Allosteric effectors that have been evaluated for the treatment of sickle cell disease (SCD) include vanillin and 5-hydroxymethyl furfural (5-HMF). Both drugs suffered from rapid metabolic degradation, however, several of their derivatives show greater pharmacological properties for SCD treatment. Our efforts have produced multiple 5-HMF derivatives which have been evaluated for their potential to treat SCD. The effectiveness of each compound was evaluated for its ability to increase O2 affinity (i.e., P50, the partial pressure at which hemoglobin is 50% saturated with O2). Multiple aryl ether derivatives have been synthesized and evaluated. Results suggest that compounds with multiple aromatic aldehydes may have enhanced biological properties. One such derivative, compound 5, which features two furan aldehyde rings, increased O2 affinity significantly (P50 = 8.82 ± 1.87 mm Hg) when compared to unmodified Hb (P50 = 13.67 ± 0.22 mm Hg). Future studies include obtaining crystal structures of our compounds complexed with Hb to confirm where the compounds bind to Hb and what type of intermolecular interactions they form.

Design synthesis and evaluation of allosteric effectors for hemoglobin

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