Quantitative assessment of the noncovalent inhibition of sickle hemoglobin gelation by phenyl derivatives and other known agents

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Abstract
The ability of a variety of phenyl derivatives to inhibit [human] sickle cell Hb gelation was placed on a quantitative scale by parallel equilibrium and kinetic assays. Modifications of the phenyl ring studied include polar, nonpolar and charged substituents; added aromatic rings; and loss of aromaticity. Other noncovalent inhibitors previously reported to have high potency were measured and placed on the same quantitative scale. Some phenyl derivatives were as effective as any other known noncovalent antigelling agent. The phenyl compounds penetrate easily into red cells and their potency is tolerant to chemical modification, which affords the possibility of designing low-toxicity derivatives. On the negative side, the level of potency obtainable appears to be inadequate for clinical use. The best phenyl inhibitors display a functionally defined inhibitory constant (Ki) of 75 mM and inhibitor concentrations over 20 mM would be necessary to obtain minimal clinically significant benefit. With the variety of modifications tested here, no impressive increase in activity could be achieved over that found in the simplest phenyl compounds.

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