Phenylalanine analogues

Methanol remains the most widely used modifier because it produces highly efficient separations, but it does not always produce the highest selectivity [8]. Recent studies have provided insight into the role of the modifier in enantioselectivity in SFC [69]. Blackwell and Stringham examined a series of phenylalanine analogues on a brush-type CSP and developed a model that allowed prediction of selectivity based on the bulk solvation parameters of various modifiers [70]. Careful choice of modifiers can be used to mask or enhance particular molecular interactions and ultimately provide control of selectivity [71]. 

As the introduction of polar aryl groups into phenylalanine analogues afforded improvements in DPP-4 potency and selectivity, alternative locations to introduce polarity into this series were examined. Replacement of the [3-methyl group with a... 

The geometric isomers 464 and 467 of 5(47/)-oxazolones prepared from acetophenones can be separated. Alternatively, the mixture can be isomerized under the appropriate reaction conditions to obtain the pure of (Z) or ) isomer. Each isomer can be converted to a pair of enantiomers 466 and 469 (only one enantiomer shown) (Scheme 7.152). The p-methyl phenylalanine analogues thus obtained are constrained phenylalanines and the effect of incorporation of a p-MePhe or p-MeTyr residue on the biological properties of H-Tyr-Tic-Phe-Phe-NH2 (TIPP, where Tic = l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) a delta opioid receptor antagonist, has been studied. ... 

Recently, the cyclopropanation of (Z)-4-benzyIidene-2-phenyl-5(4//)-oxazolone 621 with phenyldiazomethane was reported to give the spirocyclopropane, rac- 21 in very high yield. Subsequent ring opening and hydrolysis of rac- 21 generated frani-l-amino-2,3-diphenyl-l-cyclopropanecarboxylic acid, rac-828 (cadiPhe) (Scheme 7.256). This new, constrained phenylalanine analogue induces a y-tum in the sohd state when incorporated into model dipeptides. The enantiomers of the Al-Boc (Boc = tert-butyloxycarbonyl) methyl ester of 828 have been resolved by HPLC. 

Cyclization of the iodoaromatic precursor 215 via Heck methodology to afford the l//-3-benzazepine-2-carboxylic ester 216 has been described (Scheme 29) <1997J(P1)447>. The ester 216 was then converted to the conforma-tionally restricted phenylalanine analogue 217 by hydrogenation and ester hydrolysis with concomitant BOC group removal under acidic conditions (HC1), followed by reaction with propene oxide. 

The P-tetralin amino acid induces the a-helical conformation by fixing the torsional angles along the peptide backbone at about -60° (< >) and -50° ( p).109 P-Tetralin amino acids may be regarded as cyclic-constrained phenylalanine analogues. As shown in Section II.A, this class of unnatural amino acids is known to stabilize distinct conformations in peptides since the two substituents at the a-cen-ter restrict the available conformational space. Cyclic a,a-dialkylated glycines and a-substituted alanines preferentially adopt a-helical conformations.205... 

Hoover et al. [47] assessed the absorption of a series of model D-phenylalanine analogues that were resistant towards enzymatic hydrolysis, after intrapulmonary administration of aerosolized peptide solution into the rat lung. Compared to oral administration, all peptides showed better absorption from the lung than from the gut, with pulmonary absorption ranging from 55.1 to 68.5% for the methylated series of these model peptides. However, some members of the non-methy-lated peptide series were metabolized during the absorption process, which was not observed in the intestinal absorption studies. Therefore, the advantage of pulmonary over oral administration must be examined on a case-by-case basis. 

Aspartase exhibits incredibly strict substrate specificity and thus is of little use in the preparation of L-aspartic acid analogues. However, a number of L-phenylalanine analogues have been prepared with various PAL enzymes from the yeast strains Rhodotorula graminis, Rhodotorula rubra, Rhodoturula glutinis, and several other sources that have been cloned into E. call.243 241 Future work in this area will likely include protein engineering to design new enzymes that offer a broader substrate specificity such that additional L-phenylalanine analogues could be prepared. 

C Appert, J Zoh, N Amrhein (2003) Kinetic analysis of the inhibition of phenylalanine ammonia-lyase by 2-aminoindan-2-phosphonic acid and other phenylalanine analogues Phytochemistry 62(3) 415-422... 

The peptides (17)-(22) were prepared by the usual solid-phase method of peptide synthesis utilizing different resins. The structures of D-Phe (22a) and its conformationally restricted phenylalanine analogue D-Tic (tetrahy-droisoquinoline-3-carboxyIic acid, 22b) positioned at the A-terminal position of the somatostatin analogues are shown. 

C.J. Wolyniak, G.L. Sacks, B.S. Pan, J.T. Brenna (2005) Carbon position-specific isotope analysis of alanine and phenylalanine analogues exhibiting nonideal pyrolytic fragmentation. Anal. Chem. 22, 1746-1752... 

Wang, P. Vaidehi, N. Tirrell, D.A. Goddard III, W.A. Virtual screening for binding of phenylalanine analogues to phenylalanyl-tRNA synthetase. JACS 2002, 124, 14,442. 

The efficient photodecarboxylation of the keto acids (77) has been studied. The reactions involve the formation of the carbanions (78). Aqueous solutions of fenofibric acid (79) at pH 7.4 show the formation of two intermediates when subjected to laser excitation. The study has indicated that the triplet state of the acid in water is of a jtji type. Photoionization is an important process in the aqueous medium. New photoreactive phenylalanine analogues (80) and (81) have been prepared. These were incorporated into position 5 of the pentapeptide, thymopentin. The resultant derivatives were photolabile and underwent decomposition on irradiation at 365 nm. Computational methods have been used to analyse the photoreactivity of the tryptophan derivative (82). The calculations were directed towards an understanding of the quenching of the fluorescence. The results indicate that hydrogen transfer alone does not quench the fluorescence, but that an aborted decarboxylation path is involved. Proton transfer... 

In addition, the same research group conducted an alternative approach to cytochalasin H (1099) by formal synthesis. For this purpose, they prepared a phenylalanine analogue of cytochalasin G (1098) and treated it with a rf ihy -Grignard reagent to yield a key intermediate for the c34ochalasin H (1099) synthesis (750). 

Gibson, S.E., Guillo, N., Middleton, R.J. etal. 997) Synthesis of conformationally constrained phenylalanine analogues via 7-, 8- and 9-endo Heck cyclisations. J. Chem. Soc., Perkin Trans. 1, 447-55. 

In vitro, pCPA exhibits typically competitive inhibition with regard to the substrate, with a Ki of about 3 x 10 M. After intraperitoneal administration to the rat (300 mg/kg), the inhibition of brain tryptophan hydroxylase is reversible by overnight dialysis. Since rat-brain tryptophan hydroxylase remains almost completely inhibited for 4 to 5 days after administration of a single and identical dose of pCPA, it would appear that this inhibition is not exclusively related to the presence of the drug in the tissues but to enzyme inactivation by incorporation of this phenylalanine analogue into tryptophan hydroxylase, followed by a slow... 

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