• The assessment of intramolecular hydrogen bonding in ortho-substituted anilines by an NMR method

      Abraham, M.H.; Abraham, R.J.; Aghamohammadi, Amin; Afarinkia, Kamyar; Liu, Xiangli (2020-10)
      We describe the Δlog P method for the assessment of intramolecular hydrogen bonds (IMHBs), and show that it is not a very general method of distinguishing between molecules in which there is an IMHB and molecules in which there is no IMHB. The ‘double’ Δlog P method of Shalaeva et al. is a much more reliable method for the assessment of IMHB but requires the synthesis of a model compound and the determination of no less than four water-solvent partition coefficients. In addition, it is difficult to apply to compounds that contain more than one hydrogen bond acidic group capable of IMHB. We then describe our NMR method of assessing IMHB, based on 1H NMR chemical shifts in solvents DMSO and CDCl3. We have determined 1H NMR chemical shifts for a number of ortho-substituted anilines and show that the only compound we have studied that forms an IMHB is methyl 2-methylaminobenzoate though there is no IMHB present in methyl 2-aminobenzoate. This apparently anomalous result is supported by both MM and ab initio calculations. The NMR method is much simpler and less time consuming than other methods for the assessment of IMHB. It provides a quantitative assessment of IMHB and can be applied to molecules with more than one hydrogen bond acidic group.
    • The assessment of intramolecular hydrogen bonding in ortho-substituted anilines by an NMR method

      Abraham, M.H.; Abraham, R.J.; Aghamohammadi, Amin; Afarinkia, Kamyar; Liu, Xiangli (2020-10-01)
      We describe the Δlog P method for the assessment of intramolecular hydrogen bonds (IMHBs), and show that it is not a very general method of distinguishing between molecules in which there is an IMHB and molecules in which there is no IMHB. The ‘double’ Δlog P method of Shalaeva et al. is a much more reliable method for the assessment of IMHB but requires the synthesis of a model compound and the determination of no less than four water-solvent partition coefficients. In addition, it is difficult to apply to compounds that contain more than one hydrogen bond acidic group capable of IMHB. We then describe our NMR method of assessing IMHB, based on 1H NMR chemical shifts in solvents DMSO and CDCl3. We have determined 1H NMR chemical shifts for a number of ortho-substituted anilines and show that the only compound we have studied that forms an IMHB is methyl 2-methylaminobenzoate though there is no IMHB present in methyl 2-aminobenzoate. This apparently anomalous result is supported by both MM and ab initio calculations. The NMR method is much simpler and less time consuming than other methods for the assessment of IMHB. It provides a quantitative assessment of IMHB and can be applied to molecules with more than one hydrogen bond acidic group.
    • Comparative responses of human keratinocyte cells (HaCaT) and human lung carcinoma epithelial cells (A549) following in vitro exposure to Silicon dioxide nanoparticles (SiO2-NP)

      Islam, I.; Khan, M.; Liu, Xiangli; Parmar, A.; Shang, Lijun (2015)
      The use of nanoparticles have provided numerous of advantages in medicine due to their unique physiochemical characteristics such as size, charge, shape and surface reactivity [1-4]. Understanding the interaction between engineered nanomaterials and living matter has attracted increasing attention in recent years. Toxicity of nanoparticles was studied in different cell types and cell lines. Nano-SiO2 has good stability, easy dispensability, and melting degeneration, and is widely used in rubber, paints, biomedical and biotechnology fields [5]. In this study, the LDH assay and the MTT assay were applied to evaluate the cytotoxicity of in vitro Silicon dioxide nanoparticles (SiO2-NP, 20nm) on cultured cell lines. Human lung adenocarcinoma epithelial cell line (A549) were used as a lung related cell line and human keratinocyte cell line (HaCaT) as a skin related cell line representing different uptake routes. The percentage cytotoxicity of the silicon dioxide nanoparticles was measured once cultured in a 24 hour incubation period. The concentration of the SiO2 nanoparticles chosen was 10, 50, 100 and 200µg/ml. To measure the cytotoxicity of nanoparticle on cultured cell lines, we used 104*cells/100 µl of cell culture media being placed in a 96 well rounded bottom plate with the LDH assay. The extracellular lactate dehydrogenase release was measured by using a colorimetric CytoTox 96 non-radioactive assay kit and the absorbance was recorded at 492nm. The MTT assay was used to evaluate mitochondrial activity which includes cell growth and cell death. This has been performed by inserting a premixed optimized dye solution in the culture wells. The Absorbance was recorded at 570 nm, from the recorded absorbance is directly proportional to the number of live cells. In order to maintain the cell lines, they were placed in a plastic T-75cm² tissue culture flasks grown in Dulbecco's Modified Eagle's Medium. Studies were performed in the absence of serum. Cytotoxicity was found in both cells the A549 and HaCaT cells and cytotoxicity increased as concentration of the silicon dioxide increased. The percentage cytotoxicity calculated was higher in HaCaT cells compared to the A549 cells. A cell count assay was plated in order to display the cell number of both the HaCaT and A549 cells. The cell count reaffirmed that cytotoxicity did occur as the cell count decreased as the concentration of the silicon dioxide increased compared to the control. These results show that silicon dioxide nanoparticles acted differently in two different cell types and that the metabolic rate of a cell can be used to determine the nanoparticles affect. Further understanding of the mechanism involving the ROS generation could provide more information on how silicon dioxide nanoparticles increase cytotoxicity.
    • Comparison of lipid membrane-water partitioning with various organic solvent-water partitions of neutral species and ionic species: Uniqueness of cerasome as a model for the stratum corneum in partition processes

