Anna Tsantili-Kakoulidou

Targeting long-term diabetic complications, as well as inflammatory pathologies, aldose reductase inhibitors (ARIs) have been gaining attention over the years. In the present work, in order to address the poor membrane permeation of previously reported ARIs, derivatives of N-phenylpyrrole, bearing groups with putative pKa≥7.4, were synthesized and evaluated for aldose reductase inhibitory activity. The 2-fluorophenol group proved the most promising moiety, and further modifications were explored. The most active compound (31), identified as a submicromolar inhibitor (IC50=0.443μM), was also selective against the homologous enzyme aldehyde reductase. Cross-docking revealed that 31 displays a peculiar interaction network that may be responsible for high affinity. Physicochemical profiling of 31 showed a pKa of 7.64, rendering it less than 50% ionized in the physiological pH range, with potentially favorable membrane permeation. The latter was supported from the successful inhibition of sorbitol formation in rat lenses and the ability to permeate rat jejunum.

The development of immobilized artificial membrane (IAM) chromatography has unfolded new perspectives for the use of chromatographic techniques in drug discovery, combining simulation of the environment of cell membranes with rapid measurements. The present review describes the characteristics of phosphatidylcholine-based stationary phases and analyses the molecular factors governing IAM retention in comparison to n-octanol-water and liposomes partitioning systems as well as to reversed phase chromatography. Other biomimetic stationary phases are also briefly discussed. The potential of IAM chromatography to model permeability through the main physiological barriers and drug membrane interactions is outlined. Further applications to calculate complex pharmacokinetic properties, related to tissue binding, and to screen drug candidates for phospholipidosis, as well as to estimate cell accumulation/retention are surveyed. The ambivalent nature of IAM chromatography, as a border case between passive diffusion and binding, defines its multiple potential applications. However, despite its successful performance in many permeability and drug-membrane interactions studies, IAM chromatography is still used as a supportive and not a stand-alone technique. Further studies looking at IAM chromatography in different biological processes are still required if this technique is to have a more focused and consistent application in drug discovery.

The potential of immobilized artificial membrane (IAM) chromatography to estimate human oral absorption (%HOA) was investigated. For this purpose, retention indices on IAM stationary phases reported previously by our group or measured by other authors under similar conditions were used to model %HOA data, compiled from literature sources. Considering the pH gradient in gastrointestinal tract, the highest logkw(IAM) values were considered, obtained either at pH7.4 or 5.5, defined as logkw(IAM)(best). Non linear models were established upon introduction of additional parameters and after exclusion of drugs which are substrates either to efflux or uptake transporters. The best model included Abraham's hydrogen-bond acidity parameter, molecular weight as well as the positively and negatively charged molecular fractions. For reasons of comparison between IAM chromatography and traditional lipophilicity, corresponding models were derived by replacing IAM retention factors with octanol-water distribution coefficients (logD). An overexpression of electrostatic interactions with phosphate anions was observed in the case of IAM retention as expressed by the negative contribution of the positively charged fraction F(+). The same parameter is statistically significant also in the logD model, but with a positive sign, indicating the attraction of basic drugs in the negatively charged inner membrane. To validate the obtained models a blind test set of 22 structurally diverse drugs was used, whose logkw(IAM)(best) values were determined and analyzed in the present study under similar conditions. IAM retention factors were further compared with MDCK cell lines permeability data taken from literature for a set of validation drugs. The overexpression of electrostatic interactions with phosphate anions on IAM surface was also evident in respect to MDCK permeability. In contrast to the clear classification between drugs with high and poor (or intermediate) absorption provided by MDCK permeability, %HOA plotted versus both IAM and logD data result in a saturation curve with a smoother ascending line.

In the current study, quantitative structure-retention relationships (QSRR) were constructed based on data obtained by a LC-(ESI)-QTOF-MS/MS method for the determination of amino acid analogues, following their derivatization via chloroformate esters. Molecules were derivatized via n-propyl chloroformate/n-propanol mediated reaction. Derivatives were acquired through a liquid-liquid extraction procedure. Chromatographic separation is based on gradient elution using methanol/water mixtures from a 70/30% composition to an 85/15% final one, maintaining a constant rate of change. The group of examined molecules was diverse, including mainly α-amino acids, yet also β- and γ-amino acids, γ-amino acid analogues, decarboxylated and phosphorylated analogues and dipeptides. Projection to latent structures (PLS) method was selected for the formation of QSRRs, resulting in a total of three PLS models with high cross-validated coefficients of determination Q(2)Y. For this reason, molecular structures were previously described through the use of descriptors. Through stratified random sampling procedures, 57 compounds were split to a training set and a test set. Model creation was based on multiple criteria including principal component significance and eigenvalue, variable importance, form of residuals, etc. Validation was based on statistical metrics Rpred(2),QextF2(2),QextF3(2) for the test set and Roy's metrics rm(Av)(2) and rm(δ)(2), assessing both predictive stability and internal validity. Based on aforementioned models, simplified equivalent were then created using a multi-linear regression (MLR) method. MLR models were also validated with the same metrics. The suggested models are considered useful for the estimation of retention times of amino acid analogues for a series of applications.

