Radioimmltnoassay Determinations of p-Hydroxiphenformin and of Apparent Phenformin in Human Plasma or Serum

Abstract

Sensitive radioimmunoassay procedures are described for measuring p-hydroxyphenformin and apparent phenformin in human plasma or serum. The p-hydroxyphenformin procedure, which requires advance phenformin analysis, offers excellent accuracy. The determinations of apparent phenformin are influenced by the phenformin and p-hydroxyphenformin contents of the samples. Over a period of four months, the methods showed a precision associated with relative standard deviations of 12% for apparent phenformin and 13% for p-hydroxyphenformin.     

Heterocycles 51: Liphophilicity investigation of some thiazole chalcones and aurones by experimental and theoretical methods

Reversed‐phase thin‐layer chromatography and reversed‐phase high‐performance liquid chromatography were used for lipophilicity determination of a library of 30 thiazole chalcones and aurones previously synthetized in our laboratory. The experimental lipophilicity data have been compared with theoretical lipophilicity parameters estimated by various computational methods. Good correlations between the experimental and calculated lipophilicity parameters have been found for both investigated classes of compounds. Correlations between the lipophilicity of the thiazole chalcones and aurones and their antiproliferative activity were discussed. The methodologies and data gathered in this study will contribute to the lipophilicity studies of chalcones and aurones derivatives, two important classes of compounds in medicinal chemistry.     

Fraction Lipophilicity Index (FLI). A drug-like metric for orally administered ionizable drugs

ABSTRACT

Fraction Lipophilicity Index (FLI) was developed as a metric for assessing drug likeness of ionizable oral drugs. Considering that both log P and log D have distinct roles in drug action, the metric FLI allocates lipophilicity to a pH dependent neutral fraction of the molecule and is a weighted combination of log P and log D. It is expressed by equation: FLI = 2 x log P–│log D│. A dataset of 368 basic and acidic drugs was analyzed. Based on available % absorption data, drugs were classified into class 1 (268 drugs) and class 2 (100 drugs). The freeware MedChem Designer was used for log P and log D calculations at pH 7.4 and pH 5.5 for acids. Based on class 1, a drug-like FLI range 0–8 was defined. FLI distribution for class 2 is shifted towards significantly lower values. Comparison of FLI with rule of 5 (Ro5) shows that it leads to fewer values outside the established range than the corresponding log P violations for class 1. For class 2 it gives more alerts than Ro5 and can be considered complementary to Ro5, while it also sets lower limits to discriminate drugs with poor absorption.     

Theoretical Study of Molecular Structure,Reactivity, Lipophilicity,and Solubility of N-Hydroxyurea,N-Hydroxythiourea,and N-Hydroxysilaurea

Ab initio molecular orbital methods at the CBS-QB3 level of theory have been used to study the structure and gas-phase stability of various tautomers and rotamers of N-hydroxyurea, N-hydroxythiourea, and N-hydroxysilaurea, their anions and protonated forms. The geometries of N-hydroxyurea, N-hydroxythiourea, and N-hydroxysilaurea, their anions and cations were optimized at the Becke3LYP/CBSB7 level of theory. For all compounds studied, the amidic form is computed to be substantially more stable than the iminolic tautomer. N-Hydroxyurea and its thio and sila derivatives are computed to behave as Nacids in the gas phase. These compounds are in gas-phase weak acids with a calculated acidity of about 1425 to 1355 kJ-mol^–1. Basicities increase in the order: N-hydroxyurea < N-hydroxythiourea < N-hydroxysilaurea. The most stable protonated structures are represented by several isomers with almost equal stability. Thus, in the N-hydroxyurea, N-hydroxythiourea, and N-hydroxysilaurea, both protonation at the double bonded (C=O, C=S and Si=O) oxygen and sulfur atoms, as well as the protonation at the N(H)OH nitrogen basic center is equally probable. The experimental pK _a value (10.6) of N-hydroxyurea and the computed value (9.7) for its monohydrated complex with the specifically hydrogen-bonded water molecule to the ionizable OH group are in a good agreement. The experimental partition coefficient of N-hydroxyurea is best reproduced by the Alog P_s method. The formation of nitroxide radical in the reaction of N-hydroxyurea and its sulfur and silicon substituted derivatives with the phenol radical is an exothermic process. Thus, the \bondN(H)OH moiety of these compounds may quench the structurally related tyrosyl radicals in the active site of ribonucleotide reductase.     