      Zhang, K.; Fahr, A.; Abraham, M.H.; Acree, W.E. Jr.; Tobin, Desmond J.; Liu, Xiangli (2015-10-15)
      Lipid membrane-water partitions (e.g., immobilized artificial membrane systems where the lipid membrane is a neutral phospholipid monolayer bound to gel beads) were compared to various organic solvent-water partitions using linear free energy relationships. To this end, we also measured the retention factors of 36 compounds (including neutral and ionic species) from water to liposomes made up of 3-sn-phosphatidylcholine and 3-sn-phosphatidyl-l-serine (80:20, mol/mol), employing liposome electrokinetic chromatography in this work. The results show that lipid membranes exhibit a considerably different chemical environment from those of organic solvents. For both neutral species and ionic species, partitions into the more polar hydroxylic solvents are chemically closer to partition into the lipid membrane as compared to partitions into the less polar hydroxylic solvents and into aprotic solvents. This means that solutes partition into the polar parts of lipid membranes, regardless of whether they are charged or not. In addition, cerasome (i.e., liposome composed mainly of stratum corneum lipids) was compared with regular phospholipid liposomes as a possible model for human stratum corneum in partitions. It was found that the cerasome-water partition exhibits a better chemical similarity to skin permeation. This is probably due to the unique structures of ceramides that occur in cerasome and in the stratum corneum lipid domain. We further show that membranes in membrane-water partitions exhibit very different properties.
    • Descriptors for adamantane and some of its derivatives

      Abraham, M.H.; Acree, W.E. Jr; Liu, Xiangli (2021-03-01)
      Literature data on solubilities of adamantane in organic solvents have been used to obtain properties, or descriptors, of adamantane. There is much less data on substituted adamantanes but we have been able to obtain descriptors for some 40 substituted adamantanes. These descriptors can then be used to estimate a wide range of physicochemical, environmental and other properties of the adamantanes. For the first time, the water-solvent partition coefficient and the gas-solvent partition coefficient into a large range of solvents, can be estimated, the latter being equivalent to Henry's Law constants. A variety of other important properties can also be estimated. These include vapor pressures, enthalpies of vaporization and sublimation, partitions from air and from blood into biological tissues, and skin permeability from water. The descriptors themselves are not exceptional. Adamantane itself has a rather low dipolarity, zero hydrogen bond acidity and a very low hydrogen bond basicity, in common with other multicyclic aliphatic compounds. These lead to adamantane being a very hydrophobic compound, as is evident from our estimated water-octanol partition coefficient.
    • Descriptors for Edaravone; Studies on its Structure, and Prediction of Properties

      Liu, Xiangli; Aghamohammadi, Amin; Afarinkia, Kamyar; Abraham, R.J.; Acree, W.E. Jr; Abraham, M.H. (2021-06-15)
      Literature solubilities and NMR and IR studies have been used to obtain properties or descriptors of edaravone. These show that edaravone has a significant hydrogen bond acidity so that it must exist in solution partly as the OH and NH forms, as found by Freyer et al. Descriptors have been assigned to the keto form which has a low hydrogen bond acidity, and which is the dominant form in nonpolar solvents. Physicochemical properties of the keto form can be been calculated such as solubilities in nonpolar solvents, partition coefficients from water to nonpolar solvents, and partition coefficients from air to biological phases.
    • Descriptors for vitamin K3 (menadione): calculation of biological and physicochemical properties

      Liu, Xiangli; Abraham, M.H.; Acree, W.E. (2021-05)
      We have used literature values for the solubility of vitamin K3 in organic solvents to obtain Abraham descriptorsfor vitamin K3. Although these descriptors themselves are not exceptional in any way, when combined withequations that we have already set out, they lead to the prediction of important properties of vitamin K3.These include the vapor pressure and heat of sublimation (necessary for the analysis of data on the concentrationof vitamin K3 in ambient air), and the partitions air-water, air-blood, air-lung, air-fat, air-skin, water-lipid, water-membrane, water-skin, as well as permeation from water through skin. Values of the partitions into biologicalphases are all quite large by comparison to those for organic compounds in general.
    • An Equation for the Prediction of Human Skin Permeability of Neutral Molecules, Ions and Ionic Species

