Natural Tetraponerines: A General Synthesis and Antiproliferative Activity

A stereocontrolled general methodology to access all natural tetraponerines from (+)-T1 to (+)-T8 is detailed. Two consecutive indium-mediated aminoallylations with the appropriate enantiomer of chiral N-tert-butylsulfinamide and a thermodynamic control at the aminal stereocenter allow the formation of each natural tetraponerine with excellent stereoselectivity. The use of 4-bromobutanal in the first aminoallylation leads to the formation of 5–6–5 tetraponerines, while 5-bromopentanal is required to build the scaffold of 6–6–5 tetraponerines. A cross-metathesis reaction of the second aminoallylation product with cis-3-hexene is used to elongate the side chain up to 5 carbons so as to prepare the tetraponerines T5 to T8. The anticancer activity of these heavier tetraponerines against four different carcinoma human cell lines is examined, observing a promising cytotoxic activity of (+)-T7 against breast carcinoma cell line MCF-7.We thank the Spanish Ministerio de Ciencia e Innovación for their financial support (CTQ2011-24165). I.B. acknowledges the Generalitat Valenciana for a predoctoral fellowship (ACIF/2011/159)

A unique Roman portrait from the forum of Florentia Iliberritana (Granada)

Se estudia un retrato romano descubierto en unas recientes excavaciones desarrolladas en la ciudad de Granada, en el barrio del Albaicín –c/ Gumiel, 6–; fue recuperado en un nivel de rellenos tardoantiguos que colmataban parte de una infraestructura abovedada que se relacionaría con las construcciones del foro de Florentia Iliberritana y que se localiza en un sector muy próximo. El análisis iconográfico y estilístico del retrato, así como los paralelos conservados –en bulto redondo y relieve–, apuntan a su elaboración en los inicios del reinado de Adriano. Presenta una singular iconografía, pero que se relaciona en determinados rasgos con el retrato de Adriano, en concreto con el llamado tipo Tarragona, creado durante la estancia del emperador en esa capital –122-123 d. C.–. Pudo representar a un miembro de la elite de Florentia Iliberritana en ese período, ya que es posible que estuviera erigido en el mismo foro municipal, con un carácter honorífico, amortizado en época tardoantiguaThis paper presents the study of a Roman portrait discovered in recent excavations in the Albaicín district –c/ Gumiel, 6– of Granada. The portrait was found in a level dated to the Late Antiquity as part of the fill of a vaulted infrastructure, possibly related to the forum buildings of Florentia Iliberritana, located close by. The iconographic and stylistic analyses of the portrait, as well as the known parallels –sculptures in the round or reliefs– suggest that it was made around the early Hadrian’s reign. It presents a unique iconography with certain features related to Hadrian’s portrait specifically known as the ‘Tarragona type’, created during the Emperor’s stay in this capital (122-123 ad). It represents a member of the elite from that period, whose honorary portrait could have been exhibited in the Florentia Iliberritana’s municipal forum, dismantled in Late Antiquity

Ética del cuidado en entornos de educación superior ante la COVID-19

La pandemia por COVID-19 visibiliza la importancia del cuidado como una de las estrategias para detener los contagios, ante el paulatino regreso a clases para el ciclo escolar 2021-2022 en México, las instituciones educativas de todos los niveles enfrentan grandes retos. En el nivel superior, las medidas de seguridad tienen que responder a la oferta educativa, proyectos de investigación, trabajo de extensión universitaria, entre otros, lleva a plantear la pregunta: ¿qué están haciendo las universidades para evitar contagios y promover la corresponsabilidad del cuidado? En este sentido, el objetivo del artículo es compartir los aprendizajes y desafíos que ha significado la continuidad de un programa universitario de intervención comunitaria ante la pandemia y el retorno a actividades presenciales, con la finalidad de iniciar un diálogo sobre el cuidado entre las comunidades universitarias. Se plantea la ética de cuidado como punto de partida para visibilizar el trabajo de cuidado dentro de la vida pública y como estrategia para fortalecer los protocolos de bioseguridad. El artículo recupera la sistematización del programa, la discusión de grupos focales entre alumnos y egresados, así los protocolos de bioseguridad ante el regreso a actividades presenciales

Concise asymmetric syntheses of novel phenanthroquinolizidines

The first preparation of enantioenriched phenanthroquinolizidines with a quaternary center at C14a was accomplished in seven steps from readily available starting materials. Key steps were an efficient dynamic kinetic allylation of a diastereomeric mixture of chiral tert-butylsulfinyl ketimines and the construction of a piperidine E ring by rhodium catalyzed hydroformylation. The Stevens rearrangement of the corresponding N-benzyl derivatives took place smoothly, allowing the installation of a benzyl moiety at C9 in a trans relationship with the methyl group. The cytoxicity of the prepared phenanthroquinolizidines was evaluated against different human cancer cell lines.We thank the Spanish Ministerio de Ciencia e Innovación (CTQ2011-24165) and the University of Alicante (VIGROB-173) for financial support. C. A.-T. thanks the ISO for a grant

