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•Improved Mizoroki–Heck cross coupling of tetrahydropyridines is reported.•The improved process allows the use of non-precious-metal additives.•The method enables a gram-scale ...synthesis of the drug substance preclamol.
Though a widely used metal-catalyzed cross-coupling process, the Mizoroki–Heck (MH) reaction can be a capricious transformation. This is particularly true for oxidation-prone alkene substrates containing ligating heteroatoms, as in the case of N-alkyl tetrahydropyridines, whose MH reactions have been underexplored due to the many side reactions that hamper the process. Since the products of tetrahydropyridine Heck reactions are direct precursors to potent pharmacophores, and therefore of commercial value, this is a significant drawback. We report here the results of our study designed to deliver an optimized, scalable MH procedure for N-alkyltetrahydropyridines and its exemplification in a gram-scale synthesis of the drug substance preclamol.
Heterocyclic architectures offer powerful creative possibilities to a range of chemistry end-users. This is particularly true of heterocycles containing a high proportion of sp
-carbon atoms, which ...confer precise spatial definition upon chemical probes, drug substances, chiral monomers and the like. Nonetheless, simple catalytic routes to new heterocyclic cores are infrequently reported, and methods making use of biomass-accessible starting materials are also rare. Here, we demonstrate a new method allowing rapid entry to spirocyclic bis-heterocycles, in which inexpensive iron(III) catalysts mediate a highly stereoselective C-C bond-forming cyclization cascade reaction using (2-halo)aryl ethers and amines constructed using feedstock chemicals readily available from plant sources. Fe(acac)
mediates the deiodinative cyclization of (2-halo)aryloxy furfuranyl ethers, followed by capture of the intermediate metal species by Grignard reagents, to deliver spirocycles containing two asymmetric centres. The reactions offer potential entry to key structural motifs present in bioactive natural products.
This report describes two methodology studies dedicated towards development of metal catalysed crosscoupling reactions in the synthesis of novel heterocyclic compounds. Firstly, a Heck-Mizoroki ...arylation reaction is reported for the direct functionalisation of tetrahydropyridines, towards the synthesis of kainoid analogues. Kainoids are a group of non-proteinogenic pyrrolidine dicarboxylic acids, which have attracted considerable interest because of their potent biological activity, including insecticidal, anthelmintic and neuroexcitatory properties. The ideal synthesis of kainoids would allow the ability to introduce various side chains at the C-4 position to access diverse pharmacologically active kainoid analogues. Tandem asymmetric Heck-Mizoroki arylation reaction and 2,3-sigmatropic rearrangement provides a quick and efficient way to access these molecules. The Heck-Mizoroki arylation of 1-methyl-1,2,5,6-tetrahydropyridine and its hydrochloride salt is reported, with the arylation in the 3- position of the tetrahydropyridine as the major product. The reaction has been applied to a variety of substituted aryliodides, with promising results, demonstrating functional group tolerance of the method, however isolation and purification of the resulting compounds has remained challengeing. Diarylation of tetrahydropyridines has also been achieved. Secondly, a new catalytic method for arylative spirocyclisation is reported, using stoichiometric Grignard reagents and iron(III) catalysts, to induce cyclisation of 2-iodo benzyl ethers of furan in a highly stereoselective manner to produce novel functionalised spirocyclic compounds. Method optimisation and application of a variety of Grignard reagents is reported with aryl cross-coupling achieved in high yields. Alkyl- cross coupling has also been achieved with ethylmagnesium bromide Grignard reagent.
