The Synthesis of (E)-4-Thio-5-(2-Bromovinyl)Uridine/Deoxyuridine and Its Characterization and Cytotoxicity

(E)-4-Thio-5-(2-brominevinyl)uridine/2'-deoxyuridine(8a/8b) were efficiently and in an environmental friendly way synthesized from uridine/2'-deoxyuridine (1a/1b) that were first transformed to (E)-(2-brominevinyl) uridine / 2'-deoxyuridine(5a/5b) via iodination, selective oxidation, Heck reaction steps. The resulting products (5a/5b) were then converted to the targets (8a/8b) through esterification, thio-reaction of carbonyl, hydrolysis steps. Two new compounds (8a/8b) and three new intermediates (7a 7b 10) were obtained, and their structures have been fully characterized by 1H NMR, 13C NMR, IR, UV, HR-MS, X-Ray. The study of 8a and their derivatives regarding cytotoxicity was carried out by using MTT experiment method, and the initial findings suggest (E)-4-Thio-5-(2-brominevinyl) uridine/ 2'-deoxyuridine (8a / 8b) would be potential antitumor drugs

Synthesis and preliminary biological screening of certain 5-aralkyl pyrrolidine-3-carboxylic acids as anticonvulsants

Synthesis of a series of 5-aralkyl pyrrolidine-3-carboxylic acid derivatives namely, 1-acetyl-4-hydroxy-5-benzyl or 5-(4-alkoxy-benzyl)-pyrrolidine-3-carboxylic acids (3a-e), 1-H-4-hydroxy-5-benzyl or 5-(4-alkoxy-benzyl)-pyrrolidine-3-carboxylic acids (4a-e), 1-acetyl-5-benzyl or 5-(4-alkoxy-benzyl)-pyrrolidine-3-carboxylic acids (8a-e), 1-H-5-benzyl or 5-(4-alkoxy-benzyl)-pyrrolidine-3-carboxylic acids (9a-e) have been accomplished. The structures of the new compounds were assigned from IR, 1H NMR, 13C NMR and elemental analyses. Compounds 3a-e, 4a-e, 8a-e and 9a-e were biologically screened for their anticonvulsant potential using the subcutaneous pentylenetetrazole seizures (scPTZ) assay and Gabapentin as reference standard. The 1-H-4-hydroxy-5-benzyl or 5-(4-alkoxy-benzyl)-pyrrolidine-3-carboxylic acids (4a-e) showed the highest anticonvulsant activity. Compound 4b was found to be the most potent one which exhibited 100% protection

A novel synthesis of 2'-hydroxy-1',3'-xylyl crown ethers

Six novel 2' - hydroxy - 1',3' - xylyl crown ethers (8a–e and 13)1 have been synthesized utilizing the allyl group to protect the OH function during the cyclization reaction. The macrocycles 6a-e were formed in yields of 26 to 52%, by intermolecular reaction of 4 - chloro - 2,6 - bis(bromomethyl) - 1 - (2 - propenyloxy)benzene (5) with polyethylene glycols; 6a was also obtained by an intramolecular cyclization reaction of monotosylate 14.\ud A 30-membered ring with a 2' - hydroxy - 1',3' - xylyl sub-unit was obtained in 87% yield by reaction of ditosylate 9 with bis [2 - (o - hydroxyphenoxy)ethyl]ether (11) in the presence of cesium fluoride. The synthesis of crown ethers with a 2' - hydroxy - 1',3' - xylyl sub-unit (1c–e, H for CH3) by demethylation of the corresponding 2'-methoxy crown ethers 1c–e with lithium iodide were unsuccessful; it would appear that the demethylation reaction is restricted to 15- and 18-membered rings. One of the 2' - hydroxy - 1',3' - xylyl crown ethers 8d forms a crystalline 1:1-complex with water

