Racemates platelets

FIGURE 7.19. (P)-helices (D-Glu-8, 28a) and (M)-helices (L-Glu-12, L-28d) first separate (a bar, 100 nm) and then (b bar 300 nm) unite to form elongated racemic platelets. Reproduced with permission of the American Chemical Society. 

Crystallization of ultrathin membrane structures in nature is also hindered by the presence of molecules with different chain lengths within these molecular assemblies. In the case of gluconamides, pseudo-racemates with alkyl chains of different lengths (e.g., Cj2 and Cg), first separate to produce left- and right-handed helices, which only later pair and rearrange to form racemic platelets within about 30 minutes (Fig. 4.5.10). 

In some cases, substrate racemization can be achieved by an appropriate change of a functional group. A good example of this strategy is the synthesis of acid 10, which is the key intermediate for roxifiban - a potent selective antagonist of the platelet plycoprotein Ilb/IIa receptor (Scheme 5.8) [27, 28]. 

As an extension of their previous work, the Tachibana group (82, 83) studied the collapse fragments that occur when monolayers of 12-hydroxystearic acid are compressed slowly (18 A /molecule hr) at surface areas of less than 21 A /molecule, the normal cross-sectional area of a hydrocarbon chain. The collapsed monolayers were transferred from the subphase to hydrophilic supports by a horizontal lifting method for electron microscopic observation, which revealed (Fig. 30) flat platelets when the sample was racemic and twisted... 

R,R)- and (S -cyclohexanediamines 102 self-assemble with cyclohexane-1,2-diol 103 forming helical fibers of 40-70 nm length whilst the racemate produces platelets [53]. 

Enantiomorphic superstructures were also observed for the N,n-octyl-L-gluconamide, while the racemic mixture was found to lead only to non-fibrous, non-twisted platelets.158... 

The sulfuric acid salt of 5 (Parnate Jatrosom ) is used as an antidepressant drug, and best results were achieved in chronic neurotic patients. (+ )-(5) was reported to be also effective as an adjuvant in Parkinson s disease therapy . Differences of activities of the pure enantiomers (for a minireview see Ref. 629 for resolution of racemic 5 see Refs 42, 103, 160, 654, 655 for g.c. separation of racemic 5 as iV-trifluoracetyl-L-prolyl derivative, see Ref. 656) and the trans-cis diastereomers 5/628 have been studied as well as the selectivities of 5 on inhibition of MAO type A and B (e.g. Refs 637, 638, 658-674). (+ )-(5) showed stronger inhibition of platelet (dopamine ... 

Figure 5.3 Scanning electron microscopy image of wax tubes in their natural environment in pine needle stomata. Similar wax tubes were obtained from chloroform solutions of natural nonacosan-lO-ol of unknown sterochemistry and of synthetic S-nonacosan-lO-ol. The synthetic racemate only produced platelets. The curvature effect was traced back to the packing of all OH groups on one side of the bilayer (a), which is not found in the racemate (b).

Phospholipid chemistry contains several well-authenticated cases of semi-synthesis particularly with respect to recent developments in the area of alkoxylipids and the chemistry of substances such as platelet activating factor (ref.95) a mediator of not only platelet activation but of other biological reactions. The synthesis of the active racemic, l-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine (90) in which the alkyl group is saturated C16 and C18 has been described by a number of workers (ref. 96) from a 1-0-alkyl-sn-glcerol as illustrated. 

In both series almost equipotent activities were observed for thromboxane receptor antagonism and thromboxane synthase inhibition (IC50 = 2-30 nM). Upon oral administration to guinea pigs the enantiomers inhibited the ex vivo U-46619-induced platelet aggregation with potencies similar to that of the corresponding racemates. This indicates... 

The binding affinity and the functional activity of the enantiomers in comparison with those of the racemic mixture are shown in Table 7. The S-diastereoisomer proved to be more potent than the R-diastereoisomer, and than the mixture as well, in all model systems. However, the most important achievement is that the platelet receptor clearly discriminates between the two compounds since R-PHPNECA is equiactive with NECA, whereas the S diastereoisomer shows an antiaggregatory potency about 30-fold that of NECA, i.e. about 7 nM, resulting in the most potent inhibitor so far known in the adenosine agonist derivatives [30]. 

It stabilizes the lyotropic liquid crystalline state of biological assemblies relative to the crystalline state, due to the so-called chiral bilayer effect, which will be discussed in more detail in Section 4.2. For example, 10-nonacosanol, extruded from the lipophilic wax layer of pine needles, forms fluid lipid tubules rather than crystals. Although it is difficult to establish the enantiopurity of the natural product, the fact that synthetic pure enantiomers produce tubules while the racemate gives platelets suggests that the biologically relevant morphology is attained because of the enantiopurity of the biomolecule. °... 

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