Exploring adamantine-like scaffolds for a wide range of therapeutic targets

[eng] For over eighty years, adamantane ring has interested organic chemists for its simplicity and symmetry. The rigid tricyclo[3.3.1.13,7]decane skeleton has provided a unique structural template for evaluating important theoretical concepts in chemistry. The physical and chemical properties of the adamantane nucleus have largely overshadowed the structure’s contribution to the discovery of human therapeutics. Nevertheless its application in medicinal chemistry has become more and more significant in the last decades, where the adamantane ring was identified as a key structural subunit in several synthetic drugs for multiple targets. Adamantane is often considered as providing just the critical lipophilicity readily available as an add-on for known pharmacophoric units. Although its valuable contribution to medicinal sciences, adamantane ring can lead to solubility and stability problems which compromise the pharmacokinetic profile of the potential drug. Hence many research teams have worked out alternatives on adamantyl-based compounds in order to avert these issues, especially by attaching polar groups at key positions. In the last few years, the research group of Dr. Santiago Vázquez from University of Barcelona has developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. So far, we have synthesized ring-contracted, ring-expanded and oxa analogues of the drugs amantadine, rimantadine and memantine with anti-influenza, NMDA receptor antagonist and trypanocidal activities, proving the capacity of these polycycles to substitute the adamantane ring. As described previously, the replacement of the adamantane ring with other polycyclic scaffolds can lead to compounds with better pharmacodynamic and pharmacokinetic profiles. In particular, my Ph.D. research has focused mainly on the substitution of the adamantane moiety in inhibitors of different targets. 1) NMDA receptor antagonists: design, synthesis, pharmacological evaluation and electrophysiological studies of new compounds. 2) 11β-HSD1: design, synthesis, pharmacological evaluation and computational studies of new compounds. 3) Soluble epoxide hydrolase inhibitors: design, synthesis, pharmacological evaluation and in vitro cellular studies of new compounds. From the results of this dissertation, we have confirmed the ability of the new scaffolds to replace the adamantane nucleus with successful outcomes. The work derived from this thesis have been published in peer scientific journals, as well as in two different patent applications

Synthesis and Antiviral Evaluation of Bisnoradamantane Sulfites and Related Compounds

The reaction of a series of 1,2-diols with thionyl chloride led to bisnoradamantane sulfites in very good yields. The reaction has also been applied to related polycyclic scaffolds. The compounds have been tested for antiviral activity but none of them showed to be active. Several attempts to generate and trap SO from these polycyclic sulfites have been unsuccessful

Escape from adamantane: scaffold optimization of novel P2X7 antagonists featuring complex polycycles

The adamantane scaffold, despite being widely used in medicinal chemistry, is not devoid of problems. In recent years we have developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. As an adamantane scaffold is a common structural feature in several P2X7 receptor antagonists, herein we report the synthesis and pharmacological evaluation of multiple replacement options of adamantane that maintain a good activity profile. Molecular modeling studies support the binding of the compounds to a site close to the central pore, rather than to the ATP-binding site and shed light on the structural requirements for novel P2X7 antagonists

Inhibitors of the M2 channel of influenza A virus

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/32392Influenza is a highly contagious, major respiratory tract disease affecting millions of people each year. At present, two classes of antivirals are available: the neuraminidase inhibitors and the M2 proton channel blockers amantadine and rimantadine. However, rapid emergence of M2 blockers resistance makes imperative the development of new anti-influenza drugs. In the last few years several groups have synthesized and evaluated several analogs of amantadine. While several of them are active against wild-type M2 channel only a few are able to inhibit the mutant ion channels that lead to amantadine-resistance

Todos muy capaces

El trabajo obtuvo un Premio Tomás García Verdejo a las buenas prácticas educativas en la Comunidad Autónoma de Extremadura para el curso académico 2015/2016. Modalidad BSe describe un proyecto llevado a cabo con alumnos de 4º de diversificación y 2º de Formación Profesional Básica del IES Bioclimático de Badajoz, que consistió en realizar diversas actividades con la asociación Aspaceba (Asociación de Parálisis Cerebral de Badajoz) y que tuvo como objetivos principales que los alumnos se informase sobre la discapacidad en general y sobre la parálisis cerebral en particular, que se acercaran al mundo de la discapacidad superarando las barreras físicas y psicológicas, que conociesen los aspectos positivos y las necesidades de apoyo y recursos de las personas con discapacidad, que trabajasen la empatía y el respeto como mecanismo para entender sentimientos y vivencias de los demás y que rechazaran situciones de injusticia hacia personas con alguna discapacidadAndalucíaES

The PLATO Mission

International audiencePLATO (PLAnetary Transits and Oscillations of stars) is ESA's M3 mission designed to detect and characterise extrasolar planets and perform asteroseismic monitoring of a large number of stars. PLATO will detect small planets (down to <2 R_(Earth)) around bright stars (<11 mag), including terrestrial planets in the habitable zone of solar-like stars. With the complement of radial velocity observations from the ground, planets will be characterised for their radius, mass, and age with high accuracy (5 %, 10 %, 10 % for an Earth-Sun combination respectively). PLATO will provide us with a large-scale catalogue of well-characterised small planets up to intermediate orbital periods, relevant for a meaningful comparison to planet formation theories and to better understand planet evolution. It will make possible comparative exoplanetology to place our Solar System planets in a broader context. In parallel, PLATO will study (host) stars using asteroseismology, allowing us to determine the stellar properties with high accuracy, substantially enhancing our knowledge of stellar structure and evolution. The payload instrument consists of 26 cameras with 12cm aperture each. For at least four years, the mission will perform high-precision photometric measurements. Here we review the science objectives, present PLATO's target samples and fields, provide an overview of expected core science performance as well as a description of the instrument and the mission profile at the beginning of the serial production of the flight cameras. PLATO is scheduled for a launch date end 2026. This overview therefore provides a summary of the mission to the community in preparation of the upcoming operational phases

The PLATO Mission

International audiencePLATO (PLAnetary Transits and Oscillations of stars) is ESA's M3 mission designed to detect and characterise extrasolar planets and perform asteroseismic monitoring of a large number of stars. PLATO will detect small planets (down to <2 R_(Earth)) around bright stars (<11 mag), including terrestrial planets in the habitable zone of solar-like stars. With the complement of radial velocity observations from the ground, planets will be characterised for their radius, mass, and age with high accuracy (5 %, 10 %, 10 % for an Earth-Sun combination respectively). PLATO will provide us with a large-scale catalogue of well-characterised small planets up to intermediate orbital periods, relevant for a meaningful comparison to planet formation theories and to better understand planet evolution. It will make possible comparative exoplanetology to place our Solar System planets in a broader context. In parallel, PLATO will study (host) stars using asteroseismology, allowing us to determine the stellar properties with high accuracy, substantially enhancing our knowledge of stellar structure and evolution. The payload instrument consists of 26 cameras with 12cm aperture each. For at least four years, the mission will perform high-precision photometric measurements. Here we review the science objectives, present PLATO's target samples and fields, provide an overview of expected core science performance as well as a description of the instrument and the mission profile at the beginning of the serial production of the flight cameras. PLATO is scheduled for a launch date end 2026. This overview therefore provides a summary of the mission to the community in preparation of the upcoming operational phases