Synthesis of metabolites from the 5-APB and 6-APB drugs of abuse

Part of the results of this work was included in the following scientific communication: Poster: I. Fino, C. Cardoso, Luísa M. Ferreira and Paula S. Branco, “Synthesis of drug metabolites of abuse of Benzo Fury´s”, in the “13º Encontro Nacional de Química Orgânica e 6º Encontro Nacional de Química Terapêutica”, Universidade de Aveiro, Aveiro, Portugal, 15- 17 of January of 2020Benzofurans, also known as "Benzo Fury´s", are synthetic phenethylamines that belong to a growing group of designer drugs so-called novel psychoactive substances (NPS). Benzofurans act preferentially by disturbing the functioning of serotonergic circuits as a serotonin-norepinephrine dopamine reuptake inhibitor. Their ability to induce entactogenic and stimulant effects, similar to classic illicit psychostimulants but with higher potency, lead to an increase in the recreational consumed. Therefore, the number of benzo fury‐related deaths has been increasing, and some recent research work put in evidence that the abuse of these NPS is an alarming threat for public health. The first benzofurans to appear on the drug scene, in 2010, were 5‐(2‐aminopropyl)benzofuran (5‐APB) and 6‐(2‐aminopropyl)benzofuran (6‐APB). These compounds have previously been patented in 2006 as potential therapeutic drugs for eating disorders and seizures. To date, there is still a lack of toxicological and clinical information regarding these compound and their metabolites. For this reason, it is essential to develop a synthesis for benzofurans metabolites and determine their in vitro toxicity. The main goal of this thesis was to develop a synthesis for 5-APB and 6-APB oxidized metabolites for toxicological studies. For the preparation of 5-APB metabolites, four different pathways were outlined. Both synthetic ways started with the methylation of 2-hydroxyphenyl acetic acid. The acid metabolite follows a general procedure: methylation, Rieche formylation, aldol reaction with nitroethane, reduction by catalytic hydrogenation. For the alcohol metabolite there were some differences, the methylation reaction is followed by a reduction reaction and alcohol protection before the formylation reaction, and besides the catalytic hydrogenation, another reduction using aluminium lithium hydride was performed. For the preparation of 6-APB metabolites, only one pathway was outlined and only one metabolite was a target of this work. The synthetic way started with the reduction of 2-(4-bromo-2-methoxyphenyl) acetic acid, followed by an alcohol protection reaction and formylation reaction. As envisaged for the alcohol metabolite of 5-APB, two different reductions were performed, catalytic hydrogenation and a reduction using aluminium lithium hydride. Only one metabolite was attained and previous synthetic stable intermediates were achieved. All compounds were chemically characterized and can be used in upcoming toxicological studies.Os benzofuranos, também conhecidos como "Benzo Fury's", são fenetilaminas sintéticas que pertencem a um grupo de “designer drugs em crescimento” chamadas novas substâncias psicoativas (NPS). Os benzofuranos perturbam preferencialmente o funcionamento dos circuitos serotonérgicos na forma de inibidor da recaptação da serotonina-norepinefrina-dopamina. A sua capacidade de induzir efeitos entactogênicos e estimulantes, semelhantes aos psicoestimulantes ilícitos clássicos mas com maior potência, levou a um aumento no consumo recreativo. Subsequentemente, o número de mortes relacionadas com benzofuranos tem aumentado, e alguns trabalhos de pesquisa recentes evidenciam que o uso abusivo das NPS se tornou uma ameaça alarmante para a saúde pública. Os primeiros benzofuranos a serem identificados foram 5‐(2‐ aminopropil) benzofurano (5‐APB) e 6‐(2‐aminopropil) benzofurano (6‐APB) em 2010. Estes compostos foram patenteados em 2006 como drogas terapêuticas com potencial para tratar distúrbios alimentares e convulsões. Até o momento, as informações toxicológicas e clínicas sobre estes compostos e os seus metabolitos é bastante reduzida. Por esse motivo, é essencial desenvolver uma via simtética para os seus metabolitos e determinar a sua toxicidade in vitro. O objetivo principal desta tese foi desenvolver uma síntese para metabolitos oxidados do 5- APB e do 6-APB para estudos toxicológicos. Para a preparação dos metabolitos do 5-APB, quatro vias diferentes foram delineadas. Ambas as vias sintéticas começaram com a metilação do ácido 2- hidroxifenilacético. O metabolito ácido seguiu um procedimento geral: metilação, formilação de Rieche, reação aldólica com nitroetano e redução por hidrogenação catalítica. Para o metabolito álcool surgiram algumas diferenças, a reação de metilação é seguida por uma reação de redução e proteção do álcool antes da reação de formilação e, além da hidrogenação catalítica, foi realizada outra redução com hidreto de alumínio lítio. Para a preparação de um dos metabolitos do 6-APB apenas uma via foi delineada. A via sintética começou com a redução do ácido 2- (4-bromo-2- metoxifenil) acético, seguida por uma reação de proteção do álcool e reação de formilação. Conforme realizado para o metabólito álcool do 5-APB, diferentes reduções foram realizadas, hidrogenação catalítica e uma redução utilizando hidreto de alumínio lítio. Apenas um metabolito foi sintetizado e outros intermediários estáveis foram obtidos. Estes novos compostos foram caracterizados quimicamente e poderão ser usados futuramente em estudos toxicológicos

