Sickle cell disease (SCD) is an inherited disorder that affects millions of people globally. Polymerization of sickle hemoglobin (Hb S) and the subsequent sickling of red blood cells (RBCs) that develop under low oxygen saturation conditions are exacerbated by the inherently low oxygen affinity of sickle RBCs – presumably as a result of increased intracellular concentration of 2,3-diphosphoglycerate in erythrocytes. This pathological process can be mitigated by increasing the oxygen affinity of Hb S, either by stabilizing the relaxed (R) state Hb and/or destabilizing the tense (T) state Hb. Covalent binding effectors of hemoglobin (Hb), such as aromatic aldehydes and ethacrynic acid (ECA) are known to exhibit these pharmacologic properties. The aldehydes form a Schiff-base with the N-terminal αVal1 nitrogen at the α-cleft of liganded Hb, and through several inter-subunit mediated interactions tie the two α-subunits together to stabilize the R-state and increase Hb affinity for oxygen. ECA, conversely increases the oxygen affinity of Hb via a Michael addition reaction between its β-unsaturated carbon and the sulfur atom of βCys93, disrupting a T-state stabilization salt-bridge interaction, shifting the allosteric equilibrium to the R-state.<br/><br/>Our objective is to develop novel antisickling agents based on the ECA pharmacophore and mode of binding to Hb that we hypothesize would bind covalently to βCys93 of oxygenated Hb and destabilize the T-state in a similar fashion as ECA, but with more potent allosteric and antisickling activities.<br/>We have developed novel compounds that are able to interact with Hb and increase the protein affinity for oxygen, and consistently decrease erythrocyte sickling. Most importantly, these compounds, unlike aromatic aldehydes appear to exhibit longer sustained action. The structural studies provide molecular level explanation to the biological activities of the compounds and offer a framework for targeted modifications to the KAUS molecules that would yield innovative and potent antisickling agents.

Identification of novel imidazolylacryloyl derivatives as potential antisickling agents

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.