Giuseppe Ermondi

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.

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

Determination of metal–proton distances and electronic relaxation times in lanthanide complexes by nuclear magnetic resonance spectroscopy

The longitudinal and transverse relaxation times of the proton resonances of three lanthanide(III) complexes of 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetate have been measured. This allows determination of the metal–proton distances and the electronic relaxation times of the paramagnetic metal ions by exploiting the Curie-spin mechanism contribution to the transverse relaxation rates, once the molecular reorientational time τr is known by an independent experiment. Values of the parameters calculated from data obtained at a single magnetic field (9.4 T) were in good agreement with those found from the evaluation of the magnetic field-induced line broadening of the proton resonances as measured at 2.1, 4.7 and 9.4 T. A chemical exchange contribution to the linewidths is excluded on the basis of experiments performed at different temperatures.

Benzofurazanyl- and benzofuroxanyl-1,4-dihydropyridines : synthesis, structure and calcium entry blocker activity

The synthesis, structural characterization and calcium blocking activity of a series of benzofurazanyl-1,4-dihydropyridines (18 and 19) and benzofuroxanyl analogues (20 and 21) are reported. 1H-NMR showed that all the benzofuroxan derivatives exist in solution as tautomeric mixtures. The predominant tautomeric form in solution of the derivative 20 (dimethyl 1,4-dihydro-2,6-dimethyl-4-(4-benzofuroxanyl)-3,5-pyridinedicarboxylate) is also the one preferred in the solid state as shown by X-ray analysis. The conformation in the solid state of the benzofurazanyl analogue is also reported. Calcium entry blocker activity of the dihydropyridine derivatives 18–21 has been evaluated in isolated rabbit basilar artery as relaxation of calcium-induced contractions in high K+-depolarizing solution. All the compounds displayed high potency. The activity of benzofurazan derivatives was not changed by the N-oxidation. The two most active compounds 18 and 20 were as potent as Nifedipine.

An application of two MIFs-based tools (Volsurf+ and Pentacle) to binary QSAR: the case of a palinurin-related data set of non-ATP competitive glycogen synthase kinase 3β (GSK-3β) inhibitors.

VolSurf+ and GRIND descriptors extract the information present in MIFs calculated by GRID: the first are simpler to interpret and generally applied to ADME-Tox topics, whereas the latter are more sophisticated and thus more suited for pharmacodynamics events. Here we present a study which compares binary QSAR models obtained with VolSurf+ descriptors and GRIND for a data set of non-ATP competitive GSK-3β inhibitors chemically related to palinurin for which the biological activity is expressed in binary format. Results suggest not only that the simpler Volsurf+ descriptors are good enough to predict and chemically interpret the investigated phenomenon but also a bioactive conformation of palinurin which may guide future design of ATP non-competitive GSK-3 inhibitors.

The Relevance of Polar Surface Area (PSA) in Rationalizing Biological Properties of Several cis-Diamminemalonatoplatinum(II) Derivatives

A panel of six cis‐diamminemalonatoplatinum(II) derivatives were designed and synthesized, and their physicochemical properties and in vitro biological activity were experimentally evaluated and studied in silico. All the complexes showed higher IC50 values (≥20 μM) than those observed for cisplatin and its malonato analogue on three different human tumor cell lines, namely A2780 ovarian carcinoma, A549 lung carcinoma, and MCF‐7 breast carcinoma. In silico studies revealed that polar surface area (PSA) is the best descriptor to explain the poor biological activity observed for this series of new compounds, which in turn is likely due to poor cellular uptake. This finding is in line with general rules that assign a major role to PSA in characterizing the transport properties of drugs, in the actual case of antiproliferative metallopharmaceuticals.