Methoxy and bromo scans on N-(5-methoxyphenyl) methoxybenzenesulphonamides reveal potent cytotoxic compounds, especially against the human breast adenocarcinoma MCF7 cell line

Thirty seven N-(5-methoxyphenyl)-4-methoxybenzenesulphonamide with methoxy or/and bromo substitutions (series 1-4) and with different substituents on the sulphonamide nitrogen have been synthesised. 21 showed sub-micromolar cytotoxicity against HeLa and HT-29 human tumour cell lines, and were particularly effective against MCF7. The most potent series has 2,5-dimethoxyanilines, especially the 4-brominated compounds 23–25. The active compounds inhibit microtubular protein polymerisation at micromolar concentrations, thus pointing at tubulin as the target. Co-treatment with the MDR inhibitor verapamil suggests that they are not MDR substrates. Compound 25 showed nanomolar antiproliferative potency. It severely disrupts the microtubule network in cells and arrests cells at the G2/M cell-cycle phase, thus confirming tubulin targeting. 25 triggered apoptotic cell death, and induced autophagy. Docking studies suggest binding in a distinct way to the colchicine site. These compounds are promising new antitumor agents acting on tubulin.We thank the people at Frigoríficos Salamanca S.A. slaughterhouse for providing us with the calf brains, “Servicio General de NMR” and “Servicio General de Espectrometría de Masas” of the University of Salamanca for equipment. M.G. acknowledges a predoctoral fellowship from the Junta de Castilla y León (ORDEN EDU/529/2017 de 26 de junio). M.O.-S. acknowledges a predoctoral fellowship from the IBSAL (IBpredoc17/00010). A.V.-B. acknowledges a predoctoral fellowship from the Spanish Ministerio de Educación, Cultura y Deporte (FPU15/02457). This research was funded by the Consejería de Educación de la Junta de Castilla y León (ORDEN EDU/529/2017 de 26 de junio, SA030U16, SA262P18 and SA116P20), co-funded by the EU’s European Regional Development Fund-FEDER, the Spanish Ministry of Science, Innovation and Universities (RTI2018-099474-BI00) and the health research program of the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness) [PI16/01920 and PI20/01569] co-funded with FEDER funds. Ministerio de Educación, Cultura y Deporte [FPU15/02457], IBSAL [IBpredoc17/00010]

Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy

Pan-Gyn cancers entail 1 in 5 cancer cases worldwide, breast cancer being the most commonly diagnosed and responsible for most cancer deaths in women. The high incidence and mortality of these malignancies, together with the handicaps of taxanes—first-line treatments—turn the development of alternative therapeutics into an urgency. Taxanes exhibit low water solubility that require formulations that involve side effects. These drugs are often associated with dose-limiting toxicities and with the appearance of multi-drug resistance (MDR). Here, we propose targeting tubulin with compounds directed to the colchicine site, as their smaller size offer pharmacokinetic advantages and make them less prone to MDR efflux. We have prepared 52 new Microtubule Destabilizing Sulfonamides (MDS) that mostly avoid MDR-mediated resistance and with improved aqueous solubility. The most potent compounds, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide 38, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 42, and N-benzyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 45 show nanomolar antiproliferative potencies against ovarian, breast, and cervix carcinoma cells, similar or even better than paclitaxel. Compounds behave as tubulin-binding agents, causing an evident disruption of the microtubule network, in vitro Tubulin Polymerization Inhibition (TPI), and mitotic catastrophe followed by apoptosis. Our results suggest that these novel MDS may be promising alternatives to taxane-based chemotherapy in chemoresistant Pan-Gyn cancers.We thank the people at Frigoríficos Salamanca S.A slaughterhouse for providing us with the calf brains, “Servicio General de NMR” and “Servicio General de Espectrofotometría de Masas” of the University of Salamanca for equipment. M.G. acknowledges a predoctoral fellowship from the Junta de Castilla y León (ORDEN EDU/529/2017 de 26 de junio). M.O.-S. acknowledges a predoctoral fellowship from the IBSAL (IBpredoc17/00010). A.V.-B. acknowledges a predoctoral fellowship from the Spanish Ministerio de Educación, Cultura y Deporte (FPU15/02457). This research was funded by the Consejería de Educación de la Junta de Castilla y León (SA030U16, SA262P18 and SA116P20), co-funded by the EU’s European Regional Development Fund-FEDER, the Spanish Ministry of Science, Innovation and Universities (RTI2018-099474-BI00) and the health research program of the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness, PI16/01920 and PI20/01569) co-funded with FEDER founds

Introducción de la gamificación en la docencia en Química en las facultades de Farmacia y de Ciencias Agrarias y Ambientales

