Anna Tsantili-Kakoulidou - Academia.edu (original) (raw)

Papers by Anna Tsantili-Kakoulidou

Bioorganic & Medicinal Chemistry, 2014

Targeting long-term diabetic complications, as well as inflammatory pathologies, aldose reductase... more 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.

Expert Opinion on Drug Discovery, 2016

The development of immobilized artificial membrane (IAM) chromatography has unfolded new perspect... more 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.

European Journal of Pharmaceutical Sciences, 2016

The potential of immobilized artificial membrane (IAM) chromatography to estimate human oral abso... more 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&amp;amp;amp;#39;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.

CHEMICAL & PHARMACEUTICAL BULLETIN, 1994

The synthesis of some novel quaternary ammonium salts, derivatives of 15-phenyl-decapentanoic aci... more The synthesis of some novel quaternary ammonium salts, derivatives of 15-phenyl-decapentanoic acid, is described. Their lipophilicity was estimated applying the Hansch-Leo fragmental procedure and measured by means of reversed phase thin layer chromatography. All compounds were tested for their antibacterial activity against Gram positive and gram negative microorganisms. The less lipophilic compounds showed weak activity, mainly against gram positive microorganisms.

… of Chromatography A, Jan 1, 2010

Analytical and …, Jan 1, 2005

Journal of Solid State …, Jan 1, 2011

The electrochemical behavior of 12 non-steroidal anti-inflammatory drugs (NSAIDs) was studied by ... more The electrochemical behavior of 12 non-steroidal anti-inflammatory drugs (NSAIDs) was studied by means of cyclic voltammetry at a glassy carbon electrode. The underlying solvent had a considerable effect to the oxidation potentials of the investigated NSAIDs due to the alteration of their polar intermediates’ solvation. Oxicams were more capable of electrochemical oxidation, and the influence of both specific and non-specific

… of pharmaceutical and …, Jan 1, 2008

The chromatographic behavior of enalapril was investigated under different stationary and mobile ... more The chromatographic behavior of enalapril was investigated under different stationary and mobile phase conditions in an effort to unravel interferences in the underlying retention mechanism, which would affect its relation to octanol-water partitioning. Extrapolated retention factors, logk(w), were used as relevant chromatographic indices. The retention/pH profile was established and the peak split phenomenon, associated with cis/trans interconversion, was also monitored as a function of pH. The pH at maximum retention and minimum peak split occurrence was chosen for further investigation, so that the presence of zwitterionic structure was guaranteed and any effect of cis/trans interconversion could be ignored. Retention of zwitterionic enalapril was found to be very sensitive to mobile phase conditions in regard to organic modifier as well to the aqueous component. The use of morpholine-propanesulfonic acid (MOPS) as buffer and the presence of n-octanol as mobile phase additive proved critical factors for maximum suppression of secondary interactions. Nevertheless, the corresponding extrapolated retention factor was considerably larger than octanol-water logD value at the isoelectric point. However, logk(w) could be successfully converted to logD by means of a calibration equation established for ionized acidic compounds.

Journal of …, Jan 1, 2011

Analytical and …, Jan 1, 2010

Microchemical Journal 110 (2013) 711-718

The lipophilicity and biomimetic retention profile of three selenium species, methyl-seleninic ac... more The lipophilicity and biomimetic retention profile of three selenium species, methyl-seleninic acid (MSA), Se-Methyl-selenocysteine (MeSeC) and dimethyl-selenourea (DMeSeU), were established. Lipophilicity was measured by the shaking flask method, while for chromatography one reversed-phase (Discovery C-18) column and three biomimetic stationary phases, namely immobilized artificial membrane (IAM), human serum albumin (HSA) and ?1-acid glycoprotein (AGP) were employed, under different mobile phase conditions. These results were combined with previous data obtained under analogous conditions on eight selenium species including selenites (Se(IV)), selenates (Se(VI)), selenomethionine (SeMet), selenocystine (SeCyst), selenocystamine (SeCM), selenourea (SeU), dimethylselenide ((CH3)2Se) and dimethyldiselenide ((CH3)2Se2). The combined data were further used to establish relations between biomimetic retention factors and lipophilicity, the effect of the presence of reduced glutathione (GSH) to retention, as well as to determine the oxidation potential by means of cyclic voltammetry. According to their anode potentials in cyclic voltammetry, only the urea analogues, SeU and, especially, DMeSeU, exhibited considerable antioxidant properties. Moreover IAM retention of Se(IV), Se(VI), SeMet and MeSeC was correlated with Caco-2 apparent permeability coefficient (Papp) available in literature. IAM retention data were further converted to percentage of human oral absorption according to a relevant equation reported in the literature, while from HSA retention results the plasma protein binding was estimated. According to these values, low biopersistence in the human body may be anticipated.

Journal of Chromatography A, 2015

In the current study, quantitative structure-retention relationships (QSRR) were constructed base... more 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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;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.

Molecular Modeling and Prediction of Bioactivity, 2000

Quantitative Structure-Activity Relationships, 1999

Drug development is currently struggling against high attrition rates and rising costs; clinical ... more 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 ...

Pharmaceutical research, 2002

To explore the quantitative structure pharmacokinetic relationships of the disposition parameters... more To explore the quantitative structure pharmacokinetic relationships of the disposition parameters: clearance (CL), apparent volume of drug distribution (V(ap)), fractal clearance (CL(f)), and fractal volume (v(f)) for 272 structurally unrelated drugs used in therapeutics. Literature data were used for CL and V(ap) whereas CL(f) and v(f) were estimated as described previously (Pharm. Res. 18, 1056, 2001 and 19, 697, 2002). A variety of molecular descriptors expressing lipophilicity, ionization, molecular size and hydrogen bonding capacity were estimated using computer packages. The data were analyzed using multivariate statistics. For each disposition parameter (CL, V(ap) CL(f), v(f)) PCA (principal component analysis) and PLS (projection to latent structures) were applied to the total set of data as well as to subsets of data. Drugs were divided into two classes (I and II) according to their v(f)/V(ap) ratio. Class I comprises 131 drugs with v(f)/V(ap) > 1, whereas class 11141 dr...

Die Pharmazie, 1998

The synthesis of benzaldehyde oximethers with suitably substituted 1,2,4-triazoles and 1,3,4-oxad... more 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.

Advanced drug delivery reviews, Jan 27, 2015

Plasma protein binding (PPB) strongly affects drug distribution and pharmacokinetic behavior with... more Plasma protein binding (PPB) strongly affects drug distribution and pharmacokinetic behavior with consequences in overall pharmacological action. Extended plasma protein binding may be associated with drug safety issues and several adverse effects, like low clearance, low brain penetration, drug-drug interactions, loss of efficacy, while influencing the fate of enantiomers and diastereoisomers by stereoselective binding within the body. Therefore in holistic drug design approaches, where ADME(T) properties are considered in parallel with target affinity, considerable efforts are focused in early estimation of PPB mainly in regard to human serum albumin (HSA), which is the most abundant and most important plasma protein. The second critical serum protein α1-acid glycoprotein (AGP), although often underscored, plays also an important and complicated role in clinical therapy and thus the last years it has been studied thoroughly too. In the present review, after an overview of the prin...