Chirality biological significance

A number of biologically significant chiral compounds are synthesized from optically active functionalized alcohols. Scheme 42 shows some naturally occurring and nonnaturally occurring chiral compounds that have been synthesized from alcoholic building blocks in recent years. 

Phosphate esters, particularly AMP, ADP and ATP, have vital biological functions and this fact has generated intense interest in their reaction mechanisms. Subtle stereochemical experiments, such as the use of isotopically chiral compounds, have been important and, since all biological phosphorylation reactions appear to involve metal ion catalysis, the stereochemistry of phosphate ion coordination has also been subject to much attention.229,230 Apart from its biological significance, this work has revealed some interesting contrasts with the stereochemistry of ligand systems in which saturated carbon units link the donor atoms. 

Additionally, a number of biologically significant molecules have in their structure a chiral nonracemic sulfinyl group. Among these molecules (Fig. 1), it is worth noting the new immunosuppressive thiaspirane sulfoxide Nuphar alkaloid type la and lb,13 the gastric antisecretory omeprazole 2,14 the new potassium channel activators of Rhone Poulenc aprikalim 3,15 the cyclic hexapeptide waiakeamide 4,16 the ACAT inhibitor 5,17 and the potent human immunodeficiency virus type 1 protease inhibitor 6.18... 

Garay AS, Czege J, Tolvaj L et al (1973) Biological significance of molecular chirality in energy balance and metabolism. Acta Biotheor 22 34-43... 

Differentiation between stereoisomers also occurs in drug disposition and is of particular significance for those processes that depend upon a direct interaction between the drug and a chiral biological macromolecule, e.g., active transport processes, binding to plasma and tissue proteins, and drug metabolism [89-95]. 

The absorption and transport of the majority of drugs across biological membranes occurs by passive diffusion, a process dependent upon physicochemical properties, i.e., lipophilicity, ionization, and molecular size. Since enantiomers have identical physicochemical properties, stereoselectivity would not be expected even though membrane phospholipids are chiral, the significance of lipophilieity appears to outweigh that of compound chirality. In contrast, differences between diastereoisomers may occur as a result of their differential solubility. However, in the case of compounds transported via earrier-mediated meehanisms, e.g., facilitated diffusion or active transport, proeesses involving a direct interaction between a substrate and a carrier maeromoleeule, stereoselectivity is expected. Preferential absorption of the l- eompared to the D-enantiomers of dopa [96] and methotrexate [97,98] have been reported. In the case of the above examples, enantioseleetivity in absorption is observed, whereas in the case of eephalexin, a eephalosporin antibiotic, diastereoselectivity for the L-epimer oeeurs. The L-epimer has shown a greater affinity than, and acted as a competitive inhibitor of o-eephalexin transport [99]. The L-epimer is also more suseeptible to enzyme-mediated hydrolysis, with the result that it cannot be detected in plasma [99]. 

Waldeck, B. Biological significance of the enantiomeric purity of drugs. Chirality 1993, 5, 350-355. 

Shaw and co-workers used a mixed Lewis acid approach to synthesize chiral furanmethanol derivatives from glycals. These compounds are important intermediates in the synthesis of many biologically significant compounds and serve as precursors for furanmethanes and 3-acylfurans. Reaction of a selectively protected 6-azido glycal with zirconium(IV) chloride and zinc(II) iodide gave the desired chiral furan selectively in 74% yield. 

LC using chiral stationary phases has been used for the separation and purification of enantiomers and is attracting great interest, particularly because of the biological significance of chirality. 

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