Drug development is currently struggling against high attrition rates and rising costs; clinical trials are becoming larger and more complex, and developing a drug from concept to market costs staggering amounts, even up to as much as $11 billion. Therefore, it is in a medicinal chemist’s best interests to assess the potential of a drug as early as possible. In this respect, Lipinski’s, now ubiquitous, Rule of Five (Ro5) defines four simple rules that apply for the majority of compounds with good oral absorption. A drawback of Ro5 is that it specifically does not take into consideration the ionization potential of a molecule. Thus, in the present work we developed a metric for assessing oral drug likeness of ionizable chemical entities. The basic concept was to allocate lipophilicity to a neutral fraction of the molecule; in this way the known problematic pharmacokinetic profile of ionic compounds having either too high or too low lipophilicities will be established and the borders ...

The synthesis of benzaldehyde oximethers with suitably substituted 1,2,4-triazoles and 1,3,4-oxadiazoles from the corresponding benzaldoximes is described. The lipophilicity of the compounds was measured as well as their antimicrobial and antifungal activity in vitro. Certain compounds showed relatively significant activity against Bacillus subtilis.

Physicochemical and molecular properties influence both pharmacokinetic and pharmacodynamic process, as well as drug safety, often in a conflicting way. In this aspect the current trend in drug discovery is to consider ADME (T) properties in parallel with target affinity. The concept of "drug-likeness" defines acceptable boundaries of fundamental properties formulated as simple rules of thumb, in order to aid the medicinal chemist to prioritize drug candidates. Special attention is given to lipophilicity and molecular weight, since there is a tendency for those parameters to increase in regard to complex compounds generated by new technologies, with potential consequences in bioavailability, while high lipophilicity is also associated with undesired effects. Such rules have the advantage to be very simple and are easy to interpret; however their drawback is that they do not take into consideration uncertainties in measurements and calculations as well as the receptor requi...

Retention of 49 structurally diverse drugs on alpha1 acid glycoprotein column was investigated under different chromatographic conditions. Acetonitrile and 2-propanol were used as organic modifiers at different percentages and the pH was adjusted at 7.0 using PBS. Analysis of extrapolated and isocratic retention in terms of lipophilicity and electrostatic interactions revealed significant effect of the nature and percentage of organic modifier, which was attributed to the different shielding degree of the charged sites on the stationary phase by the buffer constituents. AGP retention factors were compared to HSA retention factors analyzed previously. Application of LSER analysis, extended to incorporate fractions ionized, demonstrated hydrogen bond acidity, dipolarity/polarizability and excess molar refraction as the most significant parameters for all AGP chromatographic indices, elucidating the differentiation of AGP retention from octanol-water partitioning and HSA retention. An ...

The transfer of xenobiotic compounds into human breast milk has raised serious concerns in the last few years. The present study is aimed to assess whether simple physicochemical properties exert significant impact on human breast milk transfer of drugs and chemicals. A large data set of 375 xenobiotic compounds with available experimental milk to plasma (M/P) ratios was systematically compiled from the literature and explored with their physicochemical properties being further analyzed with respect to their extent to transfer into breast milk. Xenobiotic compounds with increased breast milk transfer (M/P ≥ 1) were characterized by enhanced lipophilicity and decreased molecular size (p < 0.05). Enhanced polarity and hydrogen bonding capacity were more frequently observed in xenobiotic compounds with reduced breast milk transfer (p < 0.0001). Xenobiotic compounds presenting increased positive charge at pH 7.4 were characterized by enhanced breast milk transfer (p < 0.001). Xenobiotic compounds presenting increased negative charge at pH 7.4 were characterized by decreased breast milk transfer (p < 0.001). The present study supports evidence that simple physicochemical properties related with lipophilicity, polarity, molecular size and ionization status exert significant impact on drugs and chemicals transport into human breast milk.