Memoria ID-0196. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2017-2018

Elaboración de informes en formato de publicación científica

Memoria ID-0150. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2017-2018

The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors

[EN] Colchicine site ligands suffer from low aqueous solubility due to the highly hydrophobic nature of the binding site. A new strategy for increasing molecular polarity without exposing polar groups—termed masked polar group incorporation (MPGI)—was devised and applied to nitrogenated combretastatin analogues. Bulky ortho substituents to the pyridine nitrogen hinder it from the hydrophobic pocket while increasing molecular polarity. The resulting analogues show improved aqueous solubilities and highly potent antiproliferative activity against several cancer cell lines of different origin. The more potent compounds showed moderate tubulin polymerization inhibitory activity, arrested the cell cycle of treated cells at the G2/M phase, and subsequently caused apoptotic cell death represented by the cells gathered at the subG0/G1 population after 48 h of treatment. Annexin V/Propidium Iodide (PI) double-positive cells observed after 72 h confirmed the induction of apoptosis. Docking studies suggest binding at the colchicine site of tubulin in a similar way as combretastatin A4, with the polar groups masked by the vicinal substituents. These results validate the proposed strategy for the design of colchicine site ligands and open a new road to increasing the aqueous solubility of ligands binding in apolar environments

Seguridad en el laboratorio. Revisión de la enseñanza práctica de la Química Orgánica en la Facultad de Farmacia

Memoria ID-136. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2018-2019

Sumando Vida a los Años. Propuesta para combatir la soledad y promover una buena salud mental en personas mayores

La mejora de las condiciones de vida y los avances de la medicina han facilitado un considerable aumento de la esperanza de vida y, como consecuencia, un importante envejecimiento poblacional. En España, las personas mayores de 65 años representan casi el 20% de la población, y se prevé que este porcentaje crezca significativamente en los próximos años. Afrontar esta situación demográfica es uno de los principales retos de la sociedad en la actualidad. Uno de los desafíos más relevantes es ocuparse de lo que se ha denominado «epidemia de la soledad», es decir, el impacto negativo que la soledad no deseada y el aislamiento social tienen en la salud mental y la calidad de vida de las personas mayores. En España, un 20% de las personas mayores de 65 años declara niveles altos de soledad, un 25% de aislamiento social y 1 de cada 4 sufre depresión. La evidencia científica apunta también a que su abordaje mediante intervenciones multidisciplinares y multidimensionales, sustentadas por recursos institucionales y comunitarios apropiados, tiene un impacto positivo en la calidad de vida y en la salud mental de las personas mayores. La soledad y la mala salud mental que padecen las personas mayores requiere de medidas urgentes orientadas a promover, entre ellas, un buen estado de salud y una calidad de vida óptima. Este documento presenta recomendaciones de actuación basadas en la investigación realizada por el Proyecto QASP - Quality of Life and Aging in Spain, Sweden and PortugalInstituto de Salud Carlos III, Subprograma Estatal de Generación de Conocimiento de la Acción Estratégica en Salud Intramural AESI 2018, Ref: PI18CIII/00046 (Proyecto QASP).N

Active ageing profiles among older adults in Spain: A Multivariate analysis based on SHARE study

Background: Following the active ageing model based on the Health, Lifelong Learning, Participation and Security pillars, this research has a twofold objective: i) to classify older adults according to active ageing profiles, taking into account the four pillars, and ii) to ascertain the relationship between the profiles and personal and contextual factors, as well as well-being and quality of life in old age. Methods: A study sample of 5,566 Spanish older adults who participated in wave 6 of the Survey of Health, Ageing and Retirement in Europe (SHARE) was included. Data were analysed in different steps applying several statistical analyses (Principal Component, Cluster, Discriminant, Multiple Correspondence and bivariate analysis with Pearson chi-square and ANOVA). Results: Five older adult profiles were obtained (I: with moderate activity; II: quasi-dependents; III: with active ageing-limiting conditions; IV: with diverse and balanced activity; V: with excellent active ageing conditions). The first three profiles were characterised by subjects with a high average age, low educational level, who were retired or housewives, and who perceived a moderate level of loneliness, satisfaction with the social network and quality of life, as well as having a larger family network, but living in small households or alone. In contrast, the latter two profiles showed better personal and contextual conditions, well-being and quality of life. Discussion and conclusions: The multidimensional approach to active ageing followed in this article has revealed the presence of several older adult profiles, which are confined to groups with better or worse active ageing conditions. In this context, if ageing is a process that reflects the previous way of life, intervention priorities will have to consider actions that promote better conditions during the life cycle.Research of this paper is a part of i) the QASP research project, funded by the Institute of Health Carlos III, Intramural Strategical Action in Health AESI 2018 (PI18CIII/00046); ii) it has also been partially funded by REDISSEC (RD16/0005/0002 and RD16/0001/0005, co-funded by European Regional Development Fund/European Social Fund “A way to make Europe” / ”Investing in your future”) projects; iii) the R&D Activities Program ENCAGEn-CM (H2019/HUM-5698) funded by the Community of Madrid and co-funded by the European Social Fund; iv) the ENVACES R&D+i project (MINECO-FEDER, ref. CSO2015-64115-R). Authors acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections

IMPORTANCE The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option. OBJECTIVE To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021. INTERVENTIONS Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or pa renteral ertapenem for the comparator group after 4 days. MAIN OUTCOMES AND MEASURES The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. RESULTS Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to infinity percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI. -infinity to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01). CONCLUSIONS AND RELEVANCE This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections