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

Xu, Guanghui; Pagare, Piyusha P.; Ghatge, Mohini S.; Safo, Ronni P.; Gazi, A.; Chen, Qiukan; David, T. Manovah; Alabbas, Alhumaidi B.; Musayev, F.N.; Venitz, Jürgen; Zhang, Yan; Safo, Martin K.; Abdulmalik, Osheiza

doi:10.1021/acs.molpharmaceut.7b00553

Cited by 45 publications

(55 citation statements)

References 43 publications

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“…GBT440 (2‐hydroxy‐6 ((2‐(1‐isopropyl‐1H‐pyrazol‐5‐yl) pyridin‐3‐yl)‐methoxy) benzaldehyde, MedChemExpress, Sollentuna, Sweden) is a novel, orally bioavailable agent currently in clinical trials for SCD . 5‐PMFC (5‐[Phenoxymethyl]‐2‐furan carbaldehyde) is an aryl ether derivative of 5‐(hydroxymethyl)furfural (5‐HMF), with a potent antisickling effect . Designated International Nonproprietary Name‐312 (INN312) is a designed and synthesized derivate of vanillin …”

Section: Methodsmentioning

confidence: 99%

“…An individual patient's tendency to “sickle” can be tested in vitro using a so‐called sickling assay: RBCs are incubated under hypoxic conditions and manually or digitally counted using a light microscope. This assay is still widely applied in research, and many preclinical and early phase pharmacologic and gene therapy trials use this assay as outcome variable to predict clinical effect . However, there are many disadvantages: It is time consuming, it has low sensitivity and high variability, and the process is not automated.…”

Section: Introductionmentioning

confidence: 99%

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Rapid and reproducible characterization of sickling during automated deoxygenation in sickle cell disease patients

et al. 2019

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In sickle cell disease (SCD), sickle hemoglobin (HbS) polymerizes upon deoxygenation, resulting in sickling of red blood cells (RBCs). These sickled RBCs have strongly reduced deformability, leading to vaso‐occlusive crises and chronic hemolytic anemia. To date, there are no reliable laboratory parameters or assays capable of predicting disease severity or monitoring treatment effects. We here report on the oxygenscan, a newly developed method to measure RBC deformability (expressed as Elongation Index ‐ EI) as a function of pO2. Upon a standardized, 22 minute, automated cycle of deoxygenation (pO2 median 16 mmHg ± 0.17) and reoxygenation, a number of clinically relevant parameters are produced in a highly reproducible manner (coefficients of variation <5%). In particular, physiological modulators of oxygen affinity, such as, pH and 2,3‐diphosphoglycerate showed a significant correlation (respectively R = ‑0.993 and R = 0.980) with Point of Sickling (PoS5%), which is defined as the pO2 where a 5% decrease in EI is observed during deoxygenation. Furthermore, in vitro treatment with antisickling agents, including GBT440, which alter the oxygen affinity of hemoglobin, caused a reproducible left‐shift of the PoS, indicating improved deformability at lower oxygen tensions. When RBCs from 21 SCD patients were analyzed, we observed a significantly higher PoS in untreated homozygous SCD patients compared to treated patients and other genotypes. We conclude that the oxygenscan is a state‐of‐the‐art technique that allows for rapid analysis of sickling behavior in SCD patients. The method is promising for personalized treatment, development of new treatment strategies and could have potential in prediction of complications.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rapid and reproducible characterization of sickling during automated deoxygenation in sickle cell disease patients

et al. 2019

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“…With about 30 picogram (pg) of hemoglobin per RBC [95,96], disruption of polymerization in less than 1.5 pg HbS per cell should in principle be sufficient to frustrate aggregation, especially considering that only between 40 and 60% of the RBCs typically undergo sickling [97]. This reasoning does not only bring HbS polymerization within the purview of non-covalent inhibition, but it also rationalizes why antisickling effects have been observed for various small molecular weight inhibitors [98][99][100]. For instance, screening for non-covalent antisickling agents that reverse HbS polymerization by altering RBC shape and volume (towards more spherical structures with larger volumes) discovered antisickling properties for gramicidin A and monensin A at concentrations of 200 pM and 2 nm, respectively [101].…”