      Zhang, K.; Abraham, M.H.; Liu, Xiangli (2017-04-15)
      Experimental values of permeability coefficients, as log Kp, of chemical compounds across human skin were collected by carefully screening the literature, and adjusted to 37 °C for the effect of temperature. The values of log Kp for partially ionized acids and bases were separated into those for their neutral and ionic species, forming a total data set of 247 compounds and species (including 35 ionic species). The obtained log Kp values have been regressed against Abraham solute descriptors to yield a correlation equation with R2 = 0.866 and SD = 0.432 log units. The equation can provide valid predictions for log Kp of neutral molecules, ions and ionic species, with predictive R2 = 0.858 and predictive SD = 0.445 log units calculated by the leave-one-out statistics. The predicted log Kp values for Na+ and Et4N+ are in good agreement with the observed values. We calculated the values of log Kp of ketoprofen as a function of the pH of the donor solution, and found that log Kp markedly varies only when ketoprofen is largely ionized. This explains why models that neglect ionization of permeants still yield reasonable statistical results. The effect of skin thickness on log Kp was investigated by inclusion of two indicator variables, one for intermediate thickness skin and one for full thickness skin, into the above equation. The newly obtained equations were found to be statistically very close to the above equation. Therefore, the thickness of human skin used makes little difference to the experimental values of log Kp.
    • Linear combination methods for prediction of drug skin permeation

      Scheler, S.; Fahr, A.; Liu, Xiangli (2015-01)
      Many in-vitro methods for prediction of skin permeability have been reported in literature. Cerasome electrokinetic chromatography is one of the most sophisticated approaches representing a maximum level of similarity to the lipid phase of the stratum corneum. One goal of this study was to investigate the affinity pattern of Cerasome and to compare it with the permeability profile of human skin. Another purpose was to study the applicability of Hansen solubility parameters for modelling skin permeation and to investigate the predictive and explanatory potential of this method. Visualisation in Hansen diagrams revealed very similar profiles of Cerasome electrokinetic chromatography retention factors and skin permeability coefficients. In both cases, the characteristic pattern with two clusters of highly retained or highly permeable substances could be shown to be mainly caused by two groups of compounds, one of them with high affinity to ceramides, fatty acids and lecithin and the other being more affine to cholesterol. If based on a sufficiently comprehensive experimental dataset, model-independent predictions of skin permeability data using three-component Hansen solubility parameters are able to achieve similar accuracy as calculations made with an Abraham linear free energy relationship model in which the compounds are characterized by seven physicochemical descriptors.
    • Linear free energy relationship analysis of permeability across polydimethylsiloxane (PDMS) membranes and comparison with human skin permeation in vitro

      Liu, Xiangli; Zhang, K.; Abraham, M.H. (2018-10-15)
      The aim of the present work is to evaluate the similarity between PDMS membranes and human skin in vitro in permeation study by linear free energy relationship (LFER) analyses. The values of the permeability coefficient log Kp (cm/s) under reliable experimental conditions were collected from the literature for a set of 94 compounds including both neutral and ionic species, which cover a broad range of structural diversity. The values of log Kp (cm/s) have been correlated with Abraham descriptors to yield an equation with R2 = 0.952 and SD = 0.38 log units. The established LFER model for log Kp (cm/s) across PDMS membranes showed no close analogy with that through human skin in vitro. A further critical analysis of the coefficients of the LFER models confirmed that the PDMS permeation system is a very poor model for human skin permeation.
    • Partition of neutral molecules and ions from water to o-nitrophenyl octyl ether and of neutral molecules from the gas phase to o-nitrophenyl octyl ether

      Abraham, M.H.; Acree Jr, W.E.; Liu, Xiangli (2018-02)
      We have set out an equation for partition of 87 neutral molecules from water to o-nitrophenyl octyl ether, NPOE, an equation for partition of the 87 neutral molecules and 21 ionic species from water to NPOE, and an equation for partition of 87 neutral molecules from the gas phase to NPOE. Comparison with equations for partition into other solvents shows that, as regards partition of neutral (nonelectrolyte) compounds, NPOE would be a good model for 1,2-dichloroethane and for nitrobenzene. In terms of partition of ions and ionic species, NPOE is quite similar to 1,2-dichloroethane and not far away from other aprotic solvents such as nitrobenzene.
    • Predicting the skin-permeating components of externally-applied medicinal herbs: application of a newly constructed linear free-energy relationship equation for human skin permeation