The 18th European Symposium on Quantitative Structure-Activity Relationships (QSAR) took place in Rhodes, Greece, on 19 - 24 September 2010. It was organized by the Hellenic Society of Medicinal Chemistry and the Cheminformatics and QSAR Society, and co-sponsored by the European Federation of Medicinal Chemistry. The conference was thematically dedicated to discovery informatics and drug design and addressed the impact of informatics in all its variants (chemoinformatics, bioinformatics, pharmacoinformatics) on drug discovery in the broader context of biological complexity. The latest scientific and technological advances in QSAR as tools for the discovery of new, safer and more efficacious drugs were discussed during the meeting. This paper highlights the most important outcomes of the symposium, commenting briefly on some of the key presentations.

A quantitative structure-retention relationship (QSRR) model has been developed for the gas chromatographic retention times of 37 phenolic derivatives in a DB-5 non-polar column (95% dimethyl and 5% diphenyl-polysiloxane). As a first step, multiple linear regression (MLR) was employed to gain informative descriptors that can predict the retention times of these compounds. Descriptors appearing in the MLR model are categorized as topological and geometric parameters that comply with the applied column. Furthermore, each molecular descriptor in this model was examined to unfold the relationship between molecular structures and their retention times. Then, a 4-4-1 neural network was developed using the descriptors selected by the MLR model. The comparison of the standard errors and correlation coefficients reveals the superiority of artificial neural networks (ANN) over the MLR model. This refers to the fact that the retention behaviors of molecules display non-linear characteristics. ...

The retention behaviour of selenites (Se(IV)), selenates (Se(VI)), seleno-dl-methionine (Se-Met), selenocystine (Se-Cyst), selenocystamine (Se-CM) and selenourea (Se-U) was investigated using a Discovery end-capped reversed-phase column as stationary phase and different mobile phase conditions. Extrapolated to 100% aqueous mobile phase retention factors (logk(w)) of the investigated Se species, determined using different methanol fractions (phi) as organic modifier, were compared with the corresponding actual values. The proper operation of this column even at 100% aqueous phase proved to be valuable for the accurate determination of logk(w) values of Se-CM and Se-Cyst, presenting a convex curvature logk=f(phi) at low MeOH fractions, often neglected in the extrapolation procedure. The effect of the presence of n-decylamine as well as saturation of the mobile phase with n-octanol was also studied. For ampholytic Se-Met and Se-Cyst the effect of n-decylamine in retention reflected the...

Thgoal of this study was to evaluate the efficacy of the antioxidant olive constituent, oleuropein, on infarct size, oxidative damage, and the metabolic profile in rabbits subjected to ischemia. Oleuropein, 10 or 20 mg/(kg x d), was administered to 8 groups that consumed a normal or hypercholesterolemic diet for 6 wk or only the higher dose for 3 wk. Circulating levels of malondialdehyde, protein carbonyl, nitrite+nitrate, cholesterol, triglycerides, SOD activity, and the metabolic profile were measured using 1H NMR spectra. In rabbits that consumed the normal diet, the infarct size (percentage of infarct to risk areas) was reduced by the administration of 10 mg oleuropein/(kg x d) (16.1 +/- 2.9%) or 20 mg oleuropein/(kg x d) for 3 wk (21.7 +/- 2.2%) or for 6 wk (24.3 +/- 1.3%) compared with the control group (48.05 +/- 2.0%, P < 0.05). Only the higher dose of 20 mg/(kg x d) reduced the infarct size in hypercholesterolemic rabbits (34.7 +/- 4.4% for 6 wk and 34.8 +/- 6.1% for 3 w...

A series of new 1H-1,2,4-triazole derivatives was synthesized and evaluated as potential antiviral (i.e. anti-influenza virus), antibacterial and antifungal agents. The lipophilicity of the compounds was also investigated using calculation procedures. Among the test compounds none showed specific activity against influenza virus, although compound 3a, the most hydrophilic member of the series, showed weak activity against Bacillus subtillis.

Human alpha1-acid glycoprotein (AAG) is a mixture of at least two genetic variants: the A variant and the F1 and/or S variant or variants, which are encoded by two different genes. In a continuation of previous studies indicating specific drug transport roles for each AAG variant according to its separate genetic origin, this work was designed to (1) determine the affinities of the two main gene products of AAG (i.e., the A variant and a mixture of the F1 and S variants) for 35 chemically diverse drugs and (2) to obtain meaningful 3D-QSARs for each binding site. Affinities were obtained by displacement experiments, leading to qualitative indications about binding site characteristics. In particular, drugs binding selectively to the A variant displayed some common structural features, but this was not seen for the F1*S variants. Three-dimensional QSAR analyses using the CoMFA method yielded a steric model for binding to the A variant, from which a simplified haptophoric model was der...