Small-molecule Precursors Research Articles

Milk fat synthesis and secretion: molecular and cellular aspects

Fatty acids esterified into triacylglycerol (TAG) by mammary epithelial cells (MEC) of lactating animals are derived either from plasma lipid or by de novo biosynthesis from small molecule precursors. The major contribution to milk lipid from plasma arises by hydrolysis of the TAG components of VLDL and chylomicrons, catalysed by lipoprotein lipase (LPL) in the mammary capillary bed; a minor contribution may come from the direct uptake of plasma non-esterified fatty acids. In the mammary gland of ruminant animals, short and medium-chain saturated fatty acids are the major products of de novo lipogenesis whereas plasma lipids contribute longer-chain and mono-unsaturated species. Human populations consuming diets disproportionately rich in saturated fatty acids experience increased risk of atherosclerosis — this association is most probably causal. Conversely, the potential health benefits associated with minor lipid components of milk fat — in particular CLA — have also recently been highlighted. This presentation will focus on selected key enzyme reactions with potential to determine and/or influence the fatty acid composition of milk lipid: ACC, SCD and FAT. Recent advances in their enzymology and molecular biology will be reviewed, emphasizing those properties that are relevant to the regulation both of their catalytic activities and of their expression. The cell biology of lipid secretion by MEC will be examined. Mammary cell/tissue models of lipid secretion will be surveyed to assess their suitability as experimental platforms for monitoring the possible effectiveness of interventions aimed at altering the amount or composition of lipid output during lactation.

Recent advances in the design and synthesis of carbon-14 labelled pharmaceuticals from small molecule precursors.

Over the past decade, the increased chemical complexity of new drug candidates has resulted in a parallel need to develop innovative syntheses of carbon-14 labelled pharmaceuticals. Faced with short time-lines and a limited number of labelled precursors, radiochemists have addressed this challenge by developing new reagents and adapting existing technology to labelled syntheses. Selected examples from the recent radiochemical literature illustrate some of the creative strategies used to rapidly solve these synthetic challenges. Examples describing the handling and use of common small molecule reagents, such as carbon-14 labelled carbon dioxide, methyl iodide, cyanide, acetic acids, sulfur and phosphorous stabilized ylides for the synthesis of labelled steroids, prostanoids, nucleosides, pyridines, quinolines, benzazepines and other heterocycles are presented. Several general strategies for radiolabelling are also discussed including the degradation strategy for accessing necessary intermediates and precursors, the radiolabelling of aromatic substrates, transition metal mediated cross-couplings, and the use of chiral auxiliaries for the enantioselective syntheses of radiolabelled pharmaceuticals.

From minerals to materials: synthesis of alumoxanes from the reaction of boehmite with carboxylic acids

Reaction of pseudo-boehmite, [Al(O)(OH)]n, with carboxylic acids (RCO2H) results in the formation of the carboxylatoalumoxanes, [Al(O)x(OH)y(O2CR)z]n where 2x + y + z = 3 and R = C1–C13. The physical properties of the alumoxanes are highly dependent on the identity of the alkyl substituents, R, and range from insoluble crystalline powders to powders which readily form solutions or gels in hydrocarbon solvents, from which films may be readily spin-coated. The physical and chemical changes that occur during the reaction of boehmite with carboxylic acids, and the resulting alumoxanes, have been characterized by scanning electron and transmission electron microscopy (SEM and TEM), IR and multinuclear NMR spectroscopy, and thermogravimetric/differential thermal analysis (TG/DTA). The carboxylatoalumoxanes reported herein are spectroscopically similar to analogues prepared from small molecule precursors. Based on the IR and NMR spectra of the alumoxanes as well as comparison with the aluminium carboxylate compounds [Me2Al(µ-O2CR)]2 and Al(O2CR)(salen)(R = CH3, n-C5H11), a model structure of the alumoxanes is proposed, consisting of a boehmite-like core with the carboxylate substituents bound in a bridging mode. Furthermore, the alumoxane particles appear as rod or sheet-like particles, not linear polymers. This is proposed to be due to the destruction of hydrogen bonding within the mineral as hydroxide groups are removed and replaced with acid functionalities. All of the alumoxanes decompose under mild thermolysis to yield alumina. Mass spectral studies indicate that upon thermolysis the volatile decomposition products are water and the carboxylic acid.

EFFECTS OF PITUITARY HORMONES AND NADPH ON ACETATE UTILIZATION IN OVARIAN AND ADRENOCORTICAL TISSUES.

In the course of the biosynthesis de novo of progesterone by corpus luteum slices in vitro, acetate-l-14C is incorporated into the steroid. Both the amounts of steroid formed (measured photometrically) and the incorporation of radioactivity are increased by exogenous gonadotropin, LH. Although exogenous NADPH (as a generating system) increases the quantity of progesterone formed de novo, it does not increase the incorporation of acetate-l-14C. The same phenomenon occurs in the biosynthesis of corticosteroids by adrenal cortex slices, with NADPH. It is concluded that the tropic hormone stimulates steroid biosynthesis from small molecule precursors, and that exogenous NADPH does not. (Endocrinology 74: 599, 1964)