Carbon–carbon bond formation is the key reaction for organic synthesis to construct the carbon framework of organic molecules. The review gives a selection of biocatalytic C–C-bond-forming reactions ...which have been investigated during the last 5 years and which have already been proven to be applicable for organic synthesis. In most cases, the reactions lead to products functionalized at the site of C–C-bond formation (e.g., α-hydroxy ketones, aminoalcohols, diols, 1,4-diketones, etc.) or allow to decorate aromatic and heteroaromatic molecules. Furthermore, examples for cyclization of (non)natural precursors leading to saturated carbocycles are given as well as the stereoselective cyclopropanation of olefins affording cyclopropanes. Although many tools are already available, recent research also makes it clear that nature provides an even broader set of enzymes to perform specific C–C coupling reactions. The possibilities are without limit; however, a big library of variants for different types of reactions is required to have the specific enzyme for a desired specific (stereoselective) reaction at hand.
Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic ...analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification.
In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 μg per kilogram of body weight (8 patients in cohort 1), 7.5 μg per kilogram (8 patients in cohort 2), 15.0 μg per kilogram (10 patients in cohort 3), or 30.0 μg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 μg per kilogram and then to 15.0 μg per kilogram, and in cohort 2, the dose was increased to 15.0 μg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months.
During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 μg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 μg per kilogram for up to 42 months.
In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).
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•A spiropyran dimer was prepared in situ through a CC coupling.•The dimerization of spiropyran was demonstrated to be induced electrochemically or Fe3+ ions.•The spiropyran and its ...dimer were observed to form a complex with Fe3+ ions.•The influence of light visible light on reversible capture or release of Fe3+ was demonstrated.•The paper-based device assisted by a smartphone was used to demonstrate the capture and release of Fe3+ ions.
A photoresponsive spiropyran derivative was synthesized and evaluated for redox and light-responsive behavior. The response of the spiropyran derivative was also investigated towards metal ions using techniques like UV–vis, digital colorimetry, and cyclic voltammetry (CV). Photochromic spiropyran displayed redox responsive behavior, which was influenced by UV and Visible lights. Redox responsive spiropyran selectively interacted with Fe3+ ions, which was exploited to demonstrate alteration in the cyclic voltammetric (CV) signal in the Fe3+ ion complex. The probe was further used as a light-controlled reversible tool for the detection of Fe3+ ions. CV studies under light irradiation indicated that the visible light (450 nm and 532 nm) exposure led to a change in the current (Ip,c &Ip,a) for the probe and probe-Fe3+ complex. However, the reversibility was witnessed in the voltammogram when solutions were exposed to 450 nm visible light. Digital colorimetry in solution and on a paper-based device aided by a smartphone was successfully used to perceive ferric ions with the help of spiropyran. The reuse of the probe on a paper-based device was demonstrated in water through digital mode assisted by a smartphone with the aid of 450 nm light.
Upon reaction with Pd(PPh3)2Cl2 benzaldehyde thiosemicarbazone undergoes a geometrical change around the imine bond and affords a mixed-ligand complex 1, incorporating an NS-coordinated ...thiosemicarbazone, a triphenylphosphine and a chloride. Similar reactions with benzophenone thiosemicarbazone and acetophenone thiosemicarbazone proceed without any geometrical change to afford complexes 2 and 3 respectively, containing a CNS-coordinated thiosemicarbazone and a triphenylphosphine. Crystal structures of complexes 1, 2 and 3 have been determined. All the complexes display intense absorptions in the visible region. Catalytic activity of complexes 1, 2 and 3 toward Suzuki type C–C coupling reactions has been examined, and all three are found to efficiently activate all types of C–X bonds (X = I, Br, Cl and even F) and bring about the C–C bond formation with high yield. These complexes are also found to catalyze C–N coupling reactions between aryl halides and primary or secondary amines. While all three complexes are found to be efficient catalysts for both C–C and C–N coupling reactions, complex 2 is found to be a better catalyst than the other two complexes.
Display omitted Benzaldehyde thiosemicarbazone undergoes a geometrical change around the imine bond during its reaction with Pd(PPh3)2Cl2 and affords complex 1. Substitution of the azomethine proton by phenyl or methyl group prevents the geometrical change and affords complexes 2 and 3 respectively. All the complexes efficiently catalyze C–C and C–N coupling reactions.
► Benzaldehyde thiosemicarbazone undergoes geometrical change upon reaction with Pd. ► Replacement of azomethine proton by Me or Ph prevents the geometrical change. ► Pd mediated C–H activation takes place with the modified thiosemicarbazones. ► The Pd complexes efficiently catalyze both C–C and C–N coupling reactions.
The objective of this review is to consider how existing human immunodeficiency virus (HIV) infrastructure may be leveraged to inform and improve hepatitis C virus (HCV) treatment efforts in the ...HIV-HCV coinfected population. Current gaps in HCV care relevant to the care continuum are reviewed. Successes in HIV treatment are then applied to the HCV treatment model for coinfected patients. Finally, the authors give examples of HCV treatment strategies for coinfected patients in both domestic and international settings.