This report describes two methodology studies dedicated towards development of metal catalysed crosscoupling reactions in the synthesis of novel heterocyclic compounds. Firstly, a Heck-Mizoroki ...arylation reaction is reported for the direct functionalisation of tetrahydropyridines, towards the synthesis of kainoid analogues. Kainoids are a group of non-proteinogenic pyrrolidine dicarboxylic acids, which have attracted considerable interest because of their potent biological activity, including insecticidal, anthelmintic and neuroexcitatory properties. The ideal synthesis of kainoids would allow the ability to introduce various side chains at the C-4 position to access diverse pharmacologically active kainoid analogues. Tandem asymmetric Heck-Mizoroki arylation reaction and 2,3-sigmatropic rearrangement provides a quick and efficient way to access these molecules. The Heck-Mizoroki arylation of 1-methyl-1,2,5,6-tetrahydropyridine and its hydrochloride salt is reported, with the arylation in the 3- position of the tetrahydropyridine as the major product. The reaction has been applied to a variety of substituted aryliodides, with promising results, demonstrating functional group tolerance of the method, however isolation and purification of the resulting compounds has remained challengeing. Diarylation of tetrahydropyridines has also been achieved. Secondly, a new catalytic method for arylative spirocyclisation is reported, using stoichiometric Grignard reagents and iron(III) catalysts, to induce cyclisation of 2-iodo benzyl ethers of furan in a highly stereoselective manner to produce novel functionalised spirocyclic compounds. Method optimisation and application of a variety of Grignard reagents is reported with aryl cross-coupling achieved in high yields. Alkyl- cross coupling has also been achieved with ethylmagnesium bromide Grignard reagent.
Cyclic AMP (cAMP)-specific phosphodiesterase-4 (PDE4) enzymes underpin compartmentalised cAMP signalling by localising to distinct signalling complexes. PDE4 long isoforms can be phosphorylated by ...mitogen-activated protein kinase-activated protein kinase 2 (MK2), which attenuates activation of such enzymes through their phosphorylation by protein kinase A. Here we show that MK2 interacts directly with PDE4 long isoforms and define the sites of interaction. One is a unique site that locates within the regulatory upstream conserved region 1 (UCR1) domain and contains a core Phe141, Leu142 and Tyr143 (FLY) cluster (PDE4A5 numbering). Located with the second site is a critical core Phe693, Glu694, Phe695 (FQF) motif that is also employed in the sequestering of PDE4 long forms by an array of other signalling proteins, including the signalling scaffold β-arrestin, the tyrosyl kinase Lyn, the SUMOylation E2 ligase UBC9, the dynein regulator Lis1 (PAFAH1B1) and the protein kinase Erk. We propose that the FQF motif lies at the heart of a multifunctional docking (MFD) site located within the PDE4 catalytic unit. It is clear from our data that, as well as aiding fidelity of interaction, the MFD site confers exclusivity of binding between PDE4 and a single specific partner protein from the cohort of signalling proteins whose interaction with PDE4 involves the FQF motif.
Infections such as group B Streptococcus (GBS) are an important cause of maternal sepsis, yet limited data on epidemiology exist. This article, the third of 11, estimates the incidence of maternal ...GBS disease worldwide.
We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature LILACS, World Health Organization Library Information System WHOLIS, and Scopus) and sought unpublished data on invasive GBS disease in women pregnant or within 42 days postpartum. We undertook meta-analyses to derive pooled estimates of the incidence of maternal GBS disease. We examined maternal and perinatal outcomes and GBS serotypes.
Fifteen studies and 1 unpublished dataset were identified, all from United Nations-defined developed regions. From a single study with pregnancies as the denominator, the incidence of maternal GBS disease was 0.38 (95% confidence interval CI, .28-.48) per 1000 pregnancies. From 3 studies reporting cases by the number of maternities (pregnancies resulting in live/still birth), the incidence was 0.23 (95% CI, .09-.37). Five studies reported serotypes, with Ia being the most common (31%). Most maternal GBS disease was detected at or after delivery.
Incidence data on maternal GBS disease in developing regions are lacking. In developed regions the incidence is low, as are the sequelae for the mother, but the risk to the fetus and newborn is substantial. The timing of GBS disease suggests that a maternal vaccine given in the late second or early third trimester of pregnancy would prevent most maternal cases.