Modeling of Anticancer Sulfonamide Derivatives Lipophilicity by Chemometric and Quantitative Structure-Retention Relationships Approaches

Sulfonamides are a classic group of chemotherapeutic drugs with a broad spectrum of pharmacological action, including anticancer activity. In this work, reversed-phase high-performance liquid chromatography and biomimetic chromatography were applied to characterize the lipophilicity of sulfonamide derivatives with proven anticancer activities against human colon cancer. Chromatographically determined lipophilicity parameters were compared with obtained logP, employing various computational approaches. Similarities and dissimilarities between experimental and computational logP were studied using principal component analysis, cluster analysis, and the sum of ranking differences. Furthermore, quantitative structure–retention relationship modeling was applied to understand the influences of sulfonamide’s molecular properties on lipophilicity and affinity to phospholipids.     

A Micellar Multitasking Device: Sensing pH Windows and Gauging the Lipophilicity of Drugs with Fluorescent Signals

A multitasking fluorescent device can be obtained by forming micelles of Triton X‐100, containing a lipophilic macrocyclic Cu²⁺ complex and the coordinating fluorophore Coumarin 343 (C343), which features a COOH moiety. At low pH the two micellised components do not interact, and the fluorescence of Courmarin 343 (C343) is intense. At intermediate pH, C343 is deprotonated and coordinates to the Cu²⁺ centre in its apical position, with fluorescence quenching. At higher pH the deprotonated C343 is displaced from Cu²⁺ by the formation of an OH^? complex, and the fluorescence is revived. This allows the system to carry out its first task as it behaves as an “on–off–on” fluorescent sensor for pH windows. The “off” part of the window ranges from pH 6 to 8. In this interval, in which the carboxylate form of C343 is apically coordinated to the Cu²⁺ complex inside micelles, the device carries out its second task, that is, it behaves as a gauge for lipophilicity. For pHs between 6 and 8, molecules containing a COOH group are in their COO^? form and distribute between bulk water and micelles proportionally to their lipophilicity. Upon entering the micelle, their COO^? moiety competes for coordination with C343, displacing it from the Cu²⁺ centre, and this results in fluorescence revival, the intensity of which is also proportional to the lipophilicity of the examined molecule. We have chosen the physiological pH value (7.4) as the working pH, and we have examined the lipophilicity of fatty acids and of the widely used family of non‐steroidal anti‐inflammatory drugs (NSAIDs). The device successfully measures their lipophilicity, expressing it with an “off–on” type fluorescent signal, as demonstrated by the correlation of the fluorescence increase with the logarithmic water/octanol partition coefficient (log P) and with the difference between the pK_a observed in micelles and that measured in water for NSAIDs.     

分子亲脂-亲水性的量子化学描述II. 氨基酸侧链的亲水指标和亲脂指标

在启发式亲脂势HMLP (heuristic molecular lipophilicity potential)的基础上提出了分子、分子片段和原子的亲水指标和亲脂指标. 计算出了20个天然氨基酸侧链的亲水、亲脂指标和亲水、亲脂表面积, 并用线性自由能函数表达氨基酸侧链的溶剂化自由能, ΔG_sol,i^θ＝b₀＋b₁L_i＋b₂H_i＋b₃S_i^＋＋b₄S_i^－. . 应用线性自由能函数和氨基酸侧链的亲水和亲脂指标, 计算了20个氨基酸残基的3种相转移自由能(蒸气-水、蒸气-正辛醇、正辛醇-水)和正辛醇-水分配系数logP_ow, 取得了与实验值高度一致的良好效果. HMLP的亲水和亲脂指标是HMLP的指标化, 扩展了这一方法的使用范围. 氨基酸侧链的亲水、亲脂指标和线性自由能函数有望用于生物大分子受体与配体的结合自由能的估算、蛋白质的结构与功能、蛋白-蛋白相互作用和识别的研究.     

