Glicomiméticos y Glicoligandos anfifílicos. Interacciones con enzimas, receptores y ácidos nucleicos

En esta Tesis hemos preparado derivados de beta-ciclodextrina, metil alfa-D-glucopiranosa y alfa,alfa’-trehalosa adaptados para su aplicación al transporte vectorizado de fármacos, la transfección génica y/o en la modulación del sistema inmune innato. Para el transporte vectorizado de fármacos se ha utilizado una estrategia de síntesis convergente en la que a un precursor monofuncionalizado de beta-ciclodextrina, que actúa como plataforma de complejación de fármacos poco solubles en agua, se acopla una antena de biorreconocimiento que facilita el transporte dirigido del fármaco; en este caso chaperonas farmacológicas con estructura de iminoazúcares sp2. Para la preparación de vectores de transfección génica se han utilizado como plataformas sacarídicas el metil alfa-D-glucopiranósido y la alfa,alfa’-trehalosa, a las que se han incorporado elementos estructurales que promueven la autoorganización mediante métodos de funcionalización selectiva. De esta manera se han obtenido derivados catiónicos mono- y disacarídicos de naturaleza anfifílica capaces de formar nanopartículas, bien de manera espontánea, bien en presencia de un plásmido. La versatilidad de esta aproximación sintética permite acceder a una colección de moléculas con gran variabilidad estructural sobre las que se han realizado estudios para establecer relaciones entre su estructura molecular y sus propiedades de autoorganización y transporte de genes. Los derivados catiónicos de la metil alfa-D-glucopiranosa y la alfa,alfa’-trehalosa, sintetizados mediante los métodos de funcionalización selectiva antes mencionados, presentan semejanza estructural con moléculas anfifílicas cargadas que tienen un importante papel modulador de la actividad del sistema inmune innato al interaccionar con el receptor “toll-like” TLR4. Dado que tanto derivados catiónicos como aniónicos son susceptibles de actuar como ligandos regulardores de la actividad del TLR4, hemos puesto a punto también la síntesis de análogos aniónicos anfifílicos y, en colaboración con el Prof. F. Peri (Universidad de Milano Biccoca) hemos evaluado la actividad moduladora de la respuesta inmune de ambas familias de glicolípidos

Trehalose-based Siamese twin amphiphiles with tunable self-assembling, DNA nanocomplexing and gene delivery properties

An original family of multivalent vectors encompassing gemini and facial amphiphilicity, namely cationic Siamese twin surfactants, has been prepared from the disaccharide trehalose; molecular engineering lets us modulate the self-assembling properties and the topology of the nanocomplexes with plasmid DNA for efficient gene delivery in vitro and in vivo.MINECO SAF2016-76083-R CTQ2015- 64425-C2-1-R CTQ2015-64425-C2-2-R RTI2018-097609-B-C21 RTI2018-097609-B-C22MCIU SAF2016-76083-R CTQ2015- 64425-C2-1-R CTQ2015-64425-C2-2-R RTI2018-097609-B-C21 RTI2018-097609-B-C22Junta de Andalucía FQM2012-1467FEDERFS

Zwiespältige Bilanz für Afrika : die Milleniumsziele der UN haben keine Gleichberechtigung in der Entwicklungszusammenarbeit gebracht

An increasing number of pathologies have been linked to Toll-like receptor 4 (TLR4) activation and signaling, therefore new hit and lead compounds targeting this receptor activation process are urgently needed. We report on the synthesis and biological properties of glycolipids based on glucose and trehalose scaffolds which potently inhibit TLR4 activation and signaling in vitro and in vivo. Structure–activity relationship studies on these compounds indicate that the presence of fatty ester chains in the molecule is a primary prerequisite for biological activity and point to facial amphiphilicity as a preferred architecture for TLR4 antagonism. The cationic glycolipids here presented can be considered as new lead compounds for the development of drugs targeting TLR4 activation and signaling in infectious, inflammatory, and autoimmune diseases. Interestingly, the biological activity of the best drug candidate was retained after adsorption at the surface of colloidal gold nanoparticles, broadening the options for clinical development.Italian, Ministry of University and Research (MIUR), PRIN 2010 - 11Ministerio de Economía y Competitividad AF2013-44021- R, CTQ2010 - 15848Junta de Andalucía FQM 1467Slovenian Research Agency P4-176, J1 - 417

Trehalose-based siamese twin amphiphiles with tunable self-assembling, DNA nanocomplexing and gene delivery properties