Syntheses and Cytotoxicity of (R)- and (S)-7-Methoxycryptopleurine

Two efficient protocols are described for the transformation of a key chiral homoallyllic sulfinamine intermediate in four steps into enantioenriched 7-methoxycryptopleurine. While one of the protocols relied on a rhodium catalyzed linear hydroformylation process, the alternative approach was based on a ring-closing metathesis from the corresponding N-allyl-sulfinamine. The cytotoxic evaluation of both enantiomers of the target compound demonstrated that the (R)-compound is much more potent than its antipode against the four cancer cell lines examined.We thank the Spanish Ministerio de Ciencia e Innovación (CTQ2011-24165) for financial support. I.B. acknowledges the Generalitat Valenciana for a postdoctoral fellowship (ACIF/2011/159). C.A.-T. thanks the ISO for a grant

Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects

Phosphodiesterase (PDE) enzymes regulate the levels of cyclic nucleotides, cAMP, and/or cGMP, being attractive therapeutic targets. In order to modulate PDE activity in a selective way, we focused our efforts on the search of allosteric modulators. Based on the crystal structure of the PDE10A GAF-B domain, a virtual screening study allowed the discovery of new hits that were also tested experimentally, showing inhibitory activities in the micromolar range. Moreover, these new PDE10A inhibitors were able to decrease the nitrite production in LPS-stimulated cells, thus demonstrating their potential as anti-inflammatory agentsFinancial support from MINECO and FEDER founds (UE program) (project SAF2012-33600) is acknowledged. A.M.G. acknowledges pre-doctoral grants to the CSIC (JAEPre program)S

Novel phthalazin-1(2H)-one derivatives displaying a dithiocarbamate moiety as potential anticancer agents

Nowadays, cancer disease seems to be the second most common cause of death worldwide. Molecular hybridization is a drug design strategy that has provided promising results against multifactorial diseases, including cancer. In this work, two series of phthalazinone-dithiocarbamate hybrids were described, compounds 6–8, which display the dithiocarbamate scaffold at N2, and compounds 9, in which this moiety was placed at C4. The proposed compounds were successfully synthesized via the corresponding aminoalkyl phthalazinone derivatives and using a one-pot reaction with carbon disulfide, anhydrous H3PO4, and different benzyl or propargyl bromides. The antiproliferative effects of the titled compounds were explored against three human cancer cell lines (A2780, NCI-H460, and MCF-7). The preliminary results revealed significant differences in activity and selectivity depending on the dithiocarbamate moiety location. Thus, in general terms, compounds 6–8 displayed better activity against the A-2780 and MCF-7 cell lines, while most of the analogues of the 9 group were selective toward the NCI-H460 cell line. Compounds 6e, 8e, 6g, 9a–b, 9d, and 9g with IC50 values less than 10 µM were the most promising. The drug-likeness and toxicity properties of the novel phthalazinone-dithiocarbamate hybrids were predicted using Swiss-ADME and ProTox web servers, respectively.Universidade de Vigo, Xunta de Galicia | Ref. ED431C 2022/20Universidade de Vigo, Xunta de Galicia | Ref. ED431G 2019/0

Nose-to-brain delivery of enveloped RNA - cell permeating peptide nanocomplexes for the treatment of neurodegenerative diseases

This document is the preprint manuscript version of a published work that appeared in final form in Biomaterials, © 2019 Elsevier Ltd. after peer review and technical editing by the publisher. To access the final edited and published work see: https://doi.org/10.1016/j.biomaterials.2019.119657Direct nose-to-brain (N-to-B) delivery enables the rapid transport of drugs to the brain, while minimizing systemic exposure. The objective of this work was to engineer a nanocarrier intended to enhance N-to-B delivery of RNA and to explore its potential utility for the treatment of neurological disorders. Our approach involved the formation of electrostatically driven nanocomplexes between a hydrophobic derivative of octaarginine (r8), chemically conjugated with lauric acid (C12), and the RNA of interest. Subsequently, these cationic nanocomplexes were enveloped (enveloped nanocomplexes, ENCPs) with different protective polymers, i.e. polyethyleneglycol - polyglutamic acid (PEG-PGA) or hyaluronic acid (HA), intended to enhance their stability and mucodiffusion across the olfactory nasal mucosa. These rationally designed ENCPs were produced in bulk format and also using a microfluidics-based technique. This technique enabled the production of a scalable nanoformulation, exhibiting; (i) a unimodal size distribution with a tunable mean size, (ii) the capacity to highly associate (100%) and protect RNA from degradation, (iii) the ability to preserve its physicochemical properties in biorelevant media and prevent the premature RNA release. Moreover, in vitro cell culture studies showed the capacity of ENCPs to interact and be efficiently taken-up by CHO cells. Finally, in vivo experiments in a mouse model of Alzheimer's disease provided evidence of a statistically significant increase of a potentially therapeutic miRNA mimic in the hippocampus area and its further effect on two mRNA targets, following its intranasal administration. Overall, these findings stress the value of the rational design of nanocarriers towards overcoming the biological barriers associated to N-to-B RNA delivery and reveal their potential value as therapeutic strategies in Alzheimer's diseaseThe work was supported by the European B-Smart Consortium, which received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 721058S

