5‐hydroxymethyl‐2‐furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells †,‡

@article{Abdulmalik20055hydroxymethyl2furfuralMI,
  title={5‐hydroxymethyl‐2‐furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells †,‡},
  author={Osheiza Abdulmalik and Martin K. Safo and Qiukan Chen and Jisheng Yang and Carlo Brugnara and Kwaku Ohene‐Frempong and Donald J. Abraham and Toshio Asakura},
  journal={British Journal of Haematology},
  year={2005},
  volume={128}
}
In an attempt to find new types of anti‐sickling agents that specifically bind to intracellular sickle haemoglobin (HbS) without inhibition by plasma and tissue proteins or other undesirable consequences, we identified 5‐hydroxymethyl‐2‐furfural (5HMF), a naturally occurring aromatic aldehyde, as an agent that fulfils this criterion. Preliminary studies in vitro showed that 5HMF forms a high‐affinity Schiff‐base adduct with HbS and inhibits red cell sickling by allosterically shifting oxygen… 

Effects of 5‐hydroxymethyl‐2‐furfural on the volume and membrane permeability of red blood cells from patients with sickle cell disease

It would appear that an important beneficial action of 5HMF, in addition to effects on HbS oxygen affinity, is reduction in Psickle‐mediated Ca2+ entry following RBC sickling, thereby inhibiting the deleterious sequelae of Gardos channel activation, RBC dehydration and also lipid scrambling.

5‐(Hydroxymethyl)furfural restores low‐oxygen rheology of sickle trait blood in vitro

Results suggest that a compound present in some food may provide a potential approach for managing risks that may be associated with SCT, and 5‐(hydroxymethyl)furfural, a natural breakdown product of glucose and fructose‐containing foods, such as fruit juices, can reduce the effects of hypoxia on SCT blood rheology in vitro, restoring near‐normal flow velocities at very low oxygen.

New developments in anti‐sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo?

The aromatic aldehyde, 5‐hydroxymethylfurfural (5‐HMF) increases oxygen affinity of sickle haemoglobin and reduces Hypoxia‐induced sickling in vitro and protects sickle cell mice from effects of hypoxia.

GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half‐life in a murine model of sickle cell disease

Oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute, and has the potential for clinical use as a disease‐modifying agent in sickle cell patients.

Antisickling Drugs Targeting βCys93 Reduce Iron Oxidation and Oxidative Changes in Sickle Cell Hemoglobin

O oxygen dissociation, oxidation, and polymerization kinetic reactions for four antisickling drugs (under different preclinical/clinical developmental stages) that either site-specifically target βCys93 or other sites on the HbS molecule are reported to provide a dual antioxidant and antisickled therapeutic benefits in treating this disease.

Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell Disease

The findings from this proof-of-concept study suggest that the incorporation of NO donor group to 5HMF and analogous molecules could be a novel beneficial strategy to treat SCD and warrants further detailed in vivo studies.

An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte Sickling

Through additional targeted modifications of the lead Michael addition compounds, the group has discovered other novel antisickling agents, designated MMA, that bind to the α-globin and/or β- globin to increase Hb affinity for oxygen and concomitantly inhibit erythrocyte sickling with significantly enhanced and sustained pharmacologic activities in vitro.

Design, Synthesis, and Biological Evaluation of Ester and Ether Derivatives of Antisickling Agent 5-HMF for the Treatment of Sickle Cell Disease.

This work structurally modified 5-HMF into 12 ether and ester derivatives and investigated 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 effect of the antisickling compound GBT1118 on the permeability of red blood cells from patients with sickle cell anemia

Findings reveal important effects of GBT1118 on protecting sickle cells and suggest that this is approach may represent a useful therapy for amelioration of the clinical complications of SCA.

Sulfated non-anticoagulant heparin derivative modifies intracellular hemoglobin, inhibits cell sickling in vitro, and prolongs survival of sickle cell mice under hypoxia

It is shown that the multimodal S-NACH can directly engage in Schiff-base reactions with HbS to decrease red blood cell sickling under both normoxia and hypoxia in vitro, prolong the survival of SCD mice under Hypoxia, and regulate the altered steady state levels of pro- and anti-inflammatory cytokines.
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