Giulia Caron

Molecular factors influencing retention on immobilized artifical membranes (IAM) compared to partitioning in liposomes and n-octanol

AbstractPurpose. To assess the effect of molecular factors influencing retention on immobilized artificial membrane (IAM) high-performance liquid chromatography columns compared to liposomal partitioning and traditional n-octanol/water partition coefficients. Methods. IAM capacity factors were measured at pH 7.0 on an IAM.PC.DD2 stationary phase. Liposomal partitioning at pH 7.0 and n-octanol/water partition coefficients were measured using the pH metric method. Partitioning in egg-phosphatidylcholine (PhC) liposomes was also measured by equilibrium dialysis for a series of β-blockers. Results. For the ionized β-blockers, potentiometry and equilibrium dialysis yielded consistent partitioning data. For relatively large bases, IAM retention correlated well with PhC liposome partitioning, hydrophobic forces being mainly involved. For more hydrophilic compounds and for heterogeneous solutes, in contrast, the balance between electrostatic and hydrophobic interactions was not the same in the two systems. Hydrogen bonding, an important factor in liposomes partitioning, played only a minor role in IAM retention. Conclusions. Partitioning in immobilized artificial membranes depends on size, hydrophobicity, and charge. When hydrophobic interactions dominate retention, IAM capacity factors are well correlated with liposomal partitioning. On the contary, for hydrophilic solutes, the two systems do not yield the same information and are not interchangeable.

Structure-Lipophilicity Relationships of Neutral and Protonated β-Blockers, Part I, Intra- and Intermolecular Effects in Isotropic Solvent Systems

The objectives of this study were to validate new experimental techniques used to measure the log P of protonated drugs, and to investigate the inter- and intramolecular forces influencing the partitioning behavior of β-blockers in isotropic biphasic solvent systems. The lipophilicity parameters of a number of β-blockers were measured by two-phase titration, centrifugal partition chromatography (CPC), and cyclic voltammetry (CV) in one or more of the following solvent systems: octanol/water, 1,2-dichloroethane/water, and dibutyl ether/water. CV proved to be a promising technique for measuring the lipophilicity of protonated β-blockers. Derived parameters such as Δlog P (difference between log P in two different solvent systems, a parameter valid for a given solute in a given electrical form) and diff (difference between log P of two different electrical forms of a given solute, in the same system) yielded insights into inter- and intramolecular interactions characteristic of β-blockers. The relevance of these parameters in structure-permeation relationships is explored.

Combined Molecular Lipophilicity Descriptors and their Role in Understanding Intramolecular Effects

Traditional lipophilicity parameters (log P and log D) are well-known physico-chemical descriptors largely used in QSAR studies. Besides their numerical value, log P data contain a variety of information about inter- and intramolecular forces affecting partitioning and its related biological phenomena. The deconvolution of information from log P can be accessed only by adequate interpretative tools, such as new lipophilic-combined descriptors, of which features and some applications are presented in this review.

Lipophilicity behaviour of the zwitterionic antihistamine cetirizine in phosphatidylcholine liposomes/water systems

AbstractPurpose. The partitioning of cetirizine in a phosphatidylcholine liposomes/water system was compared with that of hydroxyzine and acrivastine to gain insight into the mechanisms of interaction of its various electrical species with membranes. Methods. The lipophilicity profiles of the compounds were obtained from equilibrium dialysis and potentiometry, and compared with changes in NMR relaxation rates. Results. The neutral form of hydroxyzine interacted mainly via hydrophobic interactions with the bilayer lipid core of the membrane, whereas for the cationic form both hydrophobic and electrostatic interactions were involved. Zwitterionic and anionic cetirizine were less lipophilic than its cation, which behaved like the corresponding species of hydroxyzine. Zwitterionic cetirizine interacted more by weak electrostatic interactions with the polar headgroups of phospholipids than by hydrophobic interactions with the membrane interior. The lipophilicity of its anion reflected the balance of repulsive electrostatic interactions between the carboxylate and phosphate groups and the hydrophobic interactions with the lipid core. Conclusion. The study confirms that various mechanisms influence the interaction of solutes with liposomes. Combining experimental techniques and using suitable reference compounds proves useful.

N-Substituted analogues of S-nitroso-N-acetyl-D,L-penicillamine: chemical stability and prolonged nitric oxide mediated vasodilatation in isolated rat femoral arteries

Previous studies show that linking acetylated glucosamine to S‐nitroso‐N‐acetyl‐D,L‐penicillamine (SNAP) stabilizes the molecule and causes it to elicit unusually prolonged vasodilator effects in endothelium‐denuded, isolated rat femoral arteries. Here we studied the propanoyl (SNPP; 3 carbon side‐chain), valeryl (SNVP; 5C) and heptanoyl (SNHP; 7C) N‐substituted analogues of SNAP (2C), to further investigate other molecular characteristics that might influence chemical stability and duration of vascular action of S‐nitrosothiols. Spectrophotometric analysis revealed that SNVP was the most stable analogue in solution. Decomposition of all four compounds was accelerated by Cu(II) and cysteine, and neocuproine, a specific Cu(I) chelator, slowed decomposition of SNHP. Generation of NO from the compounds was confirmed by electrochemical detection at 37°C. Bolus injections of SNAP (10 μl; 10−8–10−3 M) into the perfusate of precontracted, isolated rat femoral arteries taken from adult male Wistar rats (400–500 g), caused concentration‐dependent, transient vasodilatations irrespective of endothelial integrity. Equivalent vasodilatations induced by SNVP and SNHP were transient in endothelium‐intact vessels but failed to recover to pre‐injection pressures at moderate and high concentrations (10−6–10−3 M) in those denuded of endothelium. This sustained effect (>1 h) was most prevalent with SNHP and was largely reversed by the NO scavenger, haemoglobin. We suggest that increased lipophilicity of SNAP analogues with longer sidechains facilitates their retention by endothelium‐denuded vessels; subsequent slow decomposition within the tissue generates sufficient NO to cause prolonged vasodilatation. This is a potentially useful characteristic for targeting NO delivery to areas of endothelial damage.

