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Summary: HbSC disease is a common form of sickle cell disease with significant morbidity and early mortality. Whether hydroxyurea is beneficial for HbSC disease is unknown. Prospective Identification of Variables as Outcomes for Treatment (PIVOT, Trial ID PACTR202108893981080) is a double‐blind, randomised, placebo‐controlled phase II trial of hydroxyurea for people with HbSC, age 5–50 years, in Ghana. After screening, participants were randomised to placebo (standard of care) or hydroxyurea. The primary outcome is the cumulative incidence of haematological toxicities during 12 months of blinded treatment; secondary outcomes include multiple laboratory and clinical assessments. Between April 2022 and June 2023, 112 children and 102 adults were randomised, including 44% females and average age 21.6 ± 14.5 years. Participants had substantial morbidity including previous hospitalisations (93%), vaso‐occlusive events (86%), malaria (79%), often received transfusions (20%), with baseline haemoglobin 11.0 ± 1.2 g/dL and foetal haemoglobin 1.8% ± 1.5%. The spleen was palpable in six children and one adult, and ultrasonographic volumes were collected. Proliferative sickle retinopathy was common (30% children, 75% adults), but proteinuria was less common (3% children, 8% adults). Whole blood viscosity, ektacytometry, point‐of‐sickling, transcranial Doppler, near‐infrared spectrometry (NIRS), 6‐minute walk, and quality of life were also measured. Now fully enrolled, PIVOT will document the safety and potential benefits of hydroxyurea on clinical and laboratory outcomes in HbSC disease. [ABSTRACT FROM AUTHOR]

A new method is developed for stereoselective glycosylation with glycosyl trichloroacetimidate donors by using cationic palladium(II). The reaction is highly stereoselective and the palladium catalysis has directed [beta]-glucosylations in the absence of neighboring group participation.

A novel method is developed for the synthesis of 1,2-cis-2-amino glycosides via nickel-catalyzed [alpha]-selective glycosylation with C(2)-N-substituted benzylidene D-glucosamine and galactosamine trichloroacetimidates. The studies have shown that the presence of the substituted benzylidene functionality at the C(2)-amino position of glycosyl donors is very important for the high [alpha]-selectivity in the coupling products and the [alpha]-orientation of the C(1)-trichloroacetimidate group on glycosyl donors is required for the coupling process to occur.

A new method is developed for the stereoselective synthesis of [alpha]-2-deoxy-2-amino glycosides. The new method is applied to both D-glucosamine and galactosamine trichloroacetimidate donors as well as an array of primary, secondary and tertiary alcohol nucleophiles to provide glycoconjugates with excellent [alpha]-selectivity.

A new glycosylation method is developed for the stereoselective synthesis of [beta]-glycosides in the absence of the traditional C(2)-ester neighboring group effect, but has relied on the ability of the cationic palladium catalyst. The formation of the seven-membered ring intermediate has directed the electivity, leading to the formation of [beta]-glycosides.

The 1 ,2-cis-2-amino glycosides are key components found within a variety of biologically important oligosaccharides and glycopeptides. Although there are remarkable advances in the synthesis of 1 ,2-cis2-amino glycosides, disadvantages of the current state-of-the-art methods include limited substrate scope, low yields, long reaction times, and anomeric mixtures. We have developed a novel method for the synthesis of 1 ,2-cis-2-amino glycosides via nickel-catalyzed ct-selective glycosylation with C(2)-N-substituted benzylidene D-glucosamine and galactosamine trichloroacetimidates. These glycosyl donors are capable of coupling to a wide variety of alcohols to provide glycoconjugates in high yields with excellent levels of α-selectivity. Additionally, only a substoichiometric amount of nickel (5-10 mol %) is required for the reaction to occur at 25 °C. The current nickel method relies on the nature of the nickel-ligand complex to control the a-selectivity. The reactive sites of the nucleophiles or the nature of the protecting groups have little effect on the a-selectivity. This methodology has also been successfully applied to both disaccharide donors and acceptors to provide the corresponding oligosaccharides in high yields and a-selectivity. The efficacy of the nickel procedure has been further applied toward the preparation of heparin disaccharides, GPI anchor pseudodisaccharides, and a-GIuNAc/GalNAc. Mechanistic studies suggest that the presence of the substituted benzylidene functionality at the C(2)-amino position of glycosyl donors is crucial for the high a-selectivity observed in the coupling products. Additionally, the a-orientation of the C(1)-trichloroacetimidate group on glycosyl donors is necessary for the coupling process to occur. [ABSTRACT FROM AUTHOR]

Background: Hemoglobin SC (HbSC) is a common sickle hemoglobinopathy that causes acute complications, chronic organ damage, and early death with no established disease-modifying treatment. In this trial, we examined the safety and efficacy of hydroxyurea treatment in patients with HbSC., Methods: Prospective Identification of Variables as Outcomes for Treatment (PIVOT) was a double-blind, randomized, placebo-controlled, non-inferiority phase 2 trial in which we assigned children and adults with HbSC in Ghana to 12 months of hydroxyurea or placebo. The primary end point was hematologic dose-limiting toxicities (DLTs), including cytopenias or elevated hemoglobin levels during 12 months of blinded treatment. Clinical end points included vaso-occlusive pain events, acute chest syndrome, hospitalizations, transfusions, and malaria. Quality-of-life measures, organ function assessments, and rheological measurements were also collected., Results: Of the 243 enrolled patients (118 female), 212 eligible participants initiated blinded treatment at 20.0±5.0 mg/kg/day. DLTs occurred in more participants on hydroxyurea (33%) than the placebo (11%), with a difference of 22 percentage points (95% confidence interval [CI],11 to 34 percentage points), which exceeded the predefined 15 percentage point noninferiority margin. Elevated levels of hemoglobin occurred in 12 participants on hydroxyurea and 10 on the placebo. Hydroxyurea treatment was associated with 57.0 versus 149.6 vaso-occlusive pain events per 100 person-years (incidence rate ratio [IRR] 0.38; 95% CI, 0.28 to 0.52), and 12.9 versus 30.6 hospitalizations per 100 person-years (IRR 0.42; 95% CI, 0.22 to 0.81). A composite of acute sickle-related events occurred in 37 participants on hydroxyurea versus 69 participants on placebo (IRR 0.39; (95% CI, 0.26 to 0.59), a difference observed in both children and adults., Conclusions: The PIVOT trial did not meet its primary end point. Hydroxyurea at 20 mg/kg in patients with HbSC was associated with more hematologic DLTs than placebo, but most were mild and transient. Hydroxyurea was associated with less vaso-occlusive pain and fewer sickle-related events in both children and adults; a new trial will need to be done to establish the efficacy of this approach. (Funded by Theravia; Pan-African Clinical Trials Registry number, PACTR 202108893981080).