Switch II Region in Gαi1: Specificity for Ric-8A

On the cell surface are G protein coupled receptors that bind to agonists, causing activation of intracellular G proteins, by catalyzing exchange of GTP for GDP at the G protein alpha subunit (Ga). G proteins are also activated by guanine nucleotide exchange factors (GEF) inside of the cell; these include Ric-8A and Ric-8B. GTP-bound Ga can stimulate the activity of intracellular enzymes. For example, Gas activates adenylyl cyclase, while Gai1 inhibits the activity of this enzyme. Biochemical studies have shown that Ric-8A is a GEF towards Gai1 whereas its isoform Ric-8B acts on Gas. Previous studies in our laboratory and others have shown that a region in Gαi1 called switch II binds to Ric-8A. In this study, we test the hypothesis that differences in amino acid sequence between Gai1 and Gas in switch II are responsible for the ability of these G proteins to discriminate between Ric-8A and Ric-8B. The switch regions of Gai1 and Gas differ in only three amino acids. We predict that, by mutating these amino acids in Gai1 to their corresponding residues in Gas, affinity for Ric-8A will be impaired. Single mutation primers (S206D, K209R and H213Q) were made, transformed and amplified through a polymerase chain reaction (PCR). Once mutant plasmid was expressed in E. coli cells, it is purified, and a tryptophan fluorescence assay is performed. This assay technique detects changes in the fluorescence of tryptophan 211, a side chain in switch II that is sensitive to the exchange of GTP for GDP. Our research sheds light on how mutants in Gai1 in the switch II region plays important role in specificity of binding for Ric-8A

Applying deep learning extreme multi-label classification to the biomedical and multilingual panoramas

Tese de mestrado em Bioinformática e Biologia Computacional, Universidade de Lisboa, Faculdade de Ciências, 2020A indexação automática de documentos é um passo fundamental para a organização de dados e para a extração de informação relevante dos mesmos. Esta extração de informação é realizada através de processos de prospecção de texto e de técnicas de processamento de linguagem natural que tornam a linguagem natural perceptível para o computador. Actualmente, muitas das soluções que são aplicadas a estes processos consistem em soluções de aprendizagem automática. No entanto, tem se assistido a um aumento contínuo da aplicação de soluções de aprendizagem profunda em tarefas de prospecção de texto e de processamento de linguagem natural visto que, graças aos desenvolvimentos contínuos ao longo dos últimos anos, estas soluções têm conseguido obter cada vez melhores resultados. Uma dessas técnicas é a classificação multi-rótulo extrema, uma técnica de processamento de linguagem natural que consiste na indexação de documentos com rótulos pertencentes a um conjunto que pode conter milhares ou mesmo milhões de possíveis rótulos. Este trabalho apresenta um sistema desenvolvido para as ciências biomédicas e para o domínio multilinguístico, através da adaptação de um algoritmo de classificação multi-rótulo extrema usando aprendizagem profunda. O sistema desenvolvido combina ainda um software de reconhecimento de entidades nomeadas com o algoritmo de classificação multi-rótulo extrema de forma a melhorar a atribuição de rótulos aos documentos biomédicos. Para testar o sistema desenvolvido, participei em três competições internacionais com foco na área das ciências biomédicas, nomeadamente na BioASQ task 8a, BioASQ task MESINESP e ainda na subtarefa CODING da competição CANTEMIST. O objectivo comum destas três competições consistia na indexação de documentos biomédicos com rótulos pertencentes a um dado vocabulário biomédico. No entanto, enquanto na task 8a os dados estavam escritos em Inglês, na task MESINESP e na CANTEMIST, os dados biomédicos estavam escritos em Espanhol. Nas competições da BioASQ, o sistema desenvolvido destacou-se sobretudo nas medidas de precisão, superando a grande maioria dos sistemas e ainda alcançando o 1º lugar por duas semanas consecutivas numa das medidas da BioASQ task 8a. Na subtarefa CODING da CANTEMIST, o sistema atingiu uma pontuação de 0.506 na medida mais relevante.Automatic document indexation is a fundamental step for data organization and information retrieval tasks. Information retrieval can be realized through processes of text mining and natural language processing techniques that make natural language understandable to the computer. Nowadays, most solutions that are applied to these processes use machine learning algorithms. However, thanks to continuous developments through recent years, there has been an increasing usage of deep learning solutions applied to text mining and natural language processing tasks, due to the continuous achievement of better results. One of those techniques is extreme multi-label classification, a natural language processing task consisting in the indexation of documents with labels from a label set that may contain thousands or even millions of possible labels. This work presents a system developed for the biomedical and multilingual panoramas based on the adaptation of a deep learning extreme multi-label classification algorithm. The developed system also combines a named entity recognition software with the extreme multi-label classification algorithm in order to improve the label classification of the biomedical documents. To test the developed system, I participated in three international challenges focused on the biomedical sciences, namely in the BioASQ task 8a, BioASQ task MESINESP and in CANTEMIST CODING subtask. The common goal of these three competitions was the indexation of biomedical documents with labels belonging to a specific biomedical vocabulary. However, while the data in task 8a was in English, in task MESINESP and in CANTEMIST the biomedical data was written in Spanish. In the BioASQ competitions, the system stood out in the precision measures, surpassing most competing systems and achieving the 1st place for two consecutive weeks in one evaluation measure in the BioASQ task 8a. In the CANTEMIST CODING subtask, the system achieved a score of 0.506 in the most relevant measure