Development of molecular hydrogen-bonding potentials (MHBPs) and their application to structure–permeation relations

Hydrogen bonds are major forces of recognition in biochemistry and molecular pharmacology; they are an essential component of intermolecular interactions and determine to a significant extent the 3D-structure of bio-macromolecules. To explore three-dimensional H-bonding properties, a new tool called Molecular Hydrogen-Bonding Potentials (MHBPs) was created. The development of this tool is based on a stepwise procedure similar to the one used successfully to generate the Molecular Lipophilicity Potential (MLP). First, a H-bonding fragmental system was developed starting from published solvatochromic parameters. An atomic H-bonding donor fragmental value (alpha) is associated to each hydrogen atom in a polar moiety. Similarly, an atomic H-bonding acceptor fragmental value (beta) is associated to each polar atom. A distance function and an angle function were defined to take into account variations of the MHBPs in space. The fragmental system and the geometric functions were then combined to generate the MHBPs. These are calculated at each point of an adequate molecular surface or on a three-dimensional grid. The MHBPs were compared with GRID interactions energies and correlated with success to oral drug absorption data. Available examples demonstrate that the MHBPs are a promising computational tool in drug design. Their combination with CoMFA and VolSurf is being studied.

Mechanisms of Liposomes/Water Partitioning of (p-Methylbenzyl)alkylamines

AbstractPurpose. The objective of this study was to compare and interpret the variations in lipophilicity of homologous (p-methylbenzyl)alkylamines (MBAAs) in isotropic (octanol/water) and anisotropic (zwitterionic liposomes/water) system. Methods. Two experimental approaches were used, namely the pH-metric method to measure lipophilicity parameters in octanol/water and liposomes/water systems, and changes in NMR relaxation rates to validate the former method and to gain additional insights into the mechanisms of liposomes/water partitioning. Results. For long-chain homologues (N-butyl to N-heptyl), the octanol/ water and liposomes/water systems mostly expressed hydrophobicity. In contrast, the lipophilicity of the shorter homologues (N-methyl to N-propyl) in the two systems expressed various electrostatic and polar interactions. Conclusions. The study sheds light on the molecular interactions between zwitterionic liposomes and amphiphilic solutes in neutral and cationic form.

Molecular and statistical modeling of reduction peak potential and lipophilicity of platinum(IV) complexes.

We report the results of the quantitative structure–property relationship analysis of 31 Pt(IV) complexes, for three of which the synthesis is reported for the first time. The X-ray structural analysis of one complex of the series was performed to demonstrate that the PM6 semiempirical method satisfactorily reproduces key features of the geometry of the complexes investigated. Molecular properties extracted from such calculations were then used to construct models of experimental data such as electrochemical peak potentials (evaluated by cyclic voltammetry) and the octanol–water partition coefficient (evaluated by a reversed-phase high performance liquid chromatography method), which are key aspects in the design of such Pt(IV) complexes as potential anticancer prodrugs. Statistically accurate models for both properties were found using combinations of surface areas, orbital energies, dipole moments, and atomic partial charges. These models could form the basis of virtual screening of potential drug molecules, allowing the prediction of properties, closely related to the antiproliferative activity of Pt(IV) complexes, directly from calculated data.

Predicting the Oxidative Metabolism of Statins: An Application of the MetaSite® Algorithm

PurposeThis study was undertaken to examine the MetaSite algorithm by comparing its predictions with experimentally characterized metabolites of statins produced by cytochromes P450 (CYPs).MethodsSeven statins were investigated, namely atorvastatin, cerivastatin, fluvastatin, pitavastatin and pravastatin which are (or were) used in their active hydroxy-acid form, and lovastatin and simvastatin which are used as the lactone prodrug. But given the fast lactone-hydroxy-acid equilibrium undergone by statins, both forms were investigated for each of the seven drugs. The MetaSite version 2.5.3 used here contains the homology 3D-models of CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. In addition, we also used the crystallographic 3D-structure of human CYP2C9 and CYP3A4. To allow a better interpretation of results, the probability function PSMi calculated by MetaSite (namely the probability of atom i to be a site of metabolism) was explicitly decomposed into its two components, namely a recognition score Ei (the accessibility of atom i) and the chemical reactivity Ri of atom i toward oxidation reactions.ResultsThe current version of MetaSite is known to work best with prior experimental knowledge of the cytochrome(s) P450 involved. And indeed, experimentally confirmed sites of oxidation were correctly given a high priority by MetaSite. In particular 77% of correct predictions (including false positive but, as discussed, this is not necessarily a shortcoming) were obtained when considering the first five metabolites indicated by MetaSite.ConclusionTo the best of our knowledge, this is the first independent report on the software. It is expected to contribute to the development of improved versions, but above all it demonstrates that the usefulness of such softwares critically depends on human experts.

Ionic partition diagram of the zwitterionic antihistamine cetirizine

Reference LEPA-ARTICLE-2001-013doi:10.1002/1522-2675(20010228)84:2 3.0.CO;2-4 Record created on 2005-11-07, modified on 2017-05-12