8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studies

Psychiatric and neurological disorders affect millions of people worldwide. Currently available treatments may help to improve symptoms, but they cannot cure the diseases. Therefore, there is an urgent need for potent and safe therapeutic solutions. 8-Amide and 8-carbamatecoumarins were synthetized and evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Comparison between both scaffolds has been established, and we hypothesized that the introduction of different substituents can modulate hMAO activity and selectivity. N-(7-Hydroxy-4-methylcoumarin-8-yl)-4-methylbenzamide (9) and ethyl N-(7-hydroxy-4-methylcoumarin-8-yl)carbamate (20) proved to be the most active and selective hMAO-A inhibitors (IC50 = 15.0 nM and IC50 = 22.0 nM, respectively), being compound 9 an irreversible hMAO-A inhibitor twenty-four times more active in vitro than moclobemide, a drug used in the treatment of depression and anxiety. Based on PAMPA assay results, both compounds proved to be good candidates to cross the blood-brain barrier. In addition, these compounds showed non-significant cytotoxicity on neuronal viability assays. Also, the best compound proved to have a t1/2 of 6.84 min, an intrinsic clearance of 195.63 μL min−1 mg−1 protein, and to be chemically stable at pH 3.0, 7.4 and 10.0. Docking studies were performed to better understand the binding affinities and selectivity profiles for both hMAO isoforms. Finally, theoretical drug-like properties calculations corroborate the potential of both scaffolds on the search for new therapeutic solutions for psychiatric disorders as depressionThis research was funded by Consellería de Cultura, Educación e Ordenación Universitaria (EM2014/016), Ministerio de Ciencia e Innovación (PID2020-116076RJ-I00/AEI/10.13039/501100011033) and Fundação para a Ciência e Tecnologia (PTDC/ASP-PES/28397/2017, CEECIND/02423/2018, UIDB/00081/2020, LA/P/0056/2020 and EXPL/BIA-BQM/0492/2021). Financial support from the Xunta de Galicia (Centro de investigación de Galicia accreditation 2019–2022) and the European Union (European Regional Development Fund - ERDF), is also gratefully acknowledged. M.I.R.-F. acknowledges the economic support from the Spanish Ministry of Science, Innovation and Universities; Spanish Research Agency; and European Regional Development Funds (grant PID2021-122650OB-I00) and from CSIC (PIE-202080E118)S

La sociedad española de bioquímica y biología molecular: objetivos y desafíos

La Sociedad Española de Bioquímica y Biología Molecular (SEBBM) fue fundada en 1963 por científicos de renombre internacional: el Premio Nobel Severo Ochoa, Alberto Sols, Santiago Grisolía, Julio Rodríguez Villanueva, Gertrudis de la Fuente y Federico Mayor Zaragoza, junto con una generación más joven de investigadores entre los que destacan Margarita Salas, Eladio Viñuela, Gabriela Morreale y Carlos Gancedo. Su esfuerzo fundacional se plasma hoy en día en una sociedad con más de 3.500 socios, convirtiéndose en la principal agrupación científica del extenso campo de la Bioquímica y la Biología Molecular. En este artículo se hace referencia entre otras cosas a las diversas actividades, los objetivos y los desafíos de esta sociedad científic

DNA is more, negatively supercoiled in bacterial plasmids than in minichromosomes isolated from budding yeast.

9 páginas; 5 figuras; 1 tablaA series of circular shuttle vectors were constructed that could replicate and transcribe in the cells of both Escherichia coli and Saccharomyces cerevisiae. 2-D agarose gel electrophoresis run without or in the presence of different concentrations of chloroquine (CHL) revealed that bacterial plasmids were more negatively (-) supercoiled than minichromosomes isolated from budding yeast. Attempts to increase (-) supercoiling in S. cerevisiae or to reduce it in E. coli have deleterious biological consequences. These observations indicate that DNA supercoiling can vary in different species but cells are exquisitely sensitive to sudden changes in supercoiling. In E. coli, the observation that cell growth as well as ColE1 plasmid copy number decrease when DNA relaxes suggests that supercoiling could affect cell viability by regulating the initiation of both transcription and replication.BIO2005-02224, to JBS and BFU 2007-62670; BFU2004-00125, PH Spanish Ministerio de Educación y CienciaPeer reviewe

New Therapeutic Strategies for Osteoarthritis by Targeting Sialic Acid Receptors

© 2020 by the authors.Osteoarthritis (OA) is the most common degenerative joint disease characterized by articular cartilage degradation and joint degeneration. The articular cartilage is mainly formed by chondrocytes and a collagen-proteoglycan extracellular matrix that contains high levels of glycosylated proteins. It was reported that the shift from glycoproteins containing α-2,6-linked sialic acids to those that contain α-2,3 was associated with the onset of common types of arthritis. However, the pathophysiology of α-2,3-sialylation in cartilage has not been yet elucidated. We show that cartilage from osteoarthritic patients expresses high levels of the α-2,3-sialylated transmembrane mucin receptor, known as podoplanin (PDPN). Additionally, the Maackia amurensis seed lectin (MASL), that can be utilized to target PDPN, attenuates the inflammatory response mediated by NF-kB activation in primary chondrocytes and protects human cartilage breakdown ex vivo and in an animal model of arthritis. These findings reveal that specific lectins targeting α-2,3-sialylated receptors on chondrocytes might effectively inhibit cartilage breakdown. We also present a computational 3D molecular model for this interaction. These findings provide mechanistic information on how a specific lectin could be used as a novel therapy to treat degenerative joint diseases such as osteoarthritis.This work was funded by the Spanish Society for Rheumatology (SER-2013) and the Spanish Society for Research on Bone and Mineral Metabolism (FEIOMM-2016) (to M.D.M.) and by the grant PI13/00591, PI16/00035, and PI19/00145 from the Health Institute “Carlos III” (ISCIII, Spain) and was cofinanced by the European Regional Development Funds, “A way of making Europe” from the European Union (to M.D.M.). Paula Carpintero-Fernández has a postdoctoral fellowship from Xunta de Galicia (IN606B 2017/014) Two predoctoral fellowships from Xunta de Galicia to Marta Varela-Eirin (ED481A 2015/188) and Raquel Gago-Fuentes (PRE/2012/165) and from University of A Coruña—INDITEX and CICA-INIBIC (AGRUP2015/05). The Spanish Ministry for Economy and Competitiveness (MINECO) grants CTQ2014-57141-R and CTQ2017-88353-R (to S.M.-S.) is gratefully acknowledged.Peer reviewe