Synthesis and antifungal activity of some new pyrido[2,3-d]pyrimidines

Some new pyrido[2,3-d]pyrimidine derivatives (3a-c) were synthesized from 2-amino-5-cyano-6-methoxy-4-(4-methoxyphenyl)pyridine-3-carboxamide. 7-methoxy-5-(4-methoxy phenyl)-4-oxo-2-phenyl-3,4-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (3b) and 7-met-hoxy-5-(4-methoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (3c) are used in synthesizing 7a,b, then 8a,b. 7-methoxy-5-(4-methoxyphenyl)-2-methyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (3a) and 4-hydrazinyl-7-methoxy-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-6-carbonitrile (8b) were condensed with different carbonyl compounds to produce compounds 4, 5, 6 and 9, 10, 11, 12. 3-Methoxy-1-(4-methoxyphenyl)-6-phenyl-7-hydropyridino[2,3-d]1,2,3,4-tetrazolo[1,5-e]pyrimidine-2-carbo-nitrile (13) was synthesized from 8a or 7a. Condensation of 8b with acetophenone to yield 14, which on further reaction gave 15 then 16. 4-Hydrazinyl-7-methoxy-5-(4-methoxyphenyl)-2-phenylpyrido[2,3-d]pyrimidine-6-carbonitrile (8a) also condensed with 4-amino antipyrine giving 17 then 18. Structures of these compounds have been deduced upon the basis of elemental analysis and spectral data. Significant antifungal activities were observed for some of the synthesized compounds

Exact solutions to the modified Korteweg-de Vries equation

A formula for certain exact solutions to the modified Korteweg-de Vries (mKdV) equation is obtained via the inverse scattering transform method. The kernel of the relevant Marchenko integral equation is written with the help of matrix exponentials as $$\Omega(x+y;t)=Ce^{-(x+y)A}e^{8A^3 t}B,$$ where the real matrix triplet $(A,B,C)$ consists of a constant $p\times p$ matrix $A$ with eigenvalues having positive real parts, a constant $p\times 1$ matrix $B$, and a constant $1\times p$ matrix $C$ for a positive integer $p$. Using separation of variables, the Marchenko integral equation is explicitly solved yielding exact solutions to the mKdV equation. These solutions are constructed in terms of the unique solution $P$ to the Sylvester equation $AP+PA=BC$ or in terms of the unique solutions $Q$ and $N$ to the respective Lyapunov equations $A^\dagger Q+QA=C^\dagger C$ and $AN+NA^\dagger=BB^\dagger$, where the $\dagger$ denotes the matrix conjugate transpose. Two interesting examples are provided.Comment: 15 pages, 1 figur

Convergent synthesis of new N -substituted 2-{[5-(1H -indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]sulfanyl}acetamides as suitable therapeutic agents

