Lipid synthetic derivatives

Lipid-protein interactions are of major importance in the structural and dynamic properties of biological membranes. Fluorescent probes can provide much information on these interactions. For example, van Paridon et al.a) used a synthetic derivative of phosphatidylinositol (PI) with a ris-parinaric acid (see formula in Figure 8.4) covalently linked on the sn-2 position for probing phospholipid vesicles and biological membranes. The emission anisotropy decays of this 2-parinaroyl-phosphatidylinositol (PPI) probe incorporated into vesicles consisting of phosphatidylcholine (PC) (with a fraction of 5 mol % of PI) and into acetylcholine receptor rich membranes from Torpedo marmorata are shown in Figure B8.3.1. 

Since the synthesis of glycolipids involves the synthesis of both the lipid and the oligosaccharide portions, we shall also discuss that part of the recorded lipid synthetic work which has involved the use of carbohydrates. In fact, some of the first-recorded applications of carbohydrate molecules as chiral templates are to be found in the lipid field particularly with the use of 1,2 5,6-di-O-isopropylidene-D-mannitol [33] as a precursor of chiral glycerol derivatives for the synthesis of phospholipids and glycolipids based on glycerol and with the use of glucosamine derivatives for the synthesis of phytosphingosines [34] and since this area has not previously been reviewed, it will be treated with a more historical perspective. 

The TLR4-MD2 hetero-dimer has complex ligand specificity. It can be activated by structurally diverse LPS molecules, and minor changes in synthetic derivatives of LPS can abolish their endotoxic potency (Raetz and Whitfield, 2002 Rietschel et al., 1994). The diversity in potency of LPS is derived from variance within lipid A, as observed in both the number and the length of fatty acid side chains and the presence of terminal phosphate residues with a variety of modifications. Optimal lipid A potency is achieved with bi-phosphorylated, hexa-acylated, lipid A species (Raetz and Whitfield, 2002). Lipid A moieties that deviate from this pattern often demonstrate a significant decrease in endotoxic activity (Alexander and Rietschel, 2001). 

Mineral Salts Immunostimulatory adjuvants Lipid particles Particulate adjuvants Mucosal adjuvants Aluminium hydroxide, aluminium phosphate, calcium phosphate Saponins (e.g., QS21), MDP derivatives, bacterial DNA (CpG oligos), LPS, MPL and synthetic derivatives, lipopeptides, cytokines (e.g., GM-CSF, IL-2, IL-12) Liposomes, virosomes, iscoms, cochleates, emulsions (e.g., Freunds adjuvant, SAF, MF59 ) Poloxamer particles, virus-like particles, PLG microparticles Cholera toxin (CT), mutant toxin (e.g., LTK63, LTR72), heat labile enterotoxin (LT), microparticles, polymerized liposomes, chitosan... 

The first entirely synthetic derivative, fluvastatin (see Ref. [19]), and its subsequent derivative, atorvastatin, have a lipid solubility that is intermediate between pravastatin and the lactone prodrugs (see Tab. 4.2), and consequently their liver specificities are less expressed. In order to benefit from selective statin uptake mechanism into the liver cells and thereby decrease passive diffusion into other cell types, the recently introduced rosuvastatin molecule was purposefully made more hydrophilic by the introduction of a sulfonamide group. Indeed, the ratio of IC5 values measured in fibroblasts and hepatocyte cultures became considerable higher than that of atorvastatin (see Tab. 4.1). The pronounced differences of inhibitory potency, lipophilicity and the extent of active OATP-linked transport jointly... 

Ascorbyl palmitate and ascorbyl stearate are synthetic derivatives of ascorbic acid. Ascorbic palmitate is soluble in lipid-containing foods because of its relatively good hydrophobicity (88). Ascorbyl palmitate is hydrolyzed by the digestive system to provide nutritionally available ascorbic acid and palmitic acid, but health claims cannot be made for its vitamin C contribution. 

Ascorbyl palmitate (Figure 6), a synthetic derivative of ascorbic acid, is a white powder with a soapy taste and citms-like odor (34). It has better lipid-solubility compared with that of ascorbic acid and its salts, and is often used in combination with a-tocopherol in lipid-containing foods (11). Ascorbyl palmitate prevents oxidative rancidity by quenching singlet oxygen, among other modes of action (34). 

Thiamphenicol is a semi-synthetic derivative of chloramphenicol. It can cause reversible bone marrow depression, but fatal aplastic anemia has not been reported in humans. Oral bioavailability in pre-ruminant calves is 60%. It is somewhat less lipid- and somewhat more water-soluble than chloramphenicol and therefore crosses cell membranes less readily. Hepatic metabolism is limited, and elimination is primarily as parent drug in the urine. Limited published data indicate that it has a high distribution volume in ruminants. It has been used in feed in pigs and chickens, but such usage is now limited. 

Steroids (1) are members of a large class of lipid compounds called terpenes that are biogenicaHy derived from the same parent compound, isoprene, C Hg Steroids contain or are derived from the perhydro-l,2-cyclopentenophenanthrene ring system (1) and are found in a variety of different marine, terrestrial, and synthetic sources. The vast diversity of the natural and synthetic members of this class depends on variations in side-chain substitution (primarily at C17), degree of unsaturation, degree and nature of oxidation, and the stereochemical relationships at the ring junctions. 

As an illustrative example for the successful realization of this concept, here the interplay between three disciplines, organic synthesis, biophysics and cell biology in the study of protein lipidation and its relevance to targeting of proteins to the plasma membrane of cells in precise molecular detail is described. The interplay is highlighted using the Ras protein as a representative example. Included herein is the development of methods for the synthesis of Ras-derived peptides and fully functional Ras proteins, the determination of the biophysical properties, in particular the ability to bind to model membranes, and finally the use of synthetic Ras peptides and Ras proteins in cell biological experiments. 

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