L-glutamate analogues

Recently, the 2-substituted L-glutamate analogue (2R)-a-(hydroxymethyl)gluta-mate (HMG) (2-151) has been reported by the group of Kozikowski to serve as a potential bioactive compound [73]. Since the synthesis of such a small molecule should be rapid and practical in order to produce it on a multi-gram scale, a domino... 

In vivo experiments using mice with LI210 mouse leukaemia were undertaken by Hutchison [51] at the Sloan-Kettering Institute in the late 1960 s. Treatment with (VIII.70) (6mg/kg, q2d x 8) afforded a 150% increase in lifespan (ILS), while the corresponding L-glutamate analogue on the same... 

An estimation of the amount of amino acid production and the production methods are shown ia Table 11. About 340,000 t/yr of L-glutamic acid, principally as its monosodium salt, are manufactured ia the world, about 85% ia the Asian area. The demand for DL-methionine and L-lysiae as feed supplements varies considerably depending on such factors as the soybean harvest ia the United States and the anchovy catch ia Pern. Because of the actions of D-amiao acid oxidase and i.-amino acid transamiaase ia the animal body (156), the D-form of methionine is as equally nutritive as the L-form, so that DL-methionine which is iaexpensively produced by chemical synthesis is primarily used as a feed supplement. In the United States the methionine hydroxy analogue is partially used ia place of methionine. The consumption of L-lysiae has iacreased ia recent years. The world consumption tripled from 35,000 t ia 1982 to 100,000 t ia 1987 (214). Current world consumption of L-tryptophan and i.-threonine are several tens to hundreds of tons. The demand for L-phenylalanine as the raw material for the synthesis of aspartame has been increasing markedly. 

Application of classical type of kinetic equations to the template polymerization was demonstrated by Kabanov at al It was shown that 4-vinylpyridine, in the presence of poly(methacrylic acid), poly(acrylic acid), poly(l-glutamic acid), and polyphosphate, polymerizes according to the classical equation and the order of reaction with respect to the monomer is 2 as demonstrated in the Figure 8.1. In log-log coordinates, for the all sets of polymerizations, experimental points fit straight lines. In the same paper dependence of the initial rate on the molar ratio of acid to monomer was examined. This relationship is shown on the Figure 8.2. The rate of polymerization in the presence of the poly(acrylic acid) is much higher than that for the low molecular analogue (acetic acid). The polymerization rate riches its maximum for the molar ratio [acid]/[monomer] 2. The authors found kinetic equation for template polymerization of 4-vinylpyridine in the presence of different polyacids in the form ... 

The first synthesis of a 3-deaza analogue, 3-deazaFA (70), was accomplished, albeit in poor yield, via the Waller condensation of 2,3,6-triamino-4-hydroxypy-ridine hydrochloride, 2,3-dibromopropionaldehyde and p-aminobenzoyl-L-glutamic acid, as shown in Scheme 3.14. This approach suffered from its equivocal nature as well as from a lengthy work-up involving repeated centrifugations and column chromatographic separations which were necessary to obtain (70) sufficiently pure to be characterized and evaluated [71]. 

In their second approach (Scheme 3.51), the known 8-hydroxymethylpurine (282), available in two steps from (276) and glycolic acid [153], was treated with thionyl chloride. The resulting labile chloromethyl derivative (283) was used to alkylate />-aminobenzoyl L-glutamic acid after an in situ Finkelstein reaction furnishing (281a) directly. Use of (31) in this reaction sequence followed by saponification afforded no improvement in yield. Finally, reaction of (35) with (283) and ester hydrolysis yielded the purine MTX analogue (281b). 

About 2 years later, a Stanford Research Institute group described the synthesis of the first true pyrimidine analogue of FA (303) which incorporated all of the structural features of FA except the pyrazine ring (see Scheme 3.55) [159], They envisioned that (303) could be assembled from appropriately protected derivatives of isocytosine, glyoxal and p-aminobenzoyl L-glutamic... 

In the first, the known aldehyde (314) [163] was condensed with dimethyl /)-aminobenzoyl L-glutamate followed by in situ imine reduction and hydrolysis to furnish (315). Alternatively, reduction of (314) to the carbinol (316) was followed by conversion to the bromomethyl derivative (317). Alkylation of (31) with crude (317) and subsequent saponification then afforded (315) in better overall yields than their earlier efforts. Repetition of this latter reaction sequence using (35) gave the MTX analogue (318). 

In one case, methyl terephthalic acid, obtained in two steps from p-formyl-benzoic acid, was converted to the phenacyl bromide (340) in the usual manner. Alkylation of 2,5-diamino-4,6-dihydroxypyrimidine with (340) with subsequent cyclization produced the dihydrooxazine pteroate ester (341), which was hydrolyzed to (342) [173]. Coupling (342) with diethyl L-glutamate using isobutyl chloroformate [ 174] yielded the diester (343a) which was then saponified to the dihydrooxazine FA analogue without the C-9,N-10 bridge (343b). 

Replacement of the benzene ring with heterocycles was also investigated (Table 3.3). Condensation of a suitably substituted heterocyclic amine with (464), followed by imine reduction and saponification, afforded (583)-(588) (Scheme 3.121) [243-246], Thiophene derivative (589) was prepared by the condensation of 6-hydroxy-2,4,5-triaminopyrimidine, 1,1,2-trichloroacetone and A-(5-aminothienyl)-L-glutamic acid [247]. The pyridine analogue of AP,... 

The intense neuroexcitatory properties of the kainoids have been well documented and this class of molecule is now inextricably linked with neurochemical research.29 They appear to act as conformationally locked analogues of L-glutamic acid 25 (Figure 6), causing neuronal death in glutaminergic systems found in the brain. 

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