1 research outputs found
Design, Synthesis, and Biological Evaluation of Ester and Ether Derivatives of Antisickling Agent 5‑HMF for the Treatment of Sickle Cell Disease
Candidate drugs to counter intracellular
polymerization of deoxygenated
sickle hemoglobin (Hb S) continue to represent a promising approach
to mitigating the primary cause of the pathophysiology associated
with sickle cell disease (SCD). One such compound is the naturally
occurring antisickling agent, 5-hydroxymethyl-2-furfural (5-HMF),
which has been studied in the clinic for the treatment of SCD. As
part of our efforts to develop novel efficacious drugs with improved
pharmacologic properties, we structurally modified 5-HMF into 12 ether
and ester derivatives. The choice of 5-HMF as a pharmacophore was
influenced by a combination of its demonstrated attractive hemoglobin
modifying and antisickling properties, well-known safety profiles,
and its reported nontoxic major metabolites. The derivatives were
investigated for their time- and/or dose-dependent effects on important
antisickling parameters, such as modification of hemoglobin, corresponding
changes in oxygen affinity, and inhibition of red blood cell sickling.
The novel test compounds bound and modified Hb and concomitantly increased
the protein affinity for oxygen. Five of the derivatives exhibited
1.5- to 4.0-fold higher antisickling effects than 5-HMF. The binding
mode of the compounds with Hb was confirmed by X-ray crystallography
and, in part, helps explain their observed biochemical properties.
Our findings, in addition to the potential therapeutic application,
provide valuable insights and potential guidance for further modifications
of these (and similar) compounds to enhance their pharmacologic properties