A series of N-substituted 2-{[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]sulfanyl}acetamides (8a-w) was synthesized in three steps. The first step involved the sequential conversion of 2-(1H-indol-3-yl)acetic acid (1) to ester (2) followed by hydrazide (3) formation and finally cyclization in the presence of CS2 and alcoholic KOH yielded 5-(1H-indole-3-yl-methyl)-1,3,4-oxadiazole-2-thiol (4). In the second step, aryl/aralkyl amines (5a-w) were reacted with 2-bromoacetyl bromide (6) in basic medium to yield 2-bromo-N-substituted acetamides (7a-w). In the third step, these electrophiles (7a-w) were reacted with 4 to afford the target compounds (8a-w). Structural elucidation of all the synthesized derivatives was done by 1H-NMR, IR and EI-MS spectral techniques. Moreover, they were screened for antibacterial and hemolytic activity. Enzyme inhibition activity was well supported by molecular docking results, for example, compound 8q exhibited better inhibitory potential against α-glucosidase, while 8g and 8b exhibited comparatively better inhibition against butyrylcholinesterase and lipoxygenase, respectively. Similarly, compounds 8b and 8c showed very good antibacterial activity against Salmonella typhi, which was very close to that of ciprofloxacin, a standard antibiotic used in this study. 8c and 8l also showed very good antibacterial activity against Staphylococcus aureus as well. Almost all compounds showed very slight hemolytic activity, where 8p exhibited the least. Therefore, the molecules synthesized may have utility as suitable therapeutic agents.Uma série de acetamidas 2-{[5-(1H-indol-3-ilmetil)-1,3,4-oxadiazol-2-il]sulfanila} N-substituídas (8a-w) foi sintetizada em três fases. A primeira etapa envolveu a conversão sequencial de ácido 2-(1H-indol-3-il)acético (1) a éster (2), seguido por hidrazida (3) e, finalmente, a e ciclização na presença de CS2 e KOH alcoólico produziu 5-(1H-indol-3-il- metil)-1,3,4-oxadiazole-2-tiol (4). Na segunda etapa, aminas arílicas/aralquílicas(5a-w) reagiram com brometo de 2-bromoacetila (6​​), em meio básico, para se obter acetamidas 2-bromo-N-substituídas (7a-w). Na terceira etapa, estes eletrófilos (7a- w) reagiram com 4, para se obter os compostos alvo (8a-w). A elucidação estrutural de todos os derivados sintetizados foi realizada por 1H-NMR, IR e técnicas de espectrometria de EI-MS. Além disso, eles foram submetidos a triagem de atividade antibacteriana e hemolítica. Análise da inibição enzimática foi bem apoiada pelos resultados de docking molecular. Por exemplo, o composto 8q exibiu melhor potencial inibitório contra α-glicosidase, e os compostos 8g e 8b exibiram, comparativamente, melhor inibição contra butirilcolinesterase (BChE) elipoxigenase (LOX), respectivamente. Do mesmo modo os compostos 8b e 8c mostraram excelente potencial antibacteriano contra SalmonellaTyphi, semelhante ao do ciprofloxacino, antibiótico padrão usado neste estudo. Os compostos 8c e 8l também mostraram excelente potencial antibacteriano contra Staphylococcus aureus . Quase todos os compostos mostraram pequena atividade hemolítica, sendo que o composto 8p apresentou menor atividade. Assim, as moléculas sintetizadas podem ter a sua utilidade como agentes terapêuticos adequados

Labdane conjugates protect cardiomyocytes from doxorubicin-induced cardiotoxicity

The cardiovascular side effects associated with doxorubicin (DOX), a wide spectrum anticancer drug, have limited its clinical application. Therefore, to explore novel strategies with cardioprotective effects, a series of new labdane conjugates were prepared (6a-6c and 8a-8d) from the natural diterpene labdanodiol (1). These hybrid compounds contain anti-inflammatory privileged structures such as naphthalimide, naphthoquinone, and furanonaphthoquinone. Biological activity of these conjugates against DOX-induced cardiotoxicity was tested in vitro and the potential molecular mechanisms of protective effects were explored in H9c2 cardiomyocytes. Three compounds 6c, 8a, and 8b significantly improved cardiomyocyte survival, via inhibition of reactive oxygen species-mediated mitogen-activated protein kinase signaling pathways (extracellular signal-regulated kinase and c-Jun N-terminal kinase) and autophagy mediated by Akt activation. Some structure-activity relationships were outlined, and the best activity was achieved with the labdane-furonaphthoquinone conjugate 8a having an N-cyclohexyl substituent. The findings of this study pave the way for further investigations to obtain more compounds with potential cardioprotective activity.This study was supported by Grant RTI2018‐094356‐BC21 from the Ministerio de Ciencia, Innovación y Universidades (MICIU) to A. E.‐B., I. C., L. G.‐C., and B. H.; Grant PI17/00012 and PI20/00018 from the Instituto de Salud Carlos III to S. H. These projects are also cofunded by the European Regional Development Fund (FEDER). A. A. and S. O.‐R. thank the Cabildo de Tenerife (Agustín de Betancourt Program).S