Recurring retrieval needs in diverse and dynamic dataspaces: Issues and reference framework

Processing information requests over heterogeneous data spaces is very challenging because aimed at guaranteeing user satisfaction with respect to conflicting requirements on result quality and response time. In [3], it has been argued that, in dynamic contexts pre-venting substantial user involvement in interpreting requests, information on similar requests recurring overtime can be exploited during query processing. In this paper, referring to a graph-based modeling of dataspaces and requests, we propose a preliminary approach in this direction centered on the enabling concept of Profiled Graph Query Pattern (PGQP) as an aggregation of information on past evaluations of a set of previously executed queries. The information maintained in PGQP is not query results, as in materialized queries, but can include different kinds of data and metadata

Calabi-Yau cones from contact reduction

We consider a generalization of Einstein-Sasaki manifolds, which we characterize in terms both of spinors and differential forms, that in the real analytic case corresponds to contact manifolds whose symplectic cone is Calabi-Yau. We construct solvable examples in seven dimensions. Then, we consider circle actions that preserve the structure, and determine conditions for the contact reduction to carry an induced structure of the same type. We apply this construction to obtain a new hypo-contact structure on S^2\times T^3.Comment: 30 pages; v2: typos corrected, presentation improved, one reference added. To appear in Ann. Glob. Analysis and Geometr

Polychrome majolica of Apulian domes: history, technique, pathology and conservation

The paper is focused on the historical-architectural evolution and material-technical qualification of polychrome majolica domes that were built between the 17th and 19th centuries in Apulian religious buildings. In particular, the cultural context in which this solution spread throughout the Mediterranean area is identified. Moreover, the case history of construction and decorative techniques that are distinctive of the regional territory is discussed in terms of underlying structure, installation of elements and surface colours. The study is then detailed on the Church of Santa Maria della Vetrana in Castellana Grotte (BA), for which the morpho-typological survey and mapping of the decay state are presented, based on the use of terrestrial and aerial digital photogrammetry. Finally, based on the identification of the main pathologies from both direct and indirect alteration factors, the most appropriate conservation and maintenance interventions are outlined, with specific focus on repair and integration of the majolica tiles, according to principles of high compatibility and low intrusiveness for a solution meeting artisan tradition and technical practice

Polychrome majolica of Apulian domes: history, technique, pathology and conservation

[EN] The paper is focused on the historical-architectural evolution and material-technical qualification of polychrome majolica domes that were built between the 17th and 19th centuries in Apulian religious buildings. In particular, the cultural context in which this solution spread throughout the Mediterranean area is identified. Moreover, the case history of construction and decorative techniques that are distinctive of the regional territory is discussed in terms of underlying structure, installation of elements and surface colours. The study is then detailed on the Church of Santa Maria della Vetrana in Castellana Grotte (BA), for which the morpho-typological survey and mapping of the decay state are presented, based on the use of terrestrial and aerial digital photogrammetry. Finally, based on the identification of the main pathologies from both direct and indirect alteration factors, the most appropriate conservation and maintenance interventions are outlined, with specific focus on repair and integration of the majolica tiles, according to principles of high compatibility and low intrusiveness for a solution meeting artisan tradition and technical practice.De Fino, M.; Porcari, VD.; Scioti, A.; Guida, A.; Fatiguso, F. (2022). Polychrome majolica of Apulian domes: history, technique, pathology and conservation. VITRUVIO - International Journal of Architectural Technology and Sustainability. 7(2):34-45. https://doi.org/10.4995/vitruvioijats.2022.1868434457