Sarcosine complexes

An alternative method of separating dipolar and contact effects of lanthanides has recently been proposed by Elgavish and Reuben (1978). The method involves measuring longitudinal relaxation rates under the assumption that these arise mainly from dipolar interactions. Since the relaxation rates for the different nuclei in a molecule depend on r , ratios of relaxation rates for various pairs of nuclei should be the same as iso-structural complexes. Such studies have provided evidence for isostructural sarcosine complexes along the lanthanide series. 

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Not surprisingly, the diacid 13 and its diamide are waterlogged with 2-4 molecules of HzO from which they are difficult to liberate. Binding experiments in CHC13, a non-competing solvent, revealed that stoichiometric complexes, e.g. 48 were formed with diketopiperazines 40) (Kh 104) and amides such as malonamide. With structures of inadequate hydrogen bonding capacity, such as sarcosine anhydride, com-plexation does not occur. 

A variation on the usual synthesis of pyrazines, reaction of 1,2-diones with diamines, was the use of the diazabutadiene 81 in place of the dione <06JOC5897>. In another paper, the same diaza compound 81 reacted with sarcosine methyl ester, in a complex set of reactions, to produce quite good yields of 5-oxy-pyrazine-2-carboxamides 82. The A-methyl was lost and direct aromatisation occurred, presumably, due to cleavage oftheN-N bond <06SL2403>. 

Coordination of ammonia or a substituted ammonia to a metal ion alters markedly the N — H dissociation rate (see See. 6.4.2). Since also proton dissoeiation of complexed ammines is base-catalyzed, then exchange can be made quite slow in an aeid medium. Thus, in a eoordinated system of the type 12, containing an asymmetric nitrogen atom (and this is the only potential souree of optical activity), there is every chance for a successful resolution in acid conditions, since inversion is expected only after deprotonation. It was not until 1966 that this was suc-eessfully performed, however, using the complex ion 12. A number of Co(III), Pt(II) and Pt(IV) complexes containing sarcosine or secondary amines have been resolved and their raeemizations studied.Asymmetrie nitrogen centers appear eonfined to d and d ... 

The pioneering work of Waley and Watson (14) was soon extended and elaborated by the studies of Ballard and Bamford (20). They showed that some of the complex features of the kinetics of sarcosine NCA polymerisation, which were reported by the former workers, arose from the catalytic action of carbon dioxide. As the reaction progressed, the pressure of COs increased in Waley and Watson s reactor, and hence the contribution of the C02 catalysis became time-dependent. To avoid the problem of variable COa pressure, Ballard and Bamford developed a technique in which the pressure of C02 was kept constant and the rate of polymerisation was then determined by measuring the increase in C02 s volume. 

Experimental support for the above mechanistic interpretation comes from the work of Bizzozero and Zweifel (9) who have studied the behavior of N-acetyl-j -phenyl al anyl- -prol i ne amide ( ) and N-acetyl-L-phenylalanyl-sarcosine amide (32) toward enzymic hydrolysis with o-chymotrypsin. These two dipeptides were found to be good competitive inhibitors with a specific substrate (Ac-Phe-0CH3 (33)) but no hydrolysis was observed. These two peptides thus form an enzyme-substrate complex and the reason for their nonreactivity has to be sought in the nature of the enzyme-substrate interactions occurring during the subsequent bond-change steps. 

Table 15. Formation of insoluble metal-salt complexes of sarcosine peptides ... 

Figure 1 Reactions involved in the glycine reduction pathway hy Clostridia. Pa, Pb, and Pc denote the components of the glycine reduction complex where Pb is specific for the substrate (e.g. glycine, betaine, sarcosine). The reduction of oxidized protein Pa occurs via a redox chain involving thioredoxin reductase (TR) and thioredoxin (TRX). The involvement of ketene as an intermediate has not yet been proven...

CH2=N(0H) V or Mo complexes —> glycine (even at-20°C ), hydantoine, sarcosine,N-carbamoylglycine, oligomers (Hatanaka Egami 1977) (4.8)... 

An interesting application for the oxidation of organic compounds is of electrochemical nature. Octacyano complexes have been used to monitor redox enzymes such as lactate oxidase (from Pediococcus sp.) and sarcosine oxidase (from Arthrobactersp.) in a suitable electrochemical system (114). Two equivalents of [M(CN)g] can, for example, be oxidized at the electrode surface to [M(CN)g], which in turn can oxidize the flavoproteien to its oxidized form. This in turn reacts with, for example, L-lactic acid to produce pyruvic acid. 

Peptoid helices are detected in structure-supporting solvents even in relatively short oligomers. Because intramolecular C=0- H-N H-bond formation cannot be the driving force for peptoid secondary structure, the steric influence of the bulky and chiral side chain is likely to provide the required constraint. Interactions between side-chain groups, and between side chains and the carbonyls of the main-chain amides, may add stability to the ordered secondary structure. However, for very short oligomers (34) or peptoids based on N-substituted a-amino acids with a small side chain (35), such as Nala (also termed sarcosine, Sar, 9), complex mixtures of conformers associated with either cis or trans tertiary amide groups have been detected. In addition to the classic CD technique, the contribution of other spectroscopies, such as pulsed ESR (36), may be of value for the 3-D structural validation of peptoid molecules. 

More recently Ballard [73] has reported that poly-L-proline does not show the chain-effect with DL-phenylalanine NCA. He has also studied a number of block copolymers of L-proline and sarcosine as initiators with results shown in Table 5. The complex behaviour observed is discussed by Ballard in terms of availability to peptide sites for NCA adsorption. It is concluded that poly-L-proline does not adsorb the NCA. The existence of a chain effect with the initiators (Sarc)j o(Pro), qX and (Sarc)5 (Pro), qX requires explanation it may be connected with the occurrence of conformations of the proline chain in which the terminal base group X is not far removed from the sarcosine tail . 

In contrast, simple proton bound dimers [A + H + B]+ show an enhancement (i.e., catalysis) for H/D exchange over their corresponding monomers. This has been shown for simple symmetrical dimers of amines [72c], homo- and heterodimers between sarcosine and glycylglycine [73d], and for the antibiotic—peptide complexes [72e]. 

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