分子亲脂-亲水性的量子化学描述II. 氨基酸侧链的亲水指标和亲脂指标

在启发式亲脂势HMLP(heuristicmolecularlipophilicitypotential)的基础上提出了分子、分子片段和原子的亲水指标和亲脂指标.计算出了20个天然氨基酸侧链的亲水、亲脂指标和亲水、亲脂表面积,并用线性自由能函数表达氨基酸侧链的溶剂化自由能,?Gsol,=b0 b1Li b2Hi b3Si b4Si.应用线性自由能函数和氨基酸侧链的亲水和亲脂! -i指标,计算了20个氨基酸残基的3种相转移自由能(蒸气-水、蒸气-正辛醇、正辛醇-水)和正辛醇-水分配系数logPow,取得了与实验值高度一致的良好效果.HMLP的亲水和亲脂指标是HMLP的指标化,扩展了这一方法的使用范围.氨基酸侧链的亲水、亲脂指标和线性自由能函数有望用于生物大分子受体与配体的结合自由能的估算、蛋白质的结构与功能、蛋白-蛋白相互作用和识别的研究.     

(Trifluoromethylselenyl)methylchalcogenyl as Emerging Fluorinated Groups: Synthesis under Photoredox Catalysis and Determination of the Lipophilicity

The synthesis of molecules bearing (trifluoromethylselenyl)methylchalcogenyl groups is described via an efficient two-step strategy based on a metal-free photoredox catalyzed decarboxylative trifluoromethylselenolation with good yields up to 88 %, which raised to 98 % in flow chemistry conditions. The flow methods allowed also to scale up the reaction. The mechanism of this key reaction was studied. The physicochemical characterization of these emerging groups was performed by determining their Hansch–Leo lipophilicity parameters with high values up to 2.24. This reaction was also extended to perfluoroalkylselenolation with yields up to 95 %. Finally, this method was successfully applied to the functionalization of relevant bioactive molecules such as tocopherol or estrone derivatives.     

Lipophilicity study of eight cephalosporins by reversed‐phase thin‐layer chromatographic method

The lipophilicity (R_M0) and specific hydrophobic surface area for the representatives of four generation cephalosporins have been determined by reversed‐phase thin‐layer chromatography, and the effect of different mobile‐phase modifiers (such as methanol, acetonitrile, acetone, 1,4‐dioxane and 2‐propanol) on the retention has been studied. The compounds studied showed typical retention behavior; their R_M values decreased linearly with increasing concentration of the organic modifier in the eluent. The linear correlations between the volume fraction of the organic solvent and the R_M values over a limited range were established for each solute, resulting in high values of correlation coefficients (>0.95 in most cases). R_M values were determined by various concentrations of organic modifier, and the correlation obtained was extrapolated to 0% of organic modifier. Chromatographically established logP (R_M0) parameters were compared with computationally calculated partition coefficients values (AClogP, ALOGP, KOWWIN, ALOGPs, XLOGP2, MLOGP and XLOGP3) and experimental octanol–water logP values (measured by the shake flask method). The received results demonstrate that RP‐TLC may be a good alternative technique for analytics in describing the lipophilic nature of investigated cephalosporins as well as the activity. Copyright © 2015 John Wiley & Sons, Ltd.     

