This nationwide multicentre study analysed the epidemiology of bacterial, viral and fungal infections in paediatric haematopoietic stem cell transplantation (HSCT) and paediatric haematology and ...oncology (PHO) patients over a period of 24 consecutive months, including incidence, hazard risk and outcome of infections as well as occurrence of multidrug-resistant bacteria. During this period, 308 HSCTs were performed and 1768 children were newly diagnosed for malignancy. Compared to PHO, the risk in HSCT patients was significantly higher for all infections (hazard ratio (HR) 2.7), bacterial (HR 1.4), fungal (HR 3.5) and viral (HR 15.7) infections. The risk was higher in allo- than auto-HSCT for bacterial (HR 1.4), fungal (HR 3.2) and viral (HR 17.7) infections. The incidence of resistant bacteria was higher in HSCT than in PHO patients for both G-negative (72.5% vs. 59.2%) and G-positive (41.4% vs. 20.5%) strains. Cumulative incidence of bacterial, fungal and viral infections in HSCT patients was 33.9, 22.8 and 38.3%, respectively. Cumulative incidence of viral infections in allo-HSCT was 28.0% for cytomegalovirus, 18.5% for BK virus, 15.5% for Epstein-Barr virus, 9.5% for adenovirus, 2.6% for varicella zoster virus, 0.9% for influenza, 0.9% for human herpesvirus 6 and 0.3% for hepatitis B virus. Survival rates from infections were lower in HSCT than in PHO patients in bacterial (96.0 vs. 98.2%), fungal (75.5 vs. 94.6%) and most viral infections. In conclusion, the risk of any infections and the occurrence of resistant bacterial strains in allo-HSCT patients were higher than in auto-HSCT and PHO patients, while the outcome of infections was better in the PHO setting.
A newly designed synthetic entry to the C1-C27 domain of okadaic acid has been developed. This incorporates substantial improvements in the preparations of the key okadaic acid building blocks ...representing the C3-C8, C9-C14, and C16-C27 portions. The synthesis of the C3-C8 lactone used (R)-glycidol as the origin of the C4 stereogenic center and featured a late-stage optional incorporation of the C7 hydroxyl group. The complementary C9-C14 fragment was synthesized in a concise route from (R)-3-tert-butyldimethylsilyloxy-2-methylpropanal and propargyl bromide. Assembly of the C3-C14 spiroketal-containing intermediate from the constitutent fragments revealed a dramatic effect of C7 functionalization upon spiroketalization efficiency. In contrast, both (9E)- and (9Z)-enones converged readily to the C8 spiroketal upon treatment with acid. Modifications to the central C16-C27 fragment of okadaic acid included the early replacement of benzylic protecting groups by more suitable functionalities to facilitate both the generation of the C15-C27 intermediate and the deprotection of the final products. These modular building blocks were deployed for the synthesis of the C1-C27 scaffold of 7-deoxyokadaic acid. This work demonstrates improvements in the formation of versatile okadaic acid intermediates, as well as a reordering of fragment couplings. This alternative order of coupling was designed to promote the late stage incorporation of nonnatural lipophilic extensions from the C27 terminus.
Fruit temperature is a key parameter for fruit growth and quality which is affected by climate, plant vigorousity, solar exposure and fruit thermal properties. In the present study, the variability ...in temperature dynamics of Styrian oil pumpkin fruits and selected interspecific hybrids involving Cucurbita argyrosperma, C. moschata, C. pepo was analysed in two different periods of hot weather. The temperatures were measured with thermistors on (a) attached fruits, (b) detached fruits exposed to the sun and (c) artificially black coloured fruits. The highest average temperatures were determined in the Styrian oil pumpkin, whereas the lowest temperatures were determined in genotypes with lighter fruit exteriors suggesting that those are less sensitive to heat stress conditions and may represent a good option for the improvements of adaptability to climatic changes. In order to combine lighter and harder pericarp, the most promising genotypes were crossed with wild Cucurbita okeechobeensis. The histological analysis showed that C. okeechobeensis was a good source of genes for obtaining a thicker sclerenchymatic layer within pericarp.
