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metodologia per la sintesi di derivati delle benzotieno[2, 3-b]piridine e dmiostrazione della loro attività come inibitori della ß-secretasi

Short peptides offer a cheap alternative to antibodies for developing sensing units in devices for concentration measurement. We here describe a computational procedure that allows designing peptides capable of binding with high affinity a target organic molecule in aqueous or nonstandard solvent environments. The algorithm is based on a stochastic search in the space of the possible sequences of the peptide, and exploits finite temperature molecular dynamics simulations in explicit solvent to check if a proposed mutation improves the binding affinity or not. The procedure automatically produces peptides which form thermally stable complexes with the target. The estimated binding free energy reaches the 13 kcal/mol for Irinotecan anticancer drug, the target considered in this work. These peptides are by construction solvent specific; namely, they recognize the target only in the solvent in which they have been designed. This feature of the algorithm calls for applications in devices in which the peptide-based sensor is required to work in denaturants or under extreme conditions of pressure and temperature.

Tri-3,4-dimethoxycinnamoyl-1,5-γ-quinide was synthesized and fully characterized by a direct synthesis from quinic acid and a large excess of 3,4-dimethoxycinnamoyl chloride. Mono-and di-3,4-dimethoxycinnamoyl-1,5-γ- quinides were also obtained from the direct coupling of 1,5-γ-quinide and 3,4-dimethoxycinnamoyl chloride in different molar ratios. Moreover, a hypothetical mechanism of the direct lactonization is proposed. Mono-, di-, and tri-3,4-dimethoxycinnamoyl-1,5-γ-quinides have been synthesized from 1,5-γ-quinide and 3,4-dimethoxycinnamoyl chloride in different molar ratios. The only triester quinide was also easily obtained by a direct synthesis from D-(-)-quinic acid in the presence of an excess of the acyl chloride.

The worldwide importance of coffee industry makes the molecules present in a coffee brew potential intriguing targets for artificial receptors: a set of selective receptors may represent a convenient tool to detect and quantify different families of compounds related with both safety and taste of coffee.

Fil: Pérez De Berti, Federico Javier. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Expresión y Plegado de Proteínas; Argentina. Pérez De Berti, F. J (2018). Estudio de la estructura tridimensional de la SCP2 de Yarrowia lipolytica. (Tesis de doctorado). Universidad Nacional de Quilmes, Bernal, Argentina. En esta tesis se desarrolló un robusto y eficiente protocolo de preparación y purificación de YLSCP2 que permite tanto su cristalización, como su obtención y estudio en su forma libre de ligando. La estructura de rayos X reportada expande significativamente el conjunto de dominios SCP2 de eucariotas y unifica el conocimiento sobre este dominio a lo largo de todos los reinos de la vida. De esta forma existe la posibilidad de realizar un completo examen comparativo de este ubicuo plegado proteico y sus propiedades.

β-Defensins play an important role in both innate and adaptive immunity. Interaction with biological membranes appears to be a central theme in modulating these activities, leading to different consequences such as membrane lysis, translocation into the cytoplasm or transfer to a receptor. We have investigated the structuring of human β-defensins (hBD2 and hBD3) and rationally designed variants, in relation to their interactions with real and model membranes. Our results indicate that structural features, such as the helical N-terminal domains and oligomerisation at the membrane surface, may modulate the efficiency of membrane insertion and selectivity for microbial or host-cell membranes. We propose that both peptides interact with membranes as extended β-sheet platforms that present amphipathic helices for insertion into the lipid bilayer.

The patent describes new peptidomimetic inhibitors of retroviral proteases, in particular of human immunodeficiency virus (HIV) protease. These inhibitors comprise as the core structure a new diaminodiol isostere of the dipeptide Phe-Pro having four stereogenic centres. The inhibitors of the invention have been shown to inhibit HIV protease and can therefore be usefully employed as antivirals for post-exposure prophylaxis and as a therapy for viral infections by a retrovirus, in particular HIV. The syntheses processes of the isosteres and inhibitors are also described.

Three diastereoisomeric hydroxyethylene isosters of the Val- Ala dipeptide were synthesized from α,β-unsaturated ketones 1 derived from N-Boc- and N,N-dibenzyl-L-valine. The enones were hydrocyanated with diethylaluminum cyanide to give the corresponding β-cyano ketones with the stereoselectivity depending on the protecting group. N-Boc protected enone 1a gave a 1:1 mixture of anti and syn adducts 4a, 5a while the corresponding N,N-dibenzyl compound 1c gave a 6:1 mixture of anti, syn adducts 4c, 5c. Borohydride reduction of the resulting cyano ketones is also controlled by the protecting group, resulting in opposite stereoselectivities for N-Boc and N,N-dibenzyl compounds. The cyano alcoholsthus obtained were converted, in several steps, into two series of enantiomerically pure hydroxyethylene isosters of the Val-Ala dipeptide. In the first series the hydroxy group and the N-terminal of the isoster are internally protected through the formation of an oxazolidine; in the second series the hydroxy group and the C-terminal are protected as lactone. Two oxazolidines (28, 29), corresponding to syn,syn and syn,anti 4-hydroxy-5-amino acid isosters, and three lactones (23−25), corresponding to syn,syn, syn,anti, and anti,anti isosters were obtained by this approach.

Cyclisation of alfa-cyano-alfa-sulfonyl-gamma,delta-epoxy carbanions proceeds with high yields and complete diastereoselectivity to yield cyclopropanolactones, useful intermediates in the synthesis of cis-substituted cyclopropane carboxylic acids.

indole derivatives are obtained from ketoenamines and nitroolefins