Lipophilicity evaluation

Gallic acid (3,4,5-trihydroxybenzoic acid) can be formed by acid hydrolysis of hydrolyzable tannins. Differences among the ester derivatives are only in the number of carbon atoms in the aliphatic side-chain. These differences confer different physicochemical characteristics, especially in lipophilicity evaluated by the value of partition coefficient (C log P). Chemical modifications in the gallic acid molecule can alter the pharmacokinetic and pharmacodynamic properties, such as changing the solubility and the degree of ionization. The names of the compounds are abbreviated according to the length of the side-chain (Locatelli et al., 2013). 

The -NH(CH2)3N(CH2)2 amide of teicoplanin factor A2-2, coded MPT. 62,873 [122173-74-4] was also prepared. The combined effect of a moderate basicity and a slightly increased lipophilicity at neutral pH probably led to a better penetration through the cell wall. MDL 62,873 was consistentiy more active than teicoplanin against CNS clinical isolates (119,120). No semisynthetic dalbaheptide is under clinical evaluation at this writing. 

Rapid dermal absorption of trichloroethylene is evident from a study in which peak blood and exhaled air concentrations occurred within 5 minutes after a human subject immersed one hand in a solution of unspecified trichloroethylene concentration for 30 minutes (Sato and Nakajima 1978). Studies on dermal absorption of trichloroethylene in humans, as well as animals, are complicated by the fact that exposure in these studies is usually by direct contact of the skin with the undiluted chemical. Trichloroethylene is a lipophilic solvent that defats the skin and disrupts the stratum comeum, thereby enhancing its own absorption. Thus, the rate of absorption probably increases in a nonlinear fashion with greater epidermal disruption. Although the extent of absorption through the skin may be relatively modest with normal industrial use (Sato and Nakajima 1978 Stewart and Dodd 1964), there is insufficient information to evaluate the effects of chronic, low-level exposure in hiunans, especially when multiple routes may be involved. 

Many different methods have been used to evaluate the antioxidant capacities of isolated molecules, carotenoids, and other natural antioxidants and of foods and food extracts containing antioxidants. It is not the purpose of this chaper to review all the methods, but some general points can be made. First, when using only one test to evaluate the antioxidant capacities of carotenoids, one should be very careful in the interpretation of obtained data. Indeed, different results can be obtained with different tests applied to the same molecules. At least two different methods should be used to evaluate the antioxidant activity of a molecule or a food extract. " Second, lipophilicity is an important factor to consider in testing the antioxidant activities... 

To evaluate the contribution of the SHG active oriented cation complexes to the ISE potential, the SHG responses were analyzed on the basis of a space-charge model [30,31]. This model, which was proposed to explain the permselectivity behavior of electrically neutral ionophore-based liquid membranes, assumes that a space charge region exists at the membrane boundary the primary function of lipophilic ionophores is to solubilize cations in the boundary region of the membrane, whereas hydrophilic counteranions are excluded from the membrane phase. Theoretical treatments of this model reported so far were essentially based on the assumption of a double-diffuse layer at the organic-aqueous solution interface and used a description of the diffuse double layer based on the classical Gouy-Chapman theory [31,34]. 

Although experimental partition coefficients are the values of reference, drug design often necessitates log evaluations before the compound has been synthesized. Consequently, various methods have been developed to predict lipophilicity [188], and they generally apply only to neutral compounds in the water-OCT system. 

The presenee of intramoleeular interaetions ean be eheeked by eomparing calculated and experimental log P values. Sueh identifieation ean yet only be obtained for the water-OCT system, sinee eomputed lipophilieity values have only been derived for this solvent pair. Due to its simplicity and its easy adaptation to eomplex structures, Rekker s calculation method is often appreciated, but more sophistieated approaches like that evaluating log P using the molecular lipophilicity potential (MLP) has also been employed. 