Micelles as Containers for Self‐Assembled Nanodevices: A Fluorescent Sensor for Lipophilicity

Potentiometric titrations, fluorescence versus pH titrations, dynamic light scattering and fluorescence polarization anisotropy studies demonstrate that inside the nanodimensioned Triton X‐100 micelles, 1‐pyrenecarboxylic acid, PCOO^?, forms an apical complex with the Zn²⁺ cation encircled by a lipophilic cyclen ligand and hugely increasing its fluorescence. The ability of the Zn²⁺‐cyclen‐PCOO^? complex plus its micellar container to act as a fluorescent sensor to evaluate the lipophilicity of molecular species is demonstrated on the fatty acid series CH₃(CH₂)_xCOOH (x=0–16). At pH 7.4 a decrease in fluorescence is observed on the addition of fatty acids that is directly related to their chain length, that is, to their tendency to enter the micellar containers, where they dislocate PCOO^? from the Zn²⁺ centre. The independent determination of fatty acid pK_a values in the presence of Triton X‐100 micelles confirms that our fluorescent micellar device is capable of sensing their lipophilicity.     

Lipophilicity of Metallic Complexes of 4-Methoxyphenyl - 4' - Chlorobenzoylhydrazine as Estimated from Principal Component Analysis of thin Layer Chromatographic Retention Data

ABSTRACT

The relative lipophilicity of ten metallic complexes of 4-methoxyphenyl-4'-chlorobenzoylhydrazine with Cu²⁺, Co²⁺, Mn²⁺, Ni²⁺, Pd²⁺, Fe³⁺, Cr³⁺, La³⁺, Ce⁴⁺ and UO₂ ²⁺ with potentially anti-inflammatory properties have been determined by reversed-phase thin-layer chromatography using C₁₈ plates and water-methanol mixtures as eluents. The R_F values of each compound increased linearly with increasing concentration of methanol in the eluent. Principal component analysis allowed a more rational and objective estimation and comparison of lipophilicity determined by RPTLC. Scatterplots of the scores onto a plane described by the first two components showed clustering of the complexes according to the nature of the central cation, obtaining in this way a "congeneric lipophilicity chart". Generally, the presence of cation increases the lipophilicity expressed as scores along the first principal component, practically in the same way. This means that the lipophilic behavior of metallic complexes depends firstly of the structure of ligand. However, the most lipophilic effect was observed in the case of Cu²⁺, Pd²⁺, La³⁺ and Cr³⁺.     

N-Nitrosodimethylamine Contamination in the Metformin Finished Products

A GC–MS/MS method with EI ionization was developed and validated to detect and quantify N-nitrosodimethylamine (NDMA) and seven other nitrosamines in 105 samples of metformin tablets from 13 different manufactures. Good linearity for each compound was demonstrated over the calibration range of 0.5–9.5 ng/mL. The assay for all substances was accurate and precise. NDMA was not detected in the acquired active pharmaceutical ingredient (API); however, NDMA was detected in 64 (85.3%) and 22 (91.7%) of the finished product and prolonged finished product samples, respectively. European Medicines Agency recommends the maximum allowed limit of 0.032 ppm in the metformin products. Hence, 28 finished products and 7 pronged dosage products were found to exceed the acceptable limit of daily intake of NDMA contamination. The implications of our findings for the testing of pharmaceutical products are discussed.     

Lipophilicity analysis of newly synthetized quinobenzothiazines by use of TLC

Lipophilicity is a very important property of chemical compound taking into consideration in drugs design. Relationships between biological activity, among others lipophilicity, and chemical structure (QSAR) of the compound are very often used by researches. Especially important is the kind of substituents connected to the basic structural fragment and how it changes the lipophilicity of the compound. The aim of this study was to determine the parameters of lipophilicity of quinobenzothiazine derivatives using reversed phase - thin-layer chromatography (RP-TLC), which would enable one to determine the structure–activity relationship. The objective of our work is a series of 15 newly synthetized quinobenzothiazines. They were analyzed by thin-layer chromatography (TLC) with the use of two different mobile phases consisting of methanol or acetone as organic modifiers. For all compounds investigated, the values of lipophilicity obtained from computational method were also determined. Cluster analysis was carried out too for all data of lipophilicity obtained. Low correlation was found between values of experimental lipophilicity and lipophilicity from computational methods for newly synthetized compounds.     

