The authors regret that the description of the synthesis of bumepamine in the above-mentioned article lacked an important aspect and is therefore incorrect.The correct synthesis of bumepamine is given below. The authors would like to apologise for any inconvenience caused. Synthesis of bumepamineBumetanide (1) (500 mg, 1.37 mmol) was dissolved in 9 mL dry N, N-dimethylformamide and N,N-diisopropylethylamine (765 μL, 4.39 mmol), followed by addition of aniline (250 μL, 2.74 mmol). The mixture was cooled on an ice-bath. COMU (707 mg, 1.65 mmol) was added in one portion and the mixture was gradually warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated aqueous NaHCO 3 solution and extracted twice with ethyl acetate (EtOAc). The combined organic layers were washed with water, brine and dried over Na 2 SO 4 . The crude product was purified by column chromatography (toluene:EtOAc:Et 3 N, 3:2:0.01). The desired product (2; the phenylamide of bumetanide) (540 mg, 1.22 mmol) was obtained in 89% yield as a slightly yellow solid. 1 H NMR (400 MHz, d 4 -MeOH) δ 7.79 (d, J = 2.1 Hz, 1H), 7.68-7.71 (m, 2H), 7.50 (d, J = 2.1 Hz, 1H), 7.36-7.40 (m, 2H), 7.28-7.32 (m, 2H), 7.14-7.19 (m, 1H), 7.05-7.09 (m, 1H), 6.93-6.96 (m, 2H), 3.17 (t, J = 6.7 Hz, 2H), 1.40-1.48 (m, 2H), 1.13-1.21 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz) d 4 -calculated for C 23 H 26 N 3 O 4 S [M+H] + 440.1644, found 440.1646.Next, the phenylamide of bumetanide (2) (250 mg, 0.57 mmol) was dissolved in 12 mL tetrahydrofuran and borane dimethylsulfide complex (90 μL, 0.95 mmol) was added at room temperature. The reaction mixture was stirred for 16 h at 70°C and cooled to room temperature. Since some starting material was still present, an additional amount of the borane dimethylsulfide complex (90 μL, 0.95 mmol) was added and the reaction was stirred for 5 h at 70°C. The reaction mixture was cooled to room temperature and then quenched with half-saturated aqueous NaHCO 3 solution. The mixture was extracted three times with EtOAc and the combined organic layers were dried over Na 2 SO 4 . The crude product was purified by column chromatography (CH 2 Cl 2 :MeOH, 50:1). The obtained oily substance was dried under vacuum for 4 hours and then dissolved in 10 mL dry diethyl ether (Et 2 O). 2M HCl in Et 2 O (135 μL, 0.27 mmol) was added and the flask left to stand for 10 minutes. The salt that was formed was filtered, washed three times with Et 2 O and the desired product (3; bumepamine) (90 mg, 0.21 mmol) was obtained as a slightly beige solid in 37% yield. 1 H NMR (400 MHz, d 4 -MeOH) δ 7.52-7.60 (m, 3H), 7.44-7.46 (m, 2H), 7.33 (d, J = 2.0 Hz, 1H), 7.68-7.30 (m, 2H), 7.04-7.08 (m, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.86-6.89 (m, 2H), 4.64 (s, 2H), 3.00 (t, J = 6.8 Hz, 2H), 1.29-1.37 (m, 2H), 1.06-1.15 (m, 2H), 0.80 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz) d 4 -
ObjectivesThe loop diuretic bumetanide has been proposed previously as an adjunct treatment for neonatal seizures because bumetanide is thought to potentiate the action of γ‐aminobutyric acid (GABA)ergic drugs such as phenobarbital by preventing abnormal intracellular accumulation of chloride and the subsequent "GABA shift." However, a clinical trial in neonates failed to demonstrate such a synergistic effect of bumetanide, most likely because this drug only poorly penetrates into the brain. This prompted us to develop lipophilic prodrugs of bumetanide, such as the N,N‐dimethylaminoethyl ester of bumetanide (DIMAEB), which rapidly enter the brain where they are hydrolyzed by esterases to the parent compound, as demonstrated previously by us in adult rodents. However, it is not known whether esterase activity in neonates is sufficient to hydrolyze ester prodrugs such as DIMAEB.MethodsIn the present study, we examined whether esterases in neonatal serum of healthy term infants are capable of hydrolyzing DIMAEB to bumetanide and whether this activity is different from the serum of adults. Furthermore, to extrapolate the findings to brain tissue, we performed experiments with brain tissue and serum of neonatal and adult rats.ResultsSerum from 1‐ to 2‐day‐old infants was capable of hydrolyzing DIMAEB to bumetanide at a rate similar to that of serum from adult individuals. Similarly, serum and brain tissue of neonatal rats rapidly hydrolyzed DIMAEB to bumetanide.SignificanceThese data provide a prerequisite for further evaluating the potential of bumetanide prodrugs as add‐on therapy to phenobarbital and other antiseizure drugs as a new strategy for improving pharmacotherapy of neonatal seizures.
Niemann-Pick disease type C1 (NPC1) is a rare genetic cholesterol storage disorder caused by mutations in the NPC1 gene. Mutations in this transmembrane late endosome protein lead to loss of normal cholesterol efflux from late endosomes and lysosomes. It has been shown that broad spectrum histone deacetylase inhibitors (HDACi's) such as Vorinostat correct the cholesterol accumulation phenotype in the majority of NPC1 mutants tested in cultured cells. In order to determine the optimal specificity for HDACi correction of the mutant NPC1s, we screened 76 HDACi's of varying specificity. We tested the ability of these HDACi's to correct the excess accumulation of cholesterol in patient fibroblast cells that homozygously express NPC1 I1061T , the most common mutation. We determined that inhibition of HDACs 1, 2, and 3 is important for correcting the defect, and combined inhibition of all three is needed to achieve the greatest effect, suggesting a need for multiple effects of the HDACi treatments. Identifying the specific HDACs involved in the process of regulating cholesterol trafficking in NPC1 will help to focus the search for more specific druggable targets.
The synthesis of β-lactams, tetracyclines, and erythromycins as three of the major families of antibiotics will be described herein. We will describe why these antibiotics were the ultimate synthetic targets in the past and how modern synthetic organic chemistry has evolved to address these challenges with new, improved strategies and methods. An additional aspect we would like to highlight here is the fact that these first syntheses had to be particularly creative as most of the modern synthetic methods were not available at that time, or were developed in the course of these syntheses.
This work describes synthesis of CH 2-skipped alternating piperazine-pyridine cycles with azide end-group starting from piperazine, 1-methylpiperazine and pyridine-2,6-dicarboxylic acid. This compound can be used to enhance binding efficiency by shielding repulsion between negatively charged phosphate groups in DNA-oligonucleotide hybridization techniques. Piperazine derivatives are useful in the treatment or prevention of many diseases like inflammation, 1 bone degradation, 2 thrombosis 3 and tumor metastasis. 4 On the other hand oligomeric piperazine compounds could be source of potential positive charge which is important factor in interactions of small molecules with biological systems. Subsequent functionality and reactivity offer a good possibility to regulate hydrophilicity/hydrophobicity, geometry, π-interaction and as a result design the appropriate molecule for certain purposes.
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