An original family of multivalent vectors encompassing gemini and facial amphiphilicity, namely cationic Siamese twin surfactants, has been prepared fromthe disaccharide trehalose; molecular engineering lets us modulate the self-assembling properties and the topology of the nanocomplexes with plasmid DNA for efficient gene delivery in vitro and in vivo

Fungal community of necrotic and healthy galls in chestnut trees colonized by Dryocosmus kuriphilus (Hymenoptera, Cynipidae)

Producción CientíficaDryocosmus kuriphilus is a non-native pest that has recently spread through Europe with a special incidence along the Mediterranean Basin. The presence of this exotic wasp (originally from Asia) threatens stands and orchards of sweet chestnut (Castanea sativa Mill.) as it reduces tree growth and consequently fruit production. In this study the living mycobiota in leaves, healthy and necrotic galls collected from two sites in Cantabria (Northern Spain) was investigated. A total of twenty-two fungal taxa based on morphological and molecular traits were determined. In addition, we calculated fungal diversity and identified the dominant taxa among members of the mycobiota. Seven log-linear models were used to analyse whether fungal abundance varied between sites, types of plant material or fungal taxa. Our findings highlight the complex interactions between plant hosts, insect and the endophytic community, and are of potential interest in relation to the biological control of this important pest

Elucidating sensing mechanisms of a pyrene excimer-based calix[4]arene for ratiometric detection of Hg(II) and Ag(I) and chemosensor behaviour as INHIBITION or IMPLICATION logic gates†

This article reports the synthesis and characterisation of two lower rim calix[4]arene derivatives with thiourea as spacer and pyrene or methylene-pyrene as fluorophore. Both derivatives exhibit a fluorimetric response towards Hg2+, Ag(+)and Cu2+. Only methylene-pyrenyl derivative2allows for selective detection of Hg(2+)and Ag(+)by enhancement or decrease of excimer emission, respectively. The limits of detection of2are 8.11 nM (Hg2+) and 2.09 nM (Ag+). DFT and TD-DFT computational studies were carried out and used to identify possible binding modes that explain the observed response during fluorescence titrations. Calculations revealed the presence of different binding sites depending on the conformation of2, which suggest a reasonable explanation for non-linear changes in fluorescence depending on the physical nature of the interaction between metal centre and conformer. INHIBITION and IMPLICATION logic gates have also been generated monitoring signal outputs at pyrene monomer (395 nm) and excimer (472 nm) emission, respectively. Thus2is a potential primary sensor towards Ag(+)and Hg(2+)able to configure two different logic gate operations.Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 3170264 3180041 1151310 1191130 USA1855_VRIDEI_1_1_3 1145-USA 1799_1_1_3 VRIDEI Departamento de Quimica Organica y Fisicoquimica (Universidad de Chile

Trehalose-based Siamese twin amphiphiles with tunable self-assembling, DNA nanocomplexing and gene delivery properties

An original family of multivalent vectors encompassing gemini and facial amphiphilicity, namely cationic Siamese twin surfactants, has been prepared fromthe disaccharide trehalose;molecular engineering lets us modulate the self-assembling properties and the topology of the nanocomplexes with plasmid DNA for efficient gene delivery in vitro and in vivo.The authors thank MINECO/MCIU (SAF2016-76083-R, CTQ2015-64425-C2-1-R, CTQ2015-64425-C2-2-R, RTI2018-097609-B-C21 and RTI2018-097609-B-C22), the Junta de Andalucía (FQM2012-1467) and the European Regional Development Funds (FEDER and FSE) for financial support. We acknowledge the CSIC (URICI) for supporting open access publication and the CITIUS (Univ. Seville) for technical support

Targeted delivery of pharmacological chaperones for Gaucher disease to macrophages by a mannosylated cyclodextrin carrier

et al.Gaucher disease (GD) is a rare monogenetic disorder leading to dysfunction of acid β-glucosidase (β-glucocerebrosidase; GCase) and accumulation of glucosylceramide in lysosomes, especially in macrophages (Gaucher cells). Many of the mutations at the origin of GD do not impair the catalytic activity of GCase, but cause misfolding and subsequent degradation by the quality control system at the endoplasmic reticulum. Pharmacological chaperones (PCs) capable of restoring the correct folding and trafficking of the endogenous mutant enzyme represent promising alternatives to the currently available enzyme replacement and substrate reduction therapies (ERT and SRT, respectively), but unfavorable biodistribution and potential side-effects remain important issues. We have now designed a strategy to enhance the controlled delivery of PCs to macrophages that exploit the formation of ternary complexes between the PC, a trivalent mannosylated β-cyclodextrin (βCD) conjugate and the macrophage mannose receptor (MMR). First, PC candidates with appropriate relative avidities towards the βCD cavity and the GCase active site were selected to ensure efficient transfer of the PC cargo from the host to the GCase active site. Control experiments confirmed that the βCD carrier was selectively recognized by mannose-specific lectins and that the corresponding PC:mannosylated βCD supramolecular complex retained both the chaperoning activity, as confirmed in human GD fibroblasts, and the MMR binding ability. Finally, fluorescence microscopy techniques proved targeting and cellular uptake of the PC-loaded system in macrophages. Altogether, the results support that combined cyclodextrin encapsulation and glycotargeting may improve the efficacy of PCs for GD. This journal is © 2014 the Partner Organisations.This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO), contract numbers SAF2010-15670 and CTQ2010-15848, the Fondo Europeo de Desarrollo Regional (FEDER), and the Fundación Ramón Areces. JRL is grateful to the Spanish Ministerio de Economía y Competitividad for a pre-doctoral FPI fellowship.Peer Reviewe

