Microwave-assisted generation and reactivity of aza- and diazafulvenium methides: heterocycles via pericyclic reactions

Azafulvenium methides and diazafulvenium methides have been generated under microwave irradiation from 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazoles and 2,2-dioxo-1H,3H-pyrazolo[1,5-c]thiazoles, respectively. Pericyclic reactions of these 1,7-dipole intermediates, namely, sigmatropic [1,8]H shifts, 1,7-electrocyclization or [8[pi]+2[pi]] cycloaddition led to the synthesis of a range of pyrrole and pyrazole derivatives. The first evidence for the azafulvenium methides by intermolecular trapping via [8[pi]+2[pi]] cycloaddition is reported.http://www.sciencedirect.com/science/article/B6THS-4SP3SM3-6/1/d6303d9db78919cfe9cd796c1a17d44

Ethyl 7-Acetyl-8a-methyl-3-(1-phenyl-1H-tetrazol-5-yl)-1,4,4a,5,6,8a-hexahydro-7H-pyrano[2,3-c]pyridazine-1-carboxylate

The Diels–Alder reaction of ethyl 3-(1-phenyl-1H-tetrazol-5-yl-1,2-diaza-1,3-butadiene-1-carboxylate with 2-acetyl-6-methyl-2,3-dihydro-4H-pyran (methyl vinyl ketone dimer) regioselectively afforded the corresponding 3-(tetrazol-5-yl)-hexahydro-7H-pyrano[2,3-c]pyridazine in quantitative yield. An X-ray crystal structure of this cycloadduct is reported.info:eu-repo/semantics/publishedVersio

New chemistry of diazafulvenium methides: one way to pyrazoles

Diazafulvenium methides generated from the solution pyrolysis of pyrazolo[1,5-c][1,3]thiazole-2,2-dioxides participate in [8[pi]+2[pi]] cycloadditions giving pyrazolo[1,5-a]pyridine derivatives. 1-Methyl-diazafulvenium, generated under flash vacuum pyrolysis reaction conditions, undergoes an intramolecular sigmatropic [1,8]H shift giving 1-vinyl-1H-pyrazoles.http://www.sciencedirect.com/science/article/B6THS-4HR7298-7/1/af0dd8d679e7977f53bc0d4af9a5b68

Synthesis and reactivity of 2-halo-2H-azirines towards nucleophiles

Nucleophilic substitution reactions of 2-halo-2H-azirine with potassium phthalimide and aniline allowed the preparation of new substituted 2H-azirines. The reactions of 2-bromo-3-phenyl-2H-azirine-2-carboxylate with methylamine led to the synthesis of [alpha]-diimines and from the reaction with water, a 3-oxazoline was obtained.http://www.sciencedirect.com/science/article/B6THS-4152YMR-K/1/e94005b66b66b6820ad27458f2562ed

A selective p53 activator and anticancer agent to improve colorectal cancer therapy

Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and in vitro and in vivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.We thank PT national funds (FCT/MCTES, Fundação para a Ciência e a Tecnologia, and Ministério da Ciência, Tecnologia e Ensino Superior) through grants UIDB/50006/2020, UID/BIO/04469/2019, UIDB/04539/2020, and UIDP/04539/2020 (CIBB); BioTecNorte operation (NORTE-01-0145-FEDER000004) and Porto Neurosciences and Neurologic Disease Research Initiative at I3S (Norte-01-0145-FEDER-000008) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte; Masaryk University (Project MUNI/A/1127/2019) and Ministry of Education, Youth and Sports of the Czech Republic (project nos. LQ1605 and LM2018125); FCT financial support through the fellowships SFRH/BD/119144/2016 (H.R.) and SFRH/BD/117949/2016 (L.R.); Fondazione AIRC (IG#18985, A.I.); and the Programa Operacional Potencial Humano (POCH), specifically the BiotechHealth Programme (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences, PD/00016/2012). We thank Dario Rizzotto for assistance in preparing the libraries for RNA sequencing. Funding: This work was supported by PT National Funds (FCT/MCTES, Fundação para a Ciência e Tecnologia, and Ministério da Ciência, Tecnologia e Ensino Superior) via the projects UIDB/50006/2020 (LAQV/REQUIMTE), UIDB/00313/2020, and UIDP/00313/2020, co-funded by COMPETE2020-UE.info:eu-repo/semantics/publishedVersio

Global Women’s Breakfast (GWB): #UnidaspelaQuímica

Global Women’s Breakfast (GWB): #BoundbyChemistry. Global Women’s Breakfast is an initiative of the International Union of Pure and Applied Chemistry, aiming to give women scientists, from all over the world, the opportunity to know each other, communicating virtually and sharing their experiences. Many countries joined this initiative and Portugal was not an exception, with its participation already at the first Networking Breakfast in 2011, celebrating the year of the centenaries of Marie Curie Nobel Prize in Chemistry, the Portuguese Chemical Society and the Faculdade de Ciências da Universidade de Lisboa as well. The success of these networking breakfasts, involving students, young researchers, and scientists, encouraged its further organization in Portugal, annually since 2019. This article describes the interventions of Portuguese women scientists, coming from Institutions throughout Portugal, in the Global Women’s Breakfast as partners in their mission as scientists, creative and open to international collaborations. Global Women's Breakfast é uma iniciativa criada pela International Union of Pure and Applied Chemistry para dar oportunidade às mulheres cientistas de todo o mundo de se conhecerem, comunicando virtualmente e compartilhando as suas experiências. A adesão dos países foi muito elevada e Portugal não foi exceção, participando já no primeiro Networking Breakfast em 2011, Ano Internacional da Química, no qual se celebraram os centenários do Prémio Nobel da Química a Marie Curie, da Sociedade Portuguesa de Química e da Faculdade de Ciências da Universidade de Lisboa. O sucesso destes pequenos-almoços em rede, que envolvem estudantes, jovens investigadoras e cientistas, encorajou a continuação da participação de Portugal anualmente, desde 2019. Este artigo descreve a intervenção de mulheres cientistas portuguesas, pertencentes a instituições de Norte a Sul do país, no Global Women’s Breakfast, cúmplices na sua missão de cientistas, criativas e abertas à colaboração internacional

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Conjugated Azomethine Ylides

The 1,3-dipolar cycloaddition of azomethine ylides is an efficient and versatile tool for the construction of five-membered nitrogen-heterocycles. When the azomethine ylide is conjugated with a double bond or a 1,3-diene moiety, other reactivity pathways are also available, namely 1,5-electrocyclization or 1,7-electrocyclization. The present review is focused on the generation and reactivity of this type of dipoles, which offer general strategies for the formation of five- and seven-membered nitrogen-heterocyclic compounds. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006

Diels−Alder Reactions of Acyclic 2-Azadienes: A Semiempirical Molecular Orbital Study

Molecular orbital calculations (AM1) have been performed to obtain the frontier orbitals' (HOMO and LUMO) energies and polarization of a series of acyclic 2-azadienes. The results are used to rationalize the reactivity of the compounds studied with both electron-rich and electron-deficient dienophiles as well as the observed regioselectivity of the corresponding Diels−Alder reactions

Meso-Substituted Corroles from Nitrosoalkenes and Dipyrromethanes

The synthesis of bilanes and hexapyrroles containing an oxime functionality, prepared by two and three consecutive hetero-Diels-Alder reactions (or conjugated additions) between nitrosoalkenes and dipyrromethanes, is described. Bilanes underwent oxidative macrocyclization to afford a new class of trans-A2B-corroles. Porphyrins could also be obtained by reacting bilanes with aldehydes in the presence of trifluoroacetic acid, followed by an oxidative step