5-HT2 receptor binding, functional activity and selectivity in N-benzyltryptamines

The last fifteen years have seen the emergence and overflow into the drug scene of “superpotent” N-benzylated phenethylamines belonging to the “NBOMe” series, accompanied by numerous research articles. Although N-benzyl substitution of 5-methoxytryptamine is known to increase its affinity and potency at 5-HT2 receptors associated with psychedelic activity, N-benzylated tryptamines have been studied much less than their phenethylamine analogs. To further our knowledge of the activity of N-benzyltryptamines, we have synthesized a family of tryptamine derivatives and, for comparison, a few 5-methoxytryptamine analogs with many different substitution patterns on the benzyl moiety, and subjected them to in vitro affinity and functional activity assays vs. the human 5-HT2 receptor subtypes. In the binding (radioligand displacement) studies some of these compounds exhibited only modest selectivity for either 5-HT2A or 5-HT2C receptors suggesting that a few of them, with affinities in the 10–100 nanomolar range for 5-HT2A receptors, might presumably be psychedelic. Unexpectedly, their functional (calcium mobilization) assays reflected very different trends. All of these compounds proved to be 5-HT2C receptor full agonists while most of them showed low efficacy at the 5-HT2A subtype. Furthermore, several showed moderateto-strong preferences for activation of the 5-HT2C subtype at nanomolar concentrations. Thus, although some N-benzyltryptamines might be abuse-liable, others might represent new leads for the development of therapeutics for weight loss, erectile dysfunction, drug abuse, or schizophreniaThis work was supported by FONDECYT (Chile) regular research grants 1110146 and 1150868 to BKC and CONICYT doctoral grant 21140358 to MT-SS

La villa romana de Salar (Granada). El programa escultórico en contexto arqueológico

This work was carried out within the framework of the Project HAR2017-89004-P, sponsored by the Ministerio de Economia y Competitividad of the Government of Spain and with ERDF Funds (Fondos FEDER), and the Project PID2019-105294GB-100/AEI/10.13039/501100011033, sponsored by the Ministerio de Ciencia e Innovacion of the Government of Spain and with ERDF Funds(Fondos FEDER); as well as the Research Groups HUM 143 and HUM 402 (Plan Andaluz de Investigacion of the Junta de Andalucia). We thank the City Council of Salar (Granada) for supporting the systematic archaeological excavation project in villa Salar, approved bythe Junta de Andalucia (Consejeria de Cultura y Patrimonio Historico) as a General Research Project.During the last decade various excavation campaigns have taken place at the Roman villa of Salar (Granada, Spain), located in the province Baetica. The excavated sector corresponds to the area surrounding a large peristyle of the pars urbana. Presiding over the open courtyard on one of the shorter sides is a triclinium, which in turn is associated with a nymphaeum. The ambulacrum on the opposite side of the peristyle was also excavated, uncovering a mosaic pavement with an interesting hunting scene, as well as other rooms that open onto it. In this work, the typological and iconographic study of the sculptural program recovered is carried out. The sculptural assemblage consists of 1) two nymph sculptures discovered in the nymphaeum associated with the triclinium; and 2) a Capitoline type Venus statue, which possibly decorated another fountain located on the southern side of the peristyle. The archaeological context and petrographic analyses add to the study of the pieces, as well as the analysis of this sculptural program related to nymphaea and garden environments.Durante la última década se han desarrollado varias campañas de excavación en la villa romana de Salar (Granada, España), situada en la provincial romana de la Bética. El sector excavado corresponde a la pars urbana, articulada en torno a un gran peristilo central. Presidiendo uno de los lados cortos del patio abierto se sitúa el triclinium, asociado con un nymphaeum. El ambulacrum en el lado opuesto del peristilo ha sido también excavado, descubriéndose un pavimento de mosaico con una interesante escena de caza, así como otras habitaciones que abren a este patio. En este trabajo se aborda el estudio tipológico e iconográfico del programa escultórico de la villa. El conjunto está integrado por: dos esculturas de ninfas, descubiertas en el nymphaeum asociado con el triclinium; y 2) una estatua de Venus, tipo Capitolina, que posiblemente decorase otra fuente, localizada en el lado sur del peristilo. El contexto arqueológico y los análisis petrográficos se integran en el estudio de las piezas, así como el análisis del programa escultórico del nymphaeum y el jardín circundante.Spanish Government HAR2017-89004-PERDF Funds (Fondos FEDER)Spanish Government PID2019-105294GB-100/AEI/10.13039/501100011033ERDF Funds(Fondos FEDER) Junta de Andalucia HUM 143 HUM 40