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The total synthesis of the natural (8E,15E,22E)-heptatriaconta-8,15,22-trien-2-one and (15E,22E)-heptatriaconta-15,22-dien-2-one is reported. Our synthesis involved a modular and convergent approach, based on the copper-catalyzed addition of Grignard reagents to allylic olefins. The obtention of these methyl ketones is an important asset for the use of these compounds as analytical patterns with application in Earth sciences., We gratefully acknowledge the Geochemistry and Pollution Research Group from the Institute of Environmental Assessment and Water Research (IDAEA-CSIC) and CSIC (201980E011) for financial support.

Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the basis of previous results, in silico drug discovery screening was used to identify a new family of lysosome-/mitochondria-targeting compounds. These novel tetracyclic hits, with a cationic amphiphilic structure, specifically eradicate leukemic cells by inducing both mitochondrial damage and apoptosis, and simultaneous lysosomal membrane leakiness. Lysosomal leakiness does not only elicit canonical lysosome-dependent cell death, but also activates the terminal differentiation of AML cells through the Ca2+-TFEB-MYC signaling axis. In addition to being an effective monotherapy, its combination with the chemotherapeutic arsenic trioxide (ATO) used in other types of leukemia is highly synergistic in AML cells, widening the therapeutic window of the treatment. Moreover, the compounds are effective in a wide panel of cancer cell lines and possess adequate pharmacological properties rendering them promising drug candidates for the treatment of AML and other neoplasias., This work was funded by AGAUR-Producte (R.M.R), Caixaimpulse Program (R.M.R), the Josep Carreras International Leukaemia Foundation (R.M.R), l’Obra Social “La Caixa”-Fundació Bancària “La Caixa” (R.M.R), CERCA Programme/Generalitat de Catalunya (IJC) and Fundació Marató TV3 (grant number: 201930-30)

The (poly)pharmacology of drug metabolites is seldom comprehensively characterized in drug discovery and development. However, some drug metabolites can reach high plasma concentrations and display relevant in vivo activity, which can be distinct from its parent drug. Here, we use computational and experimental methods to comprehensively characterise the kinase polypharmacology of M324, the major metabolite of the FDA-approved PARP inhibitor rucaparib. We experimentally demonstrate that M324 displays a distinct in vitro kinome profile from its parent drug, characterized by potent in vitro inhibition of GSK3A and PLK2 at clinically-relevant concentrations. These confirmed kinase activities of M324 could have potential implications for the efficacy and safety of rucaparib and therefore warrant further clinical investigation. The study reported here highlights the importance of thoroughly characterizing the activity of significant drug metabolites to better understanding drug responses in the clinic and maximally exploit the current drug arsenal in personalized and precision medicine.

IntroductionObservational studies have shown gastric bypass to be superior to sleeve gastrectomy in terms of low-density lipoprotein (LDL) cholesterol improvement. If these results are confirmed in randomised controlled trials, presurgical LDL cholesterol status could be a relevant factor in surgical procedure election. Furthermore, it is also necessary to establish the mechanisms by which LDL cholesterol improves after surgery and whether qualitative and quantitative changes occur in the different lipoprotein subclasses. The first objective is to ascertain whether high LDL cholesterol levels before surgery can be considered an additional factor when selecting the most appropriate surgical procedure for each patient (gastric bypass or sleeve gastrectomy). Hence, the 1-year remission rates of high LDL cholesterol after gastric bypass and sleeve gastrectomy in patients with morbid obesity will be compared. Secondary objectives were (1) to compare changes in other lipoproteins and LDL composition and (2) to study the pathophysiologic mechanisms related to LDL cholesterol remission.Methods and analysisA randomised clinical trial, with intention-to-treat analysis, will be conducted to compare LDL cholesterol remission between gastric bypass and sleeve gastrectomy, with a 12-month follow-up. Inclusion criteria will be patients between 18 and 60 years of age with body mass index ≥40 kg/m2or ≥35 kg/m2with significant obesity-related comorbidity and high LDL cholesterol levels. Patients will be evaluated preoperatively and at 3, 6 and 12 months after bariatric surgery. Examinations will include routine blood chemistry, anthropometric measurements, food intake recall, physical activity questionnaires and serum samples for lipidomic and lipoprotein characterisation.Ethics and disseminationEthics approval has been granted by the Parc de Salut Mar Ethics Committee (2019/8471/I). The study and its conclusions regarding the primary and secondary objectives will be presented as manuscripts submitted for peer-reviewed journal publication.Trial registration numberNCT03975478.

Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium.

A general method for the selective cleavage of tert-butyldimethylsilyl ethers in the presence of tert-butyldiphenylsilyl ones has been established using a combination of H2O and a concentrated solution of LiCl in DMF at 90 °C. Since no acids, bases, reducing or oxidizing agents are used, the method seems to be very appropiate for the deprotection of TBDMS ethers in the presence of other sensitive functional groups.

A stable sulfate derivative of N -nitrouridine has been obtained for the first time; it shows synthetic advantages in relation to its α-epoxide counterpart. A new iodide-mediated denitration reaction is reported.

A stable sulfate derivative of N -nitrouridine has been obtained for the first time; it shows synthetic advantages in relation to its α-epoxide counterpart. A new iodide-mediated denitration reaction is reported.

High-performance liquid chromatography (HPLC) and micellar electrokinetic capillary chromatography (MECC) methods for the determination of different pesticides mixtures have been developed. These mixtures include triazine, phenylurea, phenoxyalkyl acid, carbamate and organophosphorous pesticides that have been selected because their use in different combinations in commercial formulations. The best results have been obtained by using mobile phase gradients in HPLC and by working with n-alcohols as mobile phase modifiers in MECC. When the quality parameters of both methods have been compared, it was observed that they are not sensitive enough for environmental analysis. In this sense two different concentration methodologies, off-line solid extraction by using Carbopack columns and a special injection MECC method, have been studied to enhance sensitivity. Off-line solid extraction can be used for both HPLC and MECC methodologies and permits to detect low ppb levels of individual pesticides. Special injection methods applied to the MECC system provides a 200-fold sensitivity improvement for the ionic pesticides.

Triflation of N 3 -protected uridines ( N COPh, N CHCHCOOMe, N NO 2 ) has been investigates. A stable 2′- O -triflyl derivative, that of N -nitro-3′,5′- O -(tetraisopropyldisiloxane-1,3-diyl)uridine, has been isolated for the first time; by contrast to its congeners, it does not give cyclonicleoside-like intermediates. Nucleophilic attacks on this substrate lead to 2′s-substituted nucleosides rather than the usual 2′α epimers. 3′- O -Triflyl N -nitro derivatives behave similarly. Several novel nucleosides ( lyxo dihalo derivatives, 2′,3′-α-epoxy derivatives) are accessible by means of this approach.