Relaciones estructura-actividad en compuestos relacionados con la benextramina : análogos heterocíclicos, oxigenados y porciones terminal y central

Tesi de Llicenciatura per a la obtenció del Grau de Farmàcia. Facultat de Farmàcia. Universitat de Barcelona. Director: David Mauleón Casellas. 1983

Regioselective alkylation reaction of purines under microwave irradiation

The alkylation of purines which is generally carried out after anion formation by treatment with a base and alkyl halide is complicated and in the best cases, mixtures of N-alkylated compounds are obtained. Purine derivatives can be acquired from alkylation at N-7 and N-9. In this work, the reaction conditions have been optimized to obtain the alkylation products of N-9 regioselectively. Different bases have been tried and tetrabutylammonium hydroxide has led to the best results. The reaction depends on the type of base and solvent used and improves considerably when the aid of microwave irradiation is used, which also considerably reduces the reaction time by reducing the formation of secondary products

Microwave-Assisted Synthesis of Substituted Pyrrolo[2,3-d]pyrimidines

A new synthetic routes to the triaryl pyrrolo[2,3-d]pyrimidines from common 4,6-dichloropyrimidine have been developed. The triarylated compounds are synthesized by three cross-coupling reactions using three different catalysts. The introduction of C-6-aryl was allowed in two step process using Sonogashira conditions followed by intramolecular cyclization and the Suzuki-Miyaura conditions led the C-4 and C-5 diarylation. This sequence allows a flexible approach to the highly arylated pyrrolopyrimidines containing different aryl group

Insight into the binding of DFG-out allosteric inhibitors to B-Raf Kinase using molecular dynamics and free energy calculations

B-Raf mutations are identified in 40-50% of patients with melanoma and among them, the substitution of valine for glutamic acid at position 600 (V600EB-Raf) is the most frequent. Treatment of these patients with B-Raf inhibitors has been associated with a clear clinical benefit. Unfortunately, multiple resistance mechanisms have been identified and new potent and selective inhibitors are currently needed. In this work, five different type II inhibitors, which bind V600EB-Raf in its DFG-out conformation, have been studied using molecular dynamics, free energy calculations and energy decomposition analysis. The ranking of calculated MM-PB/GBSA binding affinities is in good agreement with the experimentally measured ones. The per-residue decomposition of ΔGbinding, within the MM-GBSA approach, has been used to identify the key residues governing the allosteric binding of the studied compounds to the V600EB-Raf protein kinase. Results indicate that although van der Waals interactions are key determinants for binding, hydrogen bonds also play an important role. This work also provides a better structural understanding of the binding of DFG-out inhibitors to V600EB-Raf, which can be used in a further step for rational design of a new class of B-Raf potent inhibitors

Substituted tetrahydroisoquinolines: synthesis, characterization, antitumor activity and other biological properties

A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors (IC50 between 0.04 and 0.71 M). Also, these highly active methyl sulfones displayed greater COX-2 activity than the parent carboxylic NSAIDs, thus indicating that the replacement of the acetic or propionic acids by a methyl sulfone group enables some of these structures to possess higher COX-2 inhibitory activity than that of the corresponding alkyl carboxylic analogues. The improved inhibitory activity is attributed to the higher flexibility of the sulfone-receptor interaction that enables more profound exploration of the binding site compared with that of acidic analogues. This observation is underpinned by molecular modeling studies that indicates a change in the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs

Optimization of Xanthatin Extraction from Xanthium spinosum L. and its cytotoxic, anti-angiogenesis and antiviral properties

The aqueous extraction of the sesquiterpene lactone xanthatin from Xanthium spinosum L. favours the conversion of xanthinium to xanthatin via the loss of acetic acid. The cytotoxic (Hep-G2 and L1210 human cell lines) and antiviral activities of isolated xanthatin are established. This natural compound shows significant cytotoxicity against the Hep-G2 cell line and our experimental results reveal its strong anti-angiogenesis capacity in vitro. The structure of xanthatin is determined by spectroscopic methods and for the first time confirmed by X-ray diffraction

Multigram scale synthesis of polycyclic lactones and evaluation of antitumor and other biological properties

An efficient four-step synthesis of tetracyclic lactones from 1,4-benzodioxine-2-carboxylic acid was developed. Ellipticine derivatives exhibit antitumor activity however only a few derivatives without carbazole subunit have been studied to date. Herein, several tetracyclic lactones were synthesized and biologically evaluated. Several compounds (2a, 3a, 4a and 5a) were found to be inhibitors of the KrasWnt pathway. The lactone 2a also exerted a potent inhibition of Tau protein translation and was shown to have capacity for CYP1A1-bioactivation. The results obtained are further evidence of the therapeutic potential of tetracyclic lactones related to ellipticine. Molecular modeling studies showed that compound 2a is inserted between helix a3 and a4 of the KRas protein making interactions with the hydrophobic residues Phe90, Glu91, Ile9364, Hie94, Leu133 and Tyr137and a hydrogen bond with residue Arg97

Synthesis of pyrazolo-enaminones, bipyrazoles and pyrazolopyrimidines and evaluation of antioxidant and antimicrobial properties

A novel pyrazolo-enaminones, bipyrazoles and bipyrazolopyridines from 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)butane-1,3-dione and 4-methyl-2-phenyl-2H-pyrazolo[3,4-b]pyridine-3,6(3aH,7H)-dione have been synthesized by assisted heating with microwave radiation without any catalyst. The pyridine and pyrazole ring formation has been developed from easily accessible enamino keto esters by formylation followed by intramolecular cyclization. The general applicability for the synthesis of the important pyrazolo-enaminones, bipyrazoles and pyrazolo-pyridines heterocycles was attributed to simplicity of operation, synthesis without catalyst, energy efficiency (shorter reaction time under microwave irradiation), good yields, more environmentally friendly and more cost-effective procedure. The antioxidant activity of new heterocyclic compounds was evaluated by free radical scavenging by DPPH assay. Several of these compounds showed good activity against both Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria

Preferències dels estudiants en relació al tema d’estudi del TFG de Farmàcia (UB)

Podeu consultar la Vuitena trobada de professorat de Ciències de la Salut completa a: http://hdl.handle.net/2445/66524El TFG del grau de farmàcia UB es porta a terme en el marc d’un àmbit docent principal i integra coneixements de com a mínim, dos àmbits docents addicionals atès la seva funció integradora. En el moment de definir les directrius i organització de l’assignatura, es van establir a la Facultat de Farmàcia 27 àmbits docents. Tanmateix, les característiques del TFG quan a tipus de projectes o estudis es van establir inicialment en base a tres opcions..

Nuevas series de compuestos con actividad bloqueadora adrenérgica-B: modificaciones moleculares de la estructura de ariloxipropanolamina

[spa] El primer objetivo del presente trabajo se encamina a la investigación de las relaciones estructura-actividad en las ariloxipropanolaminas beta bloqueadoras, centrándonos en la parte de la molécula comprendida entre el anillo aromático y la cadena de oxipropanolamina. En la nueva serie de moléculas que proponemos se efectúa un alejamiento progresivo entre ambas zonas, mediante la introducción de grupos metileno o de sus bioisósteros entre el oxígeno etéreo y el anillo aromático. También se estudia en esta familia de compuestos el efecto de la restricción conformacional originada por la introducción de un elemento de rigidez parcial, o bien la formación de un ciclo que proporciona una rigidez mucho mayor