Noncovalent Inhibitors of Sickle Hemoglobin Gelation; Effects of Tetrasubstituted Ammonium Salts

Abstract

The effects of various tetrasubstituted ammonium compounds on the solubility of deoxygenated sickle hemoglobin were evaluated. These conclusions were drawn from the slopes of the solubility profiles obtained: (1) for the homologous series of tetraalkylammonium chloride salts (R₄NCl), antigelling potency increased with increasing chain length of the R group: CH₃ < C₂H₅ < C₃H₇ < C₄H₉; (2) for halide salts of the tetrabutyl-ammonium cation there was no difference in effectiveness among the anions examined (Br⁻, Cl⁻, F⁻), presumably because of the extremely potent salting-in effect of this cation; (3) substitution of a benzyl for an alkyl group in three tetraalkylammonium chloride salts, C₆H₅CH₂(R)₃NCl, where R = CH₃, C₂H₅, or C₄H₉, potentiated the antigelling capacity by as much as eight-fold. Because they are substantially more water soluble than any other class of noncovalent inhibitors examined to date, further manipulation of the aryl substituent on these compounds may contribute to the design of an effective antisickling agent.