The study of the lipophilicity of some aminoalkanol derivatives with anticonvulsant activity

A series of new (phenoxyethyl)aminoalkanol derivatives were synthesized and evaluated for their anticonvulsant activity. The most promising compound seemed to be (R,S)‐1N‐[(2,6‐dimethyl)phenoxyethyl]amino‐2‐butanol, which displayed anti‐MES activity (in mice, i.p.) with protective index (TD₅₀/ED₅₀) of 5.712, corresponding to that of phenytoin (6.6), carbamazepine (4.9) and valproate (1.7). The lipophilicity of compounds 1–17 exhibiting anticonvulsant activity was investigated. Their lipophilicities (R_M0) were determined using reversed‐phase thin‐layer chromatography (RP‐TLC) with a mixture of acetone and water as mobile phases. The partition coefficients of 1–17 (logP) were also calculated using two computer programs (Pallas and ALOGPS) and compared with R_M0. The relationship between anticonvulsant activity and lipophilicity of the tested substances was estimated. Copyright © 2010 John Wiley & Sons, Ltd.     

Improved Lipophilicity and Aqueous Solubility Prediction with Composite Graph Neural Networks

The accurate prediction of molecular properties, such as lipophilicity and aqueous solubility, are of great importance and pose challenges in several stages of the drug discovery pipeline. Machine learning methods, such as graph-based neural networks (GNNs), have shown exceptionally good performance in predicting these properties. In this work, we introduce a novel GNN architecture, called directed edge graph isomorphism network (D-GIN). It is composed of two distinct sub-architectures (D-MPNN, GIN) and achieves an improvement in accuracy over its sub-architectures employing various learning, and featurization strategies. We argue that combining models with different key aspects help make graph neural networks deeper and simultaneously increase their predictive power. Furthermore, we address current limitations in assessment of deep-learning models, namely, comparison of single training run performance metrics, and offer a more robust solution.     

Determination of metformin and other biguanides in forensic whole blood samples by hydrophilic interaction liquid chromatography-electrospray tandem mass spectrometry

Metformin is an anti-diabetic drug in the biguanide class which also includes phenformin and buformin. Because of the potential adverse effects of the biguanides, a reliable liquid chromatography-tandem mass spectrometry method using pneumatically assisted electrospray ionization was developed for the quantification of the drugs in both live and post-mortem human whole blood. The blood proteins were precipitated by the addition of a mixture of methanol and acetonitrile, and the extract was cleaned up by cation-exchange solid-phase extraction to eliminate ion suppression effects. The separation was performed by hydrophilic interaction liquid chromatography. Matrix-matched calibrants combined with isotope dilution of metformin were used for calibration. The detection limits were 0.01 mg/L for metformin and phenformin and the relative intra-laboratory reproducibility standard deviations were less than 6% at concentrations of 1-10 mg/L. The mean true recoveries were greater than 86%.     

A Study of Structure-Carcinogenicity Relationship for 86 Compounds from NTP Data Base Using Topological Indices as Descriptors

Abstract

86 compounds from NTP carcinogenic potency data base have been used to derive neural network models. Compounds were described with topological indices. Carcinogenicity has been given as a binary quantity - a compound is carcinogenic or non carcinogenic. Several models have been tested with a recognition ability test and with the leave-one-out cross validation method. For the best model the ratio between correct and wrong classifications was 70/30. Furthermore, the model has been used to classify 17 compounds not used for setting of the models. The predicted carcinogenic classes and the neighbors in the neural network influencing the predictions have been discussed.