Catalysis in Transacylation Reactions. The principal objective of the study was to evaluate 4 as an effective organic soluble lipophilic catalyst for transacylation reactions of carboxylic and phosphoric acid derivatives in aqueous and two-phase aqueous-organic solvent media. Indeed 4 catalyzes the conversion of benzoyl chloride to benzoic anhydride in well-stirred suspensions of CH2CI2 and 1.0 M aqueous NaHCC>3 (Equations 1-3). The results are summarized in Table 1 where yields of isolated acid, anhydride and recovered acid chloride are reported. The reaction is believed to involve formation of the poly(benzoyloxypyridinium) ion intermediate (5) in the organic phase (Equation 1) and 5 then quickly reacts with bicarbonate ion and/or hydroxide ion at the interphase to form benzoate ion (Equation 2 and 3). Apparently most of the benzoate ion is trapped by additional 5 in the organic layer or at the interphase to produce benzoic anhydride (Equation 4), an example of normal phase-... 

Great interest in diphosphino complexes of technetium arose when Deutsch and co-workers found that lipophilic cations are able to be accumulated in heart tissue and can thus be candidates for myocardium perfusion agents [120]. Both the Tc(V) DMPE complex, [Tc02L2]+, and the [TcL2X2] + and [TcL3] + species in oxidation states +3 and +1 have been evaluated. Whereas the [Tc02L2] +... 

Molecules with a large molecular weight or size are confined to the transcellular route and its requirements related to the hydrophobicity of the molecule. The transcellular pathway has been evaluated for many years and is thought to be the main route of absorption of many drugs, both with respect to carrier-mediated transport and passive diffusion. The most well-known requirement for the passive part of this route is hydrophobicity, and a relationship between permeability coefficients across cell monolayers such as the Caco-2 versus log P and log D 7.4 or 6.5 have been established [102, 117]. However, this relationship appears to be nonlinear and reaches a plateau at around log P of 2, while higher lipophilicities result in reduced permeability [102, 117, 118]. Because of this, much more attention has recently been paid towards molecular descriptors other than lipophilicity [86, 119-125] (see section 5.5.6.). The relative contribution between the para-cellular and transcellular components has also been evaluated using Caco-2 cells, and for a variety of compounds with different charges [110, 112] and sizes [112] (see Section 5.4.5). 

Some of the compounds have been evaluated for their ability to induce mitochondrial membrane permeabilization, which is believed to play a fundamental role in the regulation of programmed cell apoptosis. The effects observed are not in line with a conventional model of action related to the accumulation of the lipophilic compounds in the cell, and further studies are necessary.281... 

The ORAC assay proposed by Ou and others (2001) is limited to hydrophilic antioxidants because of the aqueous environment of the assay. However, lipophilic antioxidants play a critical role in biological defense systems. Huang and others (2002) expanded the assay to the lipidic fraction by introducing a randomly methylated 13-cyclodextrin (RMCD) as a water-solubility enhancer for lipophilic antioxidants. Various kinds of foods, including fruit juices and drinks, fruits, vegetables, nuts, and dried fruits, have been evaluated with this method (Zhou and Yu 2006 Wu and others 2004 Kevers and others 2007 Wang and Ballington 2007 Almeida and others 2008 Mullen and others 2007). 

One of the simplest and most common ways to evaluate a molecule for ADME properties is a qualitative examination of its basic descriptor values such as molecular weight (MW), ClogP for lipophilicity, polar surface area (PSA), counts of hydrogen bond donors and acceptors (HBD, HBA), and count of rotatable bonds (RB). This type of approach popularized by Lipinski s famous Rule of 5 was published a decade ago [6]. Lipinski et al. established cutoffs for MW (500), ClogP (5), HBA (10), and HBD (5). These cutoffs were based on the 90th percentile of distributions of molecules in the World Drug Index having USAN or INN names. The Rule of 5 considers a violation of any two of these cutoffs to be an alert for poor absorption or permeability. 

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