Synthesis, Docking, 3-D-Qsar, and Biological Assays of Novel Indole Derivatives Targeting Serotonin Transporter, Dopamine D2 Receptor, and Mao-A Enzyme: In the Pursuit for Potential Multitarget Directed Ligands

A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1H-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7(a-o) and (2-{4-[3-(1H-3-indolyl)-propyl]-1-piperazinyl}-acetylamine)-N-(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13(a-l) were synthesized and evaluated as novel multitarget ligands towards dopamine D-2 receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). All the assayed compounds showed affinity for SERT in the nanomolar range, with five of them displaying Ki values from 5 to 10 nM. Compounds 7k, Ki = 5.63 +/- 0.82 nM, and 13c, Ki = 6.85 +/- 0.19 nM, showed the highest potencies. The affinities for D-2 ranged from micro to nanomolar, while MAO-A inhibition was more discrete. Nevertheless, compounds 7m and 7n showed affinities for the D-2 receptor in the nanomolar range (7n: Ki = 307 +/- 6 nM and 7m: Ki = 593 +/- 62 nM). Compound 7n was the only derivative displaying comparable affinities for SERT and D-2 receptor (D-2/SERT ratio = 3.6) and could be considered as a multitarget lead for further optimization. In addition, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds in the most relevant protein targets were carried out. Furthermore, in order to obtain information on the structure-activity relationship of the synthesized series, a 3-D-QSAR CoMFA and CoMSIA study was conducted and validated internally and externally (q(2) = 0.625, 0.523 for CoMFA and CoMSIA and r(ncv)(2) = 0.967, 0.959 for CoMFA and CoMSIA, respectively).Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 1170269 1170662 3180602 Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT

Synthesis, in vitro evaluation and molecular docking of a new class of indolylpropyl benzamidopiperazines as dual AChE and SERT ligands for Alzheimer’s disease

During the last decade, the one drug-one target strategy has resulted to be inefficient in facing diseases with complex ethiology like Alzheimer's disease and many others. In this context, the multitarget paradigm has emerged as a promising strategy. Based on this consideration, we aim to develop novel molecules as promiscuous ligands acting in two or more targets at the same time. For such purpose, a new series of indolylpropyl-piperazinyl oxoethyl-benzamido piperazines were synthesized and evaluated as multitarget-directed drugs for the serotonin transporter (SERT) and acetylcholinesterase (AChE). The ability to decrease beta-amyloid levels as well as cell toxicity of all compounds were also measured. In vitro results showed that at least four compounds displayed promising activity against SERT and AChE. Compounds 18 and 19 (IC50 = 3.4 and 3.6 mu M respectively) exhibited AChE inhibition profile in the same order of magnitude as donepezil (DPZ, IC50 = 2.17 mu M), also displaying nanomolar affinity in SERT. Moreover, compounds 17 and 24 displayed high SERT affinities (IC50 = 9.2 and 1.9 nM respectively) similar to the antidepressant citalopram, and significant micromolar AChE activity at the same time. All the bioactive compounds showed a low toxicity profile in the range of concentrations studied. Molecular docking allowed us to rationalize the binding mode of the synthesized compounds in both targets. In addition, we also show that compounds 11 and 25 exhibit significant beta-amyloid lowering activity in a cell-based assay, 11 (50% inhibition, 10 mu M) and 25 (35% inhibition, 10 mu M).Comisión Nacional de Investigación Cientifica y Tecnológica (CONICYT) CONICYT FONDECYT 1170269 1170662 3170264 FONDEQUIP EQM 160042 Conicyt-PFCHA/Doctorado Nacional 2018-21180427 Fisher Foundation for Alzheimer's Researc