Application of High Performance Liquid Chromatography for the Measurements of Lipophilicity and Biomimetic Binding Properties in Drug Discovery

Valkó, Klára

doi:10.5599/obp.7.2

Cited by 8 publications

(19 citation statements)

References 97 publications

(95 reference statements)

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“…All compounds were run on 12 min isocratic acetonitrile/water (0.1% formic acid) HPLC gradients on a 3.5 μm C18 (XBridge, 50 mm × 4.6 mm) column at 1.2 mL/min to assess relative lipophilicty. 51 AlogP. AlogP 52 values were calculated using Virtual Computational Chemistry Laboratory http://wwww.vcclab.org.…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

Going Out on a Limb: Delineating The Effects of β-Branching, N-Methylation, and Side Chain Size on the Passive Permeability, Solubility, and Flexibility of Sanguinamide A Analogues

et al. 2015

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It is well established that intramolecular hydrogen bonding and N-methylation play important roles in the passive permeability of cyclic peptides, but other structural features have been explored less intensively. Recent studies on the oral bioavailability of the cyclic heptapeptide sanguinamide A have raised the question of whether steric occlusion of polar groups via β-branching is an effective, yet untapped, tool in cyclic peptide permeability optimization. We report the structures of 17 sanguinamide A analogues designed to test the relative contributions of β-branching, N-methylation, and side chain size to passive membrane permeability and aqueous solubility. We demonstrate that β-branching has little effect on permeability compared to the effects of aliphatic carbon count and N-methylation of exposed NH groups. We highlight a new N-methylated analogue of sanguinamide A with a Leu substitution at position 2 that exhibits solvent-dependent flexibility and improved permeability over that of the natural product.

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Section: ■ Experimental Proceduresmentioning

confidence: 99%

Going Out on a Limb: Delineating The Effects of β-Branching, N-Methylation, and Side Chain Size on the Passive Permeability, Solubility, and Flexibility of Sanguinamide A Analogues

et al. 2015

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“…However, other experimental methods can be used provided that they show an acceptable level of quality assurance [5]. This is clearly the case of dual-phase potentiometric titration procedures [6,7], commonly used in pharmaceutical research for ionizable drugs with pK a values in a measurable pH range (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), which provide reliable and accurate log P o/w values [8].…”

Section: Meekc As High-throughput Surrogate Model For the Determinatimentioning

confidence: 99%

“…Several methods based on chromatographic retention have been proposed in order to measure lipophilicity, mainly using reversed-phase columns and acetonitrile/aqueous buffer mobile phases [9]. These approaches are much more time-efficient compared to shake-flask and potentiometric methods, with the additional benefit of a separation technique that does not require high purity samples.…”

Section: Meekc As High-throughput Surrogate Model For the Determinatimentioning

confidence: 99%

“…For instance, octanol and C18 phases exhibit a different interaction with hydrogen-bond donor solutes; in the chromatographic system solutes with H-bond acidity are discouraged from partitioning out of the hydro-organic mixture and into the poorer H-bond acceptor C18 phase, whereas octanol (either containing water or other H-bond acceptor moieties) can form hydrogen bonds. Therefore, the introduction of molecular descriptors, either experimental or calculated, allows better correlations between chromatographic retention and log P o/w values [9][10][11][12], but is limited to unionized molecules. However, a lower accuracy from chromatographic methods (±0.5 log units [4]) can be expected in relation to the shake-flask method (±0.3 [3]).…”

Section: Meekc As High-throughput Surrogate Model For the Determinatimentioning

confidence: 99%

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Lipophilicity determination of acidic compounds: MEEKC as a reliable high-throughput methodology

2018

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In the present study a pressure-assisted MEEKC method with reversed-polarity using a conventional CE instrument with UV detection and uncoated fused silica capillaries is validated as a high-throughput methodology for the lipophilicity determination of the neutral species of acidic compounds (pK a > 3.5). After the calibration of the system with four standard compounds of known log P o/w , mass distribution ratios (log k MEEKC ) of new molecules can be directly converted into log P o/w values by means of a simple linear equation (log P o/w =a·log k MEEKC +b). The method was internally and externally validated for a log

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“…To compare retention using different organic phase concentrations, they are extrapolated to the same condition, which is normally to zero organic solvent concentration. In gradient chromatographic methods, a linear gradient increase of the organic solvent concentration in the mobile phase during a chromatographic run helps to elute compounds over a wide range of lipophilicities (Valkó, ). It has been shown that the gradient retention times are in good correlation to the isocratically obtained hydrophobicity index ( φ 0 ) (Valkó, Bevan, & Reynolds, ).…”

Section: Introductionmentioning

confidence: 99%

Lipophilicity and bio‐mimetic properties determination of phytoestrogens using ultra‐high‐performance liquid chromatography

Lasić

Bokulić

Milić

et al. 2019

Biomedical Chromatography

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This paper presents lipophilicity and bio-mimetic property determination of 15 phytoestrogens, namely biochanin A, daidzein, formononetin, genistein, genistein-4,7-dimethylether, prunetin, 3,4,7-trihydroxyisoflavon, 4,6,7-trihydroxyisoflavon, 4,6,7-trimethoxyisoflavon, daidzin, genistin, ononin, sissotrin, coumestrol and coumestrol dimethylether. High-performance liquid chromatography with fast gradient elution and Caco-2 cell line were used to determine the physicochemical properties of selected phytoestrogens. Lipophilicity was determined on octadecyl-sylane stationary phase using pH 2.0 and pH 7.4 buffers. Immobilized artificial membrane chromatography was used for prediction of interaction with biological membranes.Protein binding was measured on human serum albumin and α-1-acid-glycoprotein (AGP) stationary phases. Caco-2 assay was used as a gold standard for assessing in vitro permeability. The obtained results differentiate phytoestrogens according to their structure where aglycones show significantly higher lipophilicity, immobilized artificial membrane partitioning, AGP binding and Caco-2 permeability compared with glucosides. However, human serum albumin binding was very high for all investigated compounds. Furthermore, a good correlation between experimentally obtained chromatographic parameters and in silico prediction was obtained for lipophilicity and human serum albumin binding, while the somewhat greater difference was obtained

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Application of High Performance Liquid Chromatography for the Measurements of Lipophilicity and Biomimetic Binding Properties in Drug Discovery

Cited by 8 publications

References 97 publications

Going Out on a Limb: Delineating The Effects of β-Branching, N-Methylation, and Side Chain Size on the Passive Permeability, Solubility, and Flexibility of Sanguinamide A Analogues

Going Out on a Limb: Delineating The Effects of β-Branching, N-Methylation, and Side Chain Size on the Passive Permeability, Solubility, and Flexibility of Sanguinamide A Analogues

Lipophilicity determination of acidic compounds: MEEKC as a reliable high-throughput methodology

Lipophilicity and bio‐mimetic properties determination of phytoestrogens using ultra‐high‐performance liquid chromatography

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