Antisickling activity of amino acid benzyl esters.

Gorecki, Marian; Acquaye, C.T.A.; Wilchek, Meir; Votano, Joseph R.; Rich, Alexander

doi:10.1073/pnas.77.1.181

Cited by 21 publications

(12 citation statements)

References 19 publications

(17 reference statements)

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“…Many known antigelling agents, such as phenylalanine, contain aromatic rings (2)(3)(4)(5). Because toluene, a simple aromatic hydrocarbon, is required for the crystallization ofhuman carbon monoxide hemoglobin A (HbCO) (6), and four to nine molecules are bound by HbCO (7,8), we argued that the toluene-binding sites might be related to the phenyl-binding sites of antigelling agents to Hb S. Because toluene is not observed in the HbCO electron density map (9), two heavy atom analogues, methylphenylmercury (MePhHg) and iodobenzene, were used to try to locate the toluene site; to our surprise, MePhHg bound to two buried cysteines, making it more suitable as a heavy atom reagent for protein crystallography than as a marker for the aromatic binding site.…”

mentioning

confidence: 99%

Physiological and x-ray studies of potential antisickling agents.

Abraham¹,

Perutz²,

Phillips³

1983

Proc. Natl. Acad. Sci. U.S.A.

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Several aromatic compounds have been found to inhibit the gelling of sickle cell hemoglobin. We have tried to correlate the antigelling activity of such compounds with the stereochemistry of their binding sites in the hemoglobin molecule. This approach led to the discovery that two known antilipoproteinemia drugs, clofibrate and gemfibrozil, have antigelling activity. X-ray analysis showed that three pairs of molecules of clofibric acid, the active metabolite of clofibrate, bound to the walls of the internal cavity of deoxyhemoglobin A; only one pair bound to a quite different site, between helices A, E, and H of the a chains of carbon monoxide hemoglobin A. Unlike other antigelling agents, clofibric acid and related compounds decrease rather than increase the oxygen affinity of hemoglobin.Many chemical compounds have been studied as possible inhibitors of the gelation of sickle cell deoxyhemoglobin (Hb S), but no agent has proved sufficiently effective and innocuous to be approved for therapeutic treatment (for review, see ref.

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mentioning

confidence: 99%

Physiological and x-ray studies of potential antisickling agents.

Abraham¹,

Perutz²,

Phillips³

1983

Proc. Natl. Acad. Sci. U.S.A.

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“…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.…”

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confidence: 75%

“…The average of three assays is listed. The apparatus to measure the filterable amount of cells has been described (9). A gas (4.06% 02/4.4% C02/balance N2) at a positive pressure of 3.5 cm Hg was used to push the cell suspension (2.5 ml, hematocrit value, =1%) through a 2.3-cm-diameter Bio-Rad membrane (5-,Am pore size).…”

Section: Resultsmentioning

confidence: 99%

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

Votano¹,

Altman²,

Wilchek³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

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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...

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“…Sodium Metabisulphite Induced Deoxygenation: 9 Erythrocyte suspension was deoxygenated with 2% sodium metabisulphite (Na 2 S 2 O 5 ) for 5 min at 37 ºC. Then the cells were placed under anaerobic conditions between glass cover slips 8 . The slides were observed after 40 min for the presence of sickle cells and count using photomicroscope with magnification at 45x, digitalization of images with DTV250 software, morphological analysis of erythrocytes was performed in duplicate, the RBCs with star shape or elongated shape were counted as sickle cells, while circular shape RBCs were counted as normal cells.…”

Section: In-vitro Antisickling Activity Models: Preparation Of Erythrmentioning

confidence: 99%

“…Then, the cells were placed under anaerobic conditions between glass cover slip (Gorecki et al, 1980). Reversal of sickling was observed after 15 min, 30 min and 45 min by using photomicroscope Table 17 and Fig.…”

Section: Table 9: Effect Of T-ayu-h On % Met-haemoglobin Of Sickle Ermentioning

confidence: 99%

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2018

IJPSR

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Sickle cell anaemia is a genetic blood disorder that is caused by a mutation in the gene that encoded -globin of haemoglobin, which results as the presence of abnormal haemoglobin HbS in the RBC. Presently, there is no universal cure for sickle cell anaemia Herbomineral formulations were standardized for organoleptic properties (colour, odour and taste), physiochemical properties, total ash value, moisture content, pH of the solution, to find effective agent in which we investigated the antisickling potential of T-AYU-HM Premium, a novel Herbomineral formulation. In-vitro sickling of homozygous sickle cells upon deoxygenation (Emmel's Test) showed dose dependent inhibition of sickling in presence. T-AYU-H and T-AYU-HM Premium (25 µg/ml, 50 µg/ml, 100 µg/ml and 500 µg/ml). Mechanistic evaluations were performed such as, t-BOOH induced oxidative haemolysis, and formation of met-haemoglobin was significantly decreased in dose dependent manner in the presence of 50 µg/ml, 100 µg/ml and 500 µg/ml of T-AYU-H and T-AYU-HM Premium. Membrane stabilization activity by osmotic fragility test showed significant dose dependent increased stabilization in the presence of 50 µg/ml, 100 µg/ml and 500 µg/ml of T-AYU-H and T-AYU-HM Premium. The T-AYU-H and T-AYU-HM Premium will provide improvement of the therapeutic profile and lesser side effects compare to available synthetic treatment such as Hydroxyurea and Decitabine, and chances of blood transfusions will also be decreased. Formulations are much more affordable compared to available cost of management of disease for sickle cell anemic patients. INTRODUCTION: Sickle cell anaemia is an autosomal recessive genetic hematologic disorder that results from point mutation in β-globin gene, a major subunit of hemoglobin. A single nucleotide substitution (GAG-GTG) in sixth codon of the βglobin gene results in substitution of valine for glutamic acid.

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Antisickling activity of amino acid benzyl esters.

Cited by 21 publications

References 19 publications

Physiological and x-ray studies of potential antisickling agents.

Physiological and x-ray studies of potential antisickling agents.

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

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