Structure-activity relationships lipid

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Lipophilicity is the measure of the partitioning of a compound between a lipidic and an aqueous phase [1]. The terms lipophilicity and hydrophobicity are often used inconsistently in the literature. Lipophilicity encodes most of the intramolecular forces that can take place between a solute and a solvent. Hydrophobicity is a consequence of attractive forces between nonpolar groups and thereby is a component of lipophilicity [2]. Lipophilicity is one of the most informative physicochemical properties in medicinal chemistry and since long successfully used in quantitative structure-activity relationship (QSAR) studies. Its... 

The above findings are supported in the other studies of the inhibitory effects of flavonoids on iron-stimulated lipid peroxidation. Quercetin was found to be an inhibitor of iron-stimulated hepatic microsomal lipid peroxidation (/50 = 200 pmol I ) [134]. Flavonoids eriodictyol, luteolin, quercetin, and taxifolin inhibited ascorbate and ferrous ion-stimulated MDA formation and oxidative stress (measured by fluorescence of 2,7,-dichlorodihydro-fluorescein) in cultured retinal cells [135]. It should be mentioned that in recent work Heijnen et al. [136] revised the structure activity relationship for the protective effects of flavonoids against lipid peroxidation. 

Fujino, T., Une, M., Imanaka, T., Inoue, K. and Nishimaki-Mogami, T. (2004) Structure-activity relationship of bile acids and bile acid analogs in regard to FXR activation. Journal of Lipid Research, 45, 132-138. 

Byk G, Dubertret C, Escriou V, et al. Synthesis, activity, and structure-activity relationship studies of novel cationic lipids for DNA transfer. J Med Chem 1998 41(2) 229-235. 

Human perception of flavor occurs from the combined sensory responses elicited by the proteins, lipids, carbohydrates, and Maillard reaction products in the food. Proteins Chapters 6, 10, 11, 12) and their constituents and sugars Chapter 12) are the primary effects of taste, whereas the lipids Chapters 5, 9) and Maillard products Chapter 4) effect primarily the sense of smell (olfaction). Therefore, when studying a particular food or when designing a new food, it is important to understand the structure-activity relationship of all the variables in the food. To this end, several powerful multivariate statistical techniques have been developed such as factor analysis Chapter 6) and partial least squares regression analysis Chapter 7), to relate a set of independent or "causative" variables to a set of dependent or "effect" variables. Statistical results obtained via these methods are valuable, since they will permit the food... 

Many questions can be posed, but presently no clear cut answers can be given regarding structure/activity relationships. Only for one biological activity, antigenic specificity, structural requirements could be identified. It should be noted, however, that so far none of the structures of the synthetic preparations is identical with that proposed for natural lipid A. 

Chemical Synthesis of Lipid A for the Elucidation of Structure-Activity Relationships... 

Unlike DOGSDSO, the present series harbor disulfide bonds in every important position of the cationic lipid. Similarly to RPR120535, these cationic hpids are not formulated with DOPE or other co-lipid(s) for optimal transfection efficiency. Based on exhaustive structure-activity relationship studies, we concluded that RPR-132688 is ten times more active than RPR120535. 

Figure 15.29 Structure-activity relationship studies on cationic lipids.

A number of cationic lipids have been prepared using solid-phase methods [147— 159]. Along with the well-known advantages that solid-phase chemistry provide (e.g. mass action, simple purification, compatibility with microwave synthesis [ 160, 161]), the main reason to use this approach is that it facilitates parallel synthesis of libraries of compounds, allowing potential structure activity relationships to be rapidly determined by the systematic modification of the cationic lipid structure per domain. 

An instructive quantitative structure-activity relationship (QSAR) analysis carried out on published data about a large set of cationic lipids, including both successful and unsuccessful compounds, permitted to delineation of a high-efficiency region... 

Niculescu-Duvaz D, Heyes J, Springer CJ (2003) Structure-activity relationship in cationic lipid mediated gene transfection. Curr Med Chem 10 1233-1261... 

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