Potential use of biaromatic L-phenylalanyl derivatives as therapeutic agents in the treatment of sickle cell disease.

Abstract

N-Phenylacetyl-L-phenylalanine (PAP) and L-phenylalanyl-3-aminopyridine (PAPA) are biaromatic agents with properties that make them suitable candidates for the development of a useful therapeutic agent for the treatment-of sickle cell disease. PAP and PAPA are taken up by the erythrocyte to give intra-/extracellular concentration ratios of 2.2 and 1.5, respectively, after a 2-hr exposure period. The intracellular buildup of PAP and PAPA produces moderate decreases in the mean corpuscular hemoglobin concentration (MCHC) of 6 and 10%, respectively, at 3 mM and a further decline in MCHC with increased concentration. Both PAP and PAPA increase the deoxy-Hb S solubility, C,. If Many of the approaches and rationales (1, 2) aimed at the development of chemical agents for the treatment of sickle cell disease have centered on agents that can interact covalently or noncovalently with the Hb S tetramer to increase the delay time of Hb S gelation. With respect to the latter, in vitro studies of small peptides, alkylureas, and amino acids (3-6), aryl-substituted alanines (7), and halogenated aryl derivatives of oxy acids (8) have revealed several general stereochemical criteria associated with antigelation activity for a noncovalent inhibitor. Biaromatic and bicyclic compounds are more effective than monocyclic compounds and aromatic moieties, more so than aliphatic groups. With regard to aromatic nuclei, the higher the degree of ring polarizability and hydrophobicity of the compound, the greater is its antigelation activity. However, little is known of erythrocyte penetration by these compounds except for amino acids and peptides.Another result was found with noncovalent binding compounds in the study of aromatic amino acid esters including L-phenylalanyl benzyl ester (9) and Cetiedil (10, 11), a tricyclic ester. Both of these compounds induce water uptake by the erythrocyte. The exact mechanism by which the benzyl ester can cause water uptake is not known whereas Cetiedil has been shown to alter cation permeability so as to induce water gain by the cell. The net effect of water uptake, of course, is a reduction in the mean corpuscular hemoglobin concentration (MCHC), with an attendent increase in the delay time for intracellular gelation (12).Drawbacks to the benzyl ester of L-phenylalanine are its low solubility and gradual hydrolysis in the cell. We have addressed these problems by synthesizing biaromatic derivatives of L-phenylalanine that are held together by a stable amide bond rather than an ester bond. We report on two such antisickling agents, one of which is N-phenylacetyl-Lphenylalanine (PAP), where the linkage is through the a-amino group of L-phenylalanine. The other is L-phenylalanyl-3-aminopyridine (PAPA), which has a linkage through the carboxyl group of L-phenylalanine. In this paper, we describe properties of both compounds as they relate to their permeability in the erythrocyte, their antigelation activity as measured by deoxy-Hb S solubility, and their effects on the MCHC. In addition, these e...

Antigelling and antisickling bisphenyl oligopeptides and peptide analogues have similar structural features

“…FOB functions as an antisickling agent by causing the erythrocyte to take up water after the bisphenyl compound has traversed the red cell membrane (Votano et al, 1984).…”

“…The antigelling agents L-lysyl-Lphenylalanyl-L-phenylalanine (KFF) and L-phenylalanylglycylglycyl-D-phenylalanine (FGGF) were synthesized as described previously (Gorecki et al, 1980a). The antisickling agents L-phenylalanine benzyl ester (FOB) and A-phenylacetyl-L-phenylalanine (PAF) were also synthesized as previously described (Gorecki et al, 1980b;Votano et al, 1984). Single-Crystal X-ray Structure Determination.…”

“…Solubility Studies. Solubility ratios were measured by using a method previously described (Votano et al, 1984). The total deoxy-HbS concentration used was 28 g/dL.…”

Evaluation and Comparison of Anti-Sickling Activities of Macerated Seeds of Cajanus Cajan and Phenylalanine

“…This anti-sickling activity of the Phe could be explained by studies which have shown that AA and in particular aromatic AA have the possibility of inhibiting the gelling of deoxyhemoglobin S and partially preventing the formation of sickle cells (Noguchi, 1977;Noguchi andAckeman, 1983). The Phe esters and Phe-containing peptides have the same property (Acquaye and al., 1982;Votano and al., 1984).…”

Photoaffinity labelling of cyanomethaemoglobin with derivatives of tryptophan and 5-bromotryptophan

“…Chemical compounds that inhibit this process are potential candidates for use as therapeutic agents. Among many compounds studied that delay the onset of polymer formation through non-covalent interactions [1][2][3][4][5][6][7][8][9], tryptophan and 5bromotryptophan (5-BrTrp), as well as the corresponding dipeptides, have been found to be among the more potent polymerization inhibitors, and the potency of the dipeptide of 5-BrTrp is on the threshold of being clinically useful [5,9]. Although the binding sites were determined crystallographically for one of the dipeptides, namely succinyl-Trp-Trp (STT) [10], the binding sites of the building blocks of these dipeptides, namely tryptophan and 5-BrTrp, have only been suggested, but not fully established, by the use of spin-labelled derivatives and computer modelling [11,12] (C. J. Yuan, L. Kar, P. Z. deCroos, B. L. Currie and M. E. Johnson, unpublished results).…”