An Efficient Total Synthesis of Okadaic Acid Forsyth, Craig J; Sabes, Steven F; Urbanek, Rebecca A
Journal of the American Chemical Society,
09/1997, Letnik:
119, Številka:
35
Journal Article
The development of an efficient and scalable synthetic route to prepare the selective D2 partial agonist (1) is described here. Regioselective nitration of tetrahydrobenzazepine 2, followed by ...reductive amination, hydrogenation, and oxidative cyclization afforded 1 in good yield, without the need of column chromatography.
The development of an efficient and scalable synthetic route to prepare the selective D2 partial agonist (1) is described here. Regioselective nitration of tetrahydrobenzazepine 2, followed by reductive amination, hydrogenation, and oxidative cyclization afforded 1 in good yield, without the need of column chromatography.
Described here are the full details of the preparation of a synthetic intermediate representing carbons 1−14 (C1−C14) of the marine natural product okadaic acid (1), the coupling of this fragment ...with the previously prepared C15−C38 domain, and the completion of an efficient total synthesis of 1. The C1−C14 intermediate was prepared in 11 steps and ∼20% overall yield from a functionalized δ-valerolactone derivative representing C3−C8 of 1. This featured a classic spiroketalization strategy to construct the highly substituted 1,7-dioxaspiro5.5undec-4-ene system, followed by incorporation of the intact C1−C2 α-hydroxyl, α-methyl carboxylate moiety using cis-(S)-lactate pivalidene enolate. The complete C1−C14 intermediate was converted into 1 in five additional steps. Coupling of the C1−C14 fragment with the C15−C38 domain of 1 via C14 aldehyde and C15 β-keto phosphonate moieties provided the complete carbon skeleton of 1 bearing a ketone at C16 and a mixed-methyl acetal at C19. Reduction of the C16 ketone using Corey's (S)-CBS/BH3 system and subsequent acid-triggered spiroketalization formed the central 1,6-dioxaspiro4.5decane ring system. Saponification of the C1−C2 pivalidene group and final reductive cleavage of the three benzyl ethers using lithium di-tert-butylbiphenylide in THF provided 1 in 48% yield from the C1−C14 aldehyde, and in 26 steps and ∼2% overall yield in the longest linear sequence from the C22−C27 synthon methyl 3-O-benzyl-α-d-altropyranoside.
Dopamine (D₂) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein ...we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D₂ partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D₂ partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model.
A convergent synthesis of the C15−C38 domain of the marine natural product okadaic acid is reported. This involved the preparation of intermediates representing the C16−C27 and C28−C38 portions of ...okadaic acid, their direct coupling, and elaboration to the complete C15−C38 intermediate. A C16−C27 intermediate bearing an aldehyde at C27 was constructed in 14-steps from methyl 3-O-benzyl-α-d-altropyranoside. A C28−C38 intermediate with a primary alkyl bromide at C28 was prepared in 10 steps from methyl (S)-3-hydroxy-2-methylpropionate. These fragments were then joined in ∼55% yield by conversion of the bromide into an alkylcerium reagent then addition to a sensitive β,γ-unsaturated C27 aldehyde to give a mixture of C27 carbinols (27R:27S = 2.5:1). The configuration at C27 of the major coupling product was inverted by a simple oxidation−reduction sequence to establish the 27S-configuration of okadaic acid. Elaboration into a C15 β-keto phosphonate completed the synthesis of the fully functionalized C15−C38 portion of okadaic acid in 19 linear steps and ∼3% overall yield from methyl 3-O-benzyl-α-d-altropyranoside.
Virtual screening was used to find replacements for aminoglycoside antibiotics that are able to block in vitro transcription and translation. A pseudoreceptor model retrieved potent vanilloid ...derivatives as sugar-mimics. These bioactive antibiotic agents were retrieved by a two-step virtual screening process. 'Fuzzy' pharmacophore models allowed for finding alternative chemotypes with lower structural complexity and greater synthetic accessibility than the query.
Okadaic acid is a potent inhibitor of select serine/threonine protein phosphatases. The importance of the C28–C38 hydrophobic domain of okadaic acid for inhibition of PP1 and PP2A was investigated. ...The hydrophobic domain is required but not sufficient for potent inhibition, and it also contributes to differential inhibition between PP1 and PP2A.
Okadaic acid is a potent inhibitor of select serine/threonine protein phosphatases. The importance of the C28–C38 hydrophobic domain of okadaic acid for inhibition of PP1 and PP2A was investigated. The hydrophobic domain is required but not sufficient for potent inhibition, and it also contributes to differential inhibition between PP1 and PP2A.
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