Section: Hbs Aggregation Is An Inefficient Processmentioning

confidence: 99%

“…Compounds whose antisickling properties are based on this concept include vanillin and pyridyl derivatives of vanillin, 5-hydroxymethylfurfural (5-HMF), and the recently approved voxelotor (GBT 440) [54,99,[106][107][108][109][110]. They bind to the N-terminal valine (and possibly lysine) residues of the α-globin chains of HbS ( Figure 4) [98], forming a reversible Schiff-base adduct which stabilizes the R-state and/or destabilizes the T-state, increasing hemoglobin solubility, and thus inhibiting HbS aggregation. Iqbal et al employed an electrochemistry-based technique to investigate HbS polymerization in the presence of vanillin and 5-HMF [86].…”

Section: Antisickling Effect and Hbs Conformationmentioning

confidence: 99%

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

2019

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Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the β-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30-40 years ago up to more promising 12-and 15-mers under consideration in recent years.Molecules 2019, 24, 4551 2 of 23 with hemoglobin reduces HbS solubility and promotes polymerization, also called sickling [3,4]. This ultimately leads to hampered O 2 binding and transport, impaired erythrocyte morphology and interaction with endothelial surfaces [5,6], premature erythrocyte rupture and anemia, painful vaso-occlusive crisis, a general poor health, and, in many cases, death [7][8][9][10][11].Despite growing understanding of the polymerization of HbS and its effects on red blood cells (RBCs), until very recently, only two drugs-hydroxyurea and L-glutamine-were approved by the United States (US) Food and Drug Administration (FDA) for the management of SCD [12]. Hydroxyurea is the most widely employed drug treatment of sickle cell anemia in different age groups [13][14][15][16][17][18]. While its clinically observed efficacy has been attributed to different effects at the cellular level [19], the most important mechanism of action relates to its ability to induce the production of fetal hemoglobin (HbF), which does not polymerize, and to increase the total concentration of hemoglobin [20,21]. Hydroxyurea remains a viable treatment option for SCD, and the concern of toxicities associated with its administration has largely been limited to side effects that resolve with medication discontinuation [22][23][24][25][26]. There have, however, been certain reports of associated malignancies [27][28][29][30][31][32], but further investigations are needed to categorically confirm these [33]. L-glutamine is the second approved drug treatment [12,34]. While its mechanism of action is not known, and only suggested to involve a reduction of oxidative stress via elevation of the levels of reduced glutathione [35,36], it is clear that it has no effect on hemo...

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“…Salminen et al made the use of H‐Beta zeolites modified with ionic liquid and achieved 46% conversion and 35% yield under inert atmosphere (entry 9). Finally, Xu et al obtained 36% of t ‐BMF using di‐ t ‐butyl dicarbonate as the t ‐butyl source and magnesium perchlorate as the catalyst under reflux conditions in dichloromethane (DCM) for 48 h (entry 10).…”

Section: An Overview Of the Main Reported Catalytic Systems For The Pmentioning

confidence: 99%

Efficient Continuous Production of the Biofuel Additive 5‐(t‐Butoxymethyl) Furfural from 5‐Hydroxymethylfurfural

et al. 2019

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The catalytic etherification of 5‐hydroxymethylfurfural (HMF) with t‐butanol to a biofuel additive 5‐(t‐butoxymethyl) furfural (t‐BMF) is studied by screening 27 heterogeneous protic and/or Lewis acids. Preyssler heteropolyacid H14[NaP5W30O110] and Montmorillonite‐based CLOI_CSP catalysts are identified as the most efficient ones, allowing the etherification to reach the t‐BMF/HMF equilibrium faster (≈1:1), thus promoting minimum side reactions. Further optimization of the batch experimental conditions, namely catalyst loading, temperature, HMF concentration, time, t‐BMF stability, and additives, allows the t‐BMF/HMF equilibrium to be reached in less than 3 h with outstanding selectivity >95%. Under optimized conditions, CLOI_CSP is reused for four cycles without significant loss of efficiency. In addition, it exhibits high efficiency under flow conditions, allowing continuous production of t‐BMF up to 0.7 g t‐BMF g−1 catalyst min−1 at high concentrations of HMF.

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

Cited by 45 publications

References 43 publications

Rapid and reproducible characterization of sickling during automated deoxygenation in sickle cell disease patients

Rapid and reproducible characterization of sickling during automated deoxygenation in sickle cell disease patients

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

Efficient Continuous Production of the Biofuel Additive 5‐(t‐Butoxymethyl) Furfural from 5‐Hydroxymethylfurfural

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