharmacological and Biophysical Characterization, and Membrane-Interaction QSAR Analysis of Cationic Amphiphilic Model Compounds

et al. 1999

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Cationic amphiphilic drugs have a propensity to interact with biological interphases. This study was designed to gain more insight into the molecular properties of catamphiphilic drugs which govern this type of interaction. A series of phenylpropylamine model compounds were synthesized in which modifications were incorporated at the aromatic part of the molecule. The replacement of (45)Ca(2+) from phosphatidylserine monolayers served to monitor drug binding to the phospholipid. The influence on the phase-transition temperature of liposomes of dipalmitoylphosphatidic acid was measured to assess the perturbing action of the drugs on the structural organization of phospholipid assemblies. The antiarrhythmic activity of the compounds was determined in Langendorff preparations of guinea pig hearts to assess the membrane-stabilizing action. Quantitative structure-activity relationship (QSAR) models for these endpoints were developed using both intra- and intermolecular QSAR descriptors. Intermolecular membrane-interaction descriptors were derived from molecular dynamics simulations of the compounds in a model phospholipid monolayer. QSAR models were derived for all endpoints using partial least-squares regression (PLS) and a genetic algorithm tool, the genetic function approximation (GFA). Membrane-interaction descriptors appear to be of a particular importance in explaining the influence of the compounds on the phase-transition temperature of DPPA liposomes, while the other endpoints can be adequately modeled by intramolecular descriptors. The calcium-displacing activity at phosphatidylserine monolayers is governed by the electrostatic properties of the compounds. Measures of lipophilicity and molecular size are of particular importance for antiarrhythmic activity. Possible improvements to both the molecular modeling and the applied computational protocol of membrane-solute systems are identified and discussed.

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QSAR and Multivariate Data Analysis of Amphiphilic Benzylamines and their Interaction with Various Phospholipids Determined by Different Methods

Cited by 17 publications

References 19 publications

Amphiphilic NO‐Donor Antioxidants

Amphiphilic NO‐Donor Antioxidants

Liposome/water lipophilicity: Methods, information content, and pharmaceutical applications

Synthesis, Pharmacological and Biophysical Characterization, and Membrane-Interaction QSAR Analysis of Cationic Amphiphilic Model Compounds

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