A palladium‐catalyzed direct C‐arylation reaction of readily available cage carboranyllithium reagents with aryl halides has been developed for the first time. This method is applicable to a wide ...range of aryl halide substrates including aryl iodides, aryl bromides, and heteroaromatic halides.
Palladium‐catalyzed direct C‐arylation of readily available cage carboranyllithium reagents with aryl halides has been developed for the first time. This method is applicable to a wide range of aryl halide substrates including aryl iodides, aryl bromides, and heteroaromatic halides.
Activated B-cell-like (ABC) and germinal center B-cell-like diffuse large B-cell lymphoma (DLBCL) represent the 2 major molecular DLBCL subtypes. They are characterized by differences in clinical ...course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these 2 subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) α/δ (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor κB signaling, prompting us to combine AZD8835 with the Bruton's tyrosine kinase inhibitor ibrutinib. This combination was synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively, our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.
•PI3Kα/δ inhibition induces cytotoxicity in ABC DLBCLs through downregulation of NF-κB signaling.•Inhibition of AKT induces cytotoxicity by downregulation of MYC in PTEN-deficient DLBCL models in vivo and in vitro.
Despite the remarkable advances in HCV treatment brought about by the advent of direct-acting antivirals, HCV remains a global public health concern. One particular concern relates to the rising ...prevalence of HCV in women of childbearing age. Active HCV during pregnancy is associated with cholestasis of pregnancy as well as the risk of mother-to-child transmission. Guidelines are increasingly recommending universal screening during pregnancy, while the treatment of HCV during pregnancy is an area of ongoing research.
We conducted an adaptive design single‐center pilot trial between October 2017 and November 2018 to determine the safety and efficacy of ultra‐short‐term perioperative pangenotypic direct acting ...antiviral (DAA) prophylaxis for deceased hepatitis C virus (HCV)‐nucleic acid test (NAT) positive donors to HCV negative kidney recipients (D+/R−). In Group 1, 10 patients received one dose of SOF/VEL (sofusbuvir/velpatasvir) pretransplant and one dose on posttransplant Day 1. In Group 2A (N = 15) and the posttrial validation (Group 2B; N = 25) phase, patients received two additional SOF/VEL doses (total 4) on Days 2 and 3 posttransplant. Development of posttransplant HCV transmission triggered 12‐week DAA therapy. For available donor samples (N = 27), median donor viral load was 1.37E + 06 IU/mL (genotype GT1a: 70%; GT2: 7%; GT3: 23%). Overall viral transmission rate was 12% (6/50; Group 1:30% 3/10; Group 2A:13% 2/15; Group 2B:4% 1/25). For the 6 viremic patients, 5 (83%) achieved sustained virologic response (3 with first‐line DAA therapy; and two after retreatment with second‐line DAA). At a median follow‐up of 8 months posttransplant, overall patient and allograft survivals were 98%, respectively. The 4‐day strategy reduced viral transmission to 7.5% (3/40; 95% confidence interval CI: 1.8%‐20.5%) and could result in avoidance of prolonged posttransplant DAA therapy for most D+/R − transplants.
This single‐center, open‐label clinical kidney transplant trial provides early evidence that it might be feasible to use ultra‐short direct‐acting antiviral drug preoperative prophylaxis to prevent hepatitis C transmission from infected donors to uninfected recipients, though emergence of resistant viral strains in some patients might pose a problem. Terrault and Sher’s editorial is on page 627.
The aspartate aminotransferase‐to‐platelet ratio index (APRI), a tool with limited expense and widespread availability, is a promising noninvasive alternative to liver biopsy for detecting hepatic ...fibrosis. The objective of this study was to update the 2007 meta‐analysis to systematically assess the accuracy of APRI in predicting significant fibrosis, severe fibrosis, and cirrhosis stage in hepatitis C virus (HCV) monoinfected and HCV / human immunodeficiency virus (HIV) coinfected individuals. Studies comparing APRI versus biopsy in HCV patients were identified via a thorough literature search. Areas under summary receiver operating characteristic curves (AUROC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were used to examine the APRI accuracy for the diagnosis of significant fibrosis, severe fibrosis, and cirrhosis. Heterogeneity was explored using meta‐regression. Twenty‐one additional studies were eligible for the update and, in total, 40 studies were included in this review (n = 8,739). The summary AUROC of the APRI for the diagnosis of significant fibrosis, severe fibrosis, and cirrhosis were 0.77, 0.80, and 0.83, respectively. For significant fibrosis, an APRI threshold of 0.7 was 77% sensitive and 72% specific. For severe fibrosis, a threshold of 1.0 was 61% sensitive and 64% specific. For cirrhosis, a threshold of 1.0 was 76% sensitive and 72% specific. Moreover, we found that the APRI was less accurate for the identification of significant fibrosis, severe fibrosis, and cirrhosis in HIV/HCV coinfected patients. Conclusion: Our large meta‐analysis suggests that APRI can identify hepatitis C‐related fibrosis with a moderate degree of accuracy. Application of this index may decrease the need for staging liver biopsy specimens among chronic hepatitis C patients. (HEPATOLOGY 2011)
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