Correspondence to Dr Chimsom T Oleka, Division of Pediatric and Adolescent Gynecology, Department of Obstetrics & Gynecology INOVA Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042, USA; ...chimsom.oleka@inova.org Female athlete health, performance, and well-being are best supported by a comprehensive team of medical providers and sports scientists that may include physicians from various specialties, allied health providers, exercise and sports scientists, mental health professionals, and dietitians. ...previous research and clinical investigation and management of AUB among non-pregnant women of reproductive age was hindered by inconsistently applied nomenclature and lack of standardised categorisation of potential etiologies.2–5 This ambiguity poses several problems, including the inability to homogeneously classify research participants experiencing AUB, difficulty comparing studies, and significantly undermining the investigative leverage of meta-analyses due to increased risk of inaccurate conclusions, as well as clinical implications (eg, ambiguous diagnoses, less precise clinical care and management and confusing communication across the medical team). ...the following general sources of bleeding were considered in the approved FIGO classification system: (1) primary disorders of the endometrium that most often manifest as disturbances of local endometrial haemostasis but may also include other entities such as altered vasculogenesis or local inflammatory response abnormalities; (2) endometrial polyps; (3) leiomyomas (fibroids); (4) adenomyosis; (5) disorders of ovulatory function; (6) systemic disorders of haemostasis known as coagulopathies; (7) malignant and premalignant conditions; (8) iatrogenic causes including gonadal steroid administration; (9) other local lesions or systemic conditions that may be rare causes of AUB (eg, arteriovenous malformations and myometrial hypertrophy) or those that can sometimes cause abnormal bleeding (eg, endometriosis). ...there are other causes of genital, urinary or gastrointestinal tract bleeding that do not originate from the uterus.6 It was envisioned that the most straightforward components of the classification system would be used in primary medical care, and subclassifications would be most relevant in specialist clinical and research settings.6 The classification system of AUB causes in the reproductive years is comprised of nine main categories that are arranged according to the acronym PALM-COEIN (pronounced ‘pahm-koin’): polyp; adenomyosis; leiomyoma; malignancy and hyperplasia (PALM); coagulopathy; ovulatory dysfunction; endometrial; iatrogenic and not otherwise classified (COEIN).
This sequential, prospective meta-analysis sought to identify risk factors among pregnant and postpartum women with COVID-19 for adverse outcomes related to disease severity, maternal morbidities, ...neonatal mortality and morbidity, and adverse birth outcomes.
We prospectively invited study investigators to join the sequential, prospective meta-analysis via professional research networks beginning in March 2020.
Eligible studies included those recruiting at least 25 consecutive cases of COVID-19 in pregnancy within a defined catchment area.
We included individual patient data from 21 participating studies. Data quality was assessed, and harmonized variables for risk factors and outcomes were constructed. Duplicate cases were removed. Pooled estimates for the absolute and relative risk of adverse outcomes comparing those with and without each risk factor were generated using a 2-stage meta-analysis.
We collected data from 33 countries and territories, including 21,977 cases of SARS-CoV-2 infection in pregnancy or postpartum. We found that women with comorbidities (preexisting diabetes mellitus, hypertension, cardiovascular disease) vs those without were at higher risk for COVID-19 severity and adverse pregnancy outcomes (fetal death, preterm birth, low birthweight). Participants with COVID-19 and HIV were 1.74 times (95% confidence interval, 1.12–2.71) more likely to be admitted to the intensive care unit. Pregnant women who were underweight before pregnancy were at higher risk of intensive care unit admission (relative risk, 5.53; 95% confidence interval, 2.27–13.44), ventilation (relative risk, 9.36; 95% confidence interval, 3.87–22.63), and pregnancy-related death (relative risk, 14.10; 95% confidence interval, 2.83–70.36). Prepregnancy obesity was also a risk factor for severe COVID-19 outcomes including intensive care unit admission (relative risk, 1.81; 95% confidence interval, 1.26–2.60), ventilation (relative risk, 2.05; 95% confidence interval, 1.20–3.51), any critical care (relative risk, 1.89; 95% confidence interval, 1.28–2.77), and pneumonia (relative risk, 1.66; 95% confidence interval, 1.18–2.33). Anemic pregnant women with COVID-19 also had increased risk of intensive care unit admission (relative risk, 1.63; 95% confidence interval, 1.25–2.11) and death (relative risk, 2.36; 95% confidence interval, 1.15–4.81).
We found that pregnant women with comorbidities including diabetes mellitus, hypertension, and cardiovascular disease were at increased risk for severe COVID-19–related outcomes, maternal morbidities, and adverse birth outcomes. We also identified several less commonly known risk factors, including HIV infection, prepregnancy underweight, and anemia. Although pregnant women are already considered a high-risk population, special priority for prevention and treatment should be given to pregnant women with these additional risk factors.
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