      Zeng, X.; Wang, Z.; Liu, Xiangli; Chen, M.; Fahr, A.; Zhang, K. (2018-06)
      A linear free-energy relationship (LFER) equation that is able to provide a valid prediction of the skin permeability coefficients (log Kp) of neutral molecules, ions and ionic species has recently been constructed and optimized. This study aimed to evaluate the feasibility of predicting the skin-permeating components (SPCs) of externally applied herbs using the LFER equation, with Evodiae fructus (EF) taken as a model herb. The log Kp values of the reported chemical components of EF at pH 4.0 were calculated using the LFER equation and their structural descriptors. The results showed that the essential oils, quinolone, acridone and indole alkaloids of EF are more permeable when compared to other main components, such as phenylpropanoids, furoquinoline alkaloids, limonoids and flavonoids. The SPCs of EF were further collected via ex vivo skin permeation experiments, and analyzed by liquid chromatography-high resolution tandem mass spectrometry. A total of 80 SPCs were detected, and part of them were tentatively identified based on their empirical molecular formulae and MS/MS spectra. The SPCs are made up of 58 alkaloids, including 23 or more quinolone alkaloids, 14 or more indole alkaloids and 1 acridone alkaloid, and 22 non-alkaloids, including 7 or more essential oils and 1 flavonoid, which is in good agreement with the prediction by the LFER equation. It is suggested that a log Kp of −7.0 may be considered as a borderline, above which are potential SPCs and below which are non-SPCs. Very interestingly, the primary SPCs give a good explanation to the antihypertensive action of externally applied EF. To sum up, the LFER equation can be used to predict the SPCs of externally applied herbs, and thus to narrow the range of their potential effective components and speed up the pharmacological study.
    • The prediction of blood–tissue partitions, water–skin partitions and skin permeation for agrochemicals

      Abraham, M.H.; Gola, J.M.R.; Ibrahim, A.; Acree, W.E. Jr.; Liu, Xiangli (2014-07)
      BACKGROUND: There is considerable interest in the blood–tissue distribution of agrochemicals, and a number of researchershave developed experimental methods for in vitro distribution. These methods involve the determination of saline–blood andsaline–tissue partitions; not only are they indirect, but they do not yield the required in vivo distribution.RESULTS: The authors set out equations for gas–tissue and blood–tissue distribution, for partition from water into skin andfor permeation from water through human skin. Together with Abraham descriptors for the agrochemicals, these equationscan be used to predict values for all of these processes. The present predictions compare favourably with experimental in vivoblood–tissue distribution where available. The predictions require no more than simple arithmetic.CONCLUSIONS: The present method represents a much easier and much more economic way of estimating blood–tissuepartitions than the method that uses saline–blood and saline–tissue partitions. It has the added advantages of yielding therequired in vivo partitions and being easily extended to the prediction of partition of agrochemicals from water into skin andpermeation from water through skin.
    • A simple method for estimating in vitro air-tissue and in vivo blood-tissue partition coefficients

      Abraham, M.H.; Gola, J.M.R.; Ibrahim, A.; Acree, W.E. Jr.; Liu, Xiangli (2015-02)
      A simple method is reported for the estimation of in vivo air-tissue partition coefficients of VOCs and of in vitro blood-tissue partition coefficients for volatile organic compounds and other compounds. Linear free energy relationships for tissues such as brain, muscle, liver, lung, kidney, heart, skin and fat are available and once the Abraham descriptors are known for a compound, no more than simple arithmetic is required to estimate air-tissue and blood-tissue partitions.
    • Structural properties governing drug-plasma protein binding determined by high-performance liquid chromatography method

      Kamble, Sharad R.; Loadman, Paul M.; Abraham, M.H.; Liu, Xiangli (2018-02)
      The high-performance liquid chromatography (HPLC) method employing stationary phases immobilized with plasma proteins was used for this study to investigate the structural properties governing drug-plasma protein binding. A set of 65 compounds with a broad range of structural diversity (in terms of volume, hydrogen-bonding, polarity and electrostatic force) were selected for this purpose. The Abraham linear free energy relationship (LFER) analyses of the retention factors on the immobilized HSA (human serum albumin) and AGP (α1-acid glycoprotein) stationary phases showed that McGowan’s characteristic molecular volume (V), dipolarity/polarizability (S) and hydrogen bond basicity (B) are the three significant molecular descriptors of solutes determining the interaction with immobilized plasma proteins, whereas excess molar refraction (E) is less important and hydrogen bond acidity (A) is not of statistical significance in both systems, for electrically neutral compounds. It was shown that ionised acids, as carboxylate anions, bind very strongly to the immobilized HSA stationary phase and that ionised bases, as cations bind strongly to the AGP stationary phase. This is the first time that the effect of ionised species on plasma protein binding has been determined quantitatively; the increased binding of acids to HSA is due almost entirely to acids in their ionised form.