Hemoglobin S antigelation agents based on 5-bromotryptophan with potential for sickle cell anemia

Abstract

5-Bromotryptophan (5-BrTrp) is the most potent amino acid derivative reported in the literature to inhibit the gelation of hemoglobin S (from sickle cell anemia patients). Trp-Trp is also more potent than Trp as an antigelation agent. Therefore, we have prepared a series of dipeptides containing 5-BrTrp and evaluated the antigelation activity. 5-BrTrp-5-BrTrp is the most potent, i.e., 5.9 times the activity of Trp, followed by 5-BrTrp-Trp and then Trp-5-BrTrp. This improved antigelation potency for 5-BrTrp-5-BrTrp and 5-BrTrp-Trp is very significant and will be pursued further as lead compounds with potential for sickle cell anemia.

On the Binding Free Energy and Molecular Origin of Sickle Cell Hemoglobin Aggregation

“…Thus, delaying or preventing the formation of such precursors could represent a potential SCD therapeutic route. Nonetheless, in spite of intensively studied, − there is no covalent or noncovalent antisickling drug able to inhibit erythrocyte sickling, and the only preventive therapeutics available consists in the administration of hydroxyurea, , which increases the levels of fetal hemoglobin that does not polymerize. , More recently, successful gene therapy results were reported for a single SCD patient and l -glutamine has been recently approved for the treatment of SCD. ,, Another important aspect of SCD concerns the differences between the disease symptoms (e.g., pain crisis frequency and severity) among genetically identical patients, suggesting that in addition to the concentration of HbS and other Hb forms, other variations in the erythrocytes’ environment (e.g., pH, osmolality) may be important to the polymerization process. ,,, …”

Serum 6-Bromotryptophan Levels Identified as a Risk Factor for CKD Progression

“…29,30 Several bromotryptophan isoforms are known to be inhibitors of hemoglobin S polymerization, and the most potent, 5-bromotryptophan, has been studied as an antigelation agent for sickle cell anemia in mice, with effectiveness in reducing the aggregation of deoxyhemoglobin S but an additional effect of decreased locomotor activity at high intraperitoneal doses. 31,32 Another recent study using the untargeted metabolomics approach of Metabolon linked lower bromotryptophan levels to higher gut permeability in children. 33 Serum 6-bromotryptophan may be a marker of levels of circulating bromide (Br 2 ), which is the ionic form of bromine.…”

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

“…It was quite unexpected that the introduction of the 4-azidotetrafluorobenzoyl group on to the amino group of tryptophan would abolish the activity completely, but it may be that the rigidity of the long 4-azidotetrafluorobenzoyl group prevented proper binding of compound 4 to haemoglobin. The second photoaffinity reagent (7) employed was based on the combination of the photoactive group diazomalonyl (which is more flexible than 4-azidotetrafluorobenzoyl) and the affinity moiety 5-BrTrp; the resulting compound retained -50 % of the anti-gelling activity of the parent compound [9]. The diazomalonyl group was introduced as a photoaffinity label superior to its predecessor, a-diazoacetyl, in that, in contrast with the latter, the carbene intermediate produced from the diazomalonyl group does not undergo Wolff rearrangement [31][32][33], which leads to the formation of a less reactive ketene.…”

“…Evaluation of anti-gelling activities of the synthesized photolabels [compound 4 (Scheme 1 below) and compound 7 (Scheme 2 below] was conducted by using a modification [9] of the method of Mazhani et al [15].…”

“…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).…”