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.

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.
...

References

SHOWING 1-10 OF 41 REFERENCES

Anti‐sickling effect of MX‐1520, a prodrug of vanillin: an in vivo study using rodents

Doses as low as 7 mg/kg prolonged the survival time and reduced the percentage of sickled cells during hypoxia exposure, demonstrating the potential for MX‐1520 to be a new and safe anti‐sickling agent for patients with SCD.

Schiff base adducts of hemoglobin. Modifications that inhibit erythrocyte sickling.

Vanillin, a potential agent for the treatment of sickle cell anemia.

Oxygen equilibrium, ektacytometry, and x-ray studies indicate that vanillin may be acting to decrease HbS polymerization by a dual mechanism of action; allosteric modulation to a high-affinity HBS molecule and by stereospecific inhibition of T state Hb S polymerization.

Additive in vitro effects of anti‐sickling drugs

Therapeutic use of anti‐sickling compounds in combination may achieve increased efficacy with lower toxicity, and additive protective rheological effect was achieved with 60–78% reduction in clogging rate of 5 μm diameter pores when compared with no drug.

Niprisan (Nix‐0699) improves the survival rates of transgenic sickle cell mice under acute severe hypoxic conditions

The effect of Niprisan (Nix‐0699), a naturally occurring antisickling agent, on the survival of transgenic (Tg) sickle mice under severe acute hypoxic conditions and entrapment of massive numbers of sickled cells in the alveolar capillaries is studied.

Characterization of the binding of the anti-sickling compound, BW12C, to haemoglobin.

The present data confirm that BW12C binds at the intended locus but reveal additional non-covalent binding at an undefined site, and weaker binding through Schiff's base formation with other amino groups.

Substituted benzaldehydes designed to increase the oxygen affinity of human haemoglobin and inhibit the sickling of sickle erythrocytes

The predicted best compound is a potent inhibitor, at low oxygen pressure, of the sickling of erythrocytes from patients homozygous for sickle cell disease, and may prove to be a clinically useful anti‐sickling agent.

Hydroxyurea and erythropoietin therapy in sickle cell anemia.

This study confirms that hydroxyurea therapy increases Hb F production and provides objective evidence of a significant reduction in hemolytic rate and intracellular polymerization and indicates that large-scale, controlled clinical trials are warranted to study the safety and efficacy of hydroxyUREa in the treatment of sickle cell disease.

Treatment with NS3623, a novel Cl-conductance blocker, ameliorates erythrocyte dehydration in transgenic SAD mice: a possible new therapeutic approach for sickle cell disease.

Feelibility for the potential use of Cl-conductance blockers to treat human sickle cell disease is indicated by a loss of the densest red cell population and a shift from a high proportion of sickled to well-hydrated discoid erythrocytes, with some echinocytes present at the highest dosage.

5-Hydroxymethylfurfural: assessment of mutagenicity, DNA-damaging potential and reactivity towards cellular glutathione.