bis(3-5-dibromosalicyl)fumarate and cetiedil

Fifteen compounds reported to be inhibitors of gelation or sickling were studied by standard methods. These tests included (1) the determination of the solubility of deoxyhemoglobin S or Csat, (2) evaluation of sickling in whole SS blood at various pO2s, (3) measurement of the oxygen affinity of hemoglobin and blood, and (4) examination of red cell indices and morphology. Among the 4 noncovalent agents tested, butylurea was the most potent inhibitor of gelation and sickling in vitro; however, relatively high concentrations were required compared to the covalent agents. In the latter group, bis-(3,5 dibromosalicyl)-fumarate, nitrogen mustard, and dimethyladipimidate were especially effective inhibitors of gelation and/or sickling. All of these compounds require further development before they can be considered for clinical use.

Topics: Anemia, Sickle Cell; Antisickling Agents; Aspirin; Azepines; Carbamyl Phosphate; Cyanates; Cystamine; Dimethyl Adipimidate; Drug Evaluation; Erythrocyte Indices; Glyceraldehyde; Hemoglobins; Humans; Imidoesters; Mechlorethamine; Oxygen Consumption; Phenylalanine; Pyridoxal; Solubility; Urea

A number of agents that prevent sickling in vitro have been discovered during the past decade. In general, such agents act directly on the hemoglobin S tetramer to inhibit gelation or alter oxygen affinity. Most currently recognized agents lack specificity for hemoglobin and modify other cellular constituents. Synthesis of reagents such as the bifunctional aspirin derivative, bis (3,5-dibromosalicyl) fumarate, with increased specificity for hemoglobin, represents a rational approach to the design of new therapeutic agents for sickle cell anemia. Membrane active agents such as cetiedil inhibit sickling in vitro but have not yet been shown to be effective in vivo. Reduction in the intracellular concentration of hemoglobin S apparently may reduce the frequency of painful crises but is difficult to achieve with current techniques. Although no antisickling therapy can yet be described as both safe and effective, the outlook for the future seems promising because of the large number of agents under active investigation.

Topics: Antisickling Agents; Aspirin; Azepines; Benzopyrans; Cyanates; Erythrocyte Aging; Erythrocytes, Abnormal; Hemoglobin, Sickle; Hormones; Humans; In Vitro Techniques