Millorem l’aprenentatge dels alumnes amb metodologies més actives

Treball Final de Màster Universitari en Professor/a d'Educació Secundària Obligatòria i Batxillerat, Formació Professional i Ensenyaments d'Idiomes. Codi: SAP119. Curs acadèmic 2014-2015El Treball Final de Màster que es presenta en aquest document pertany a la modalitat de Millora Educativa d’acord amb la normativa de TFM de la Universitat Jaume I. En ell es pretén demostrar que la transformació de les metodologies tradicionals en unes altres més actives augmenta l’interés dels alumnes de 3r d’ESO per l’assignatura de Física i Química tot generant un aprenentatge significatiu. Els alumnes manifesten un alt grau d’avorriment en les classes de Física i Química, el qual es tradueix en un baix interés per l’assignatura i uns mals resultats acadèmics. Aquest fet s’ha pogut detectar gràcies a l’observació directa durant el període de pràctiques i als resultats de les enquestes realitzades als alumnes sobre la seua percepció de l’assignatura. Aquest estudi s’ha desenvolupat seguint les pautes marcades segons la metodologia d’investigació-acció. La hipòtesi d’acció abordada inclou quatre activitats relacionades amb els temes de Reaccions químiques i Quantitat de substància, les quals han estat dissenyades segons les tècniques de participació activa i d’aprenentatge cooperatiu. S’incorpora també una cinquena activitat amb la qual es pretén verificar si realment les noves metodologies de treball introduïdes han millorat l’aprenentatge i el rendiment acadèmic dels alumnes a nivell individual. Per tal de recollir els resultats derivats de l’aplicació de la millora educativa s’han utilitzat instruments variats per obtenir informació, així com s’han fixat una sèrie d’indicadors per valorar fins a quin punt s’han aconseguit els objectius proposats. En general, després de l’anàlisi dels resultats, es pot concloure que aquesta nova dinàmica de treball ha estat ben rebuda pels alumnes i ha complert les expectatives proposades. A més a més, el caràcter cíclic i autoreflexiu de la metodologia d’investigació-acció ha permés identificar nous problemes a tractar en futurs treballs

Novel multitarget inhibitors with antiangiogenic and immunomodulator properties

By means of docking studies, seventeen compounds T.1-T17 have been designed and evaluated as multitarget inhibitors of VEGFR-2 and PD-L1 proteins in order to overcome resistance phenomena offered by cancer. All these designed molecules display a urea moiety as a common structural feature and eight of them (T.1-T8) further contain a 1,2,3-triazol moiety. The antiproliferative activity of these molecules on several tumor cell lines (HT-29, MCF-7, HeLa, A549, HL-60), on the endothelial cell line HMEC-1 and on the non-tumor cell line HEK-293 has been determined. The urea derivatives were also evaluated for their antiangiogenic properties, whereby their ability to inhibit tubulogenesis and kinase activity employing flow cytometry, ELISA, immunofluorescence and western blot techniques was measured. In addition, these techniques were also employed to investigate the immunomodulator action of the synthetic compounds on the inhibition of PD-L1 and c-Myc proteins. Compound T.2, 1-(3-chlorophenyl)-3-(2-(4-(4-methoxybenzyl)-1H-1,2,3-triazol-1-yl)ethyl)urea, has shown similar results to sorafenib in both down-regulation of VEGFR-2 and inhibition of the kinase activity of this receptor. Furthermore, compound T.14, (E)-1-(4-chlorophenyl)-3-(3-(4-methoxystyryl)phenyl)urea, improves the effect of T.2 as regards tube formation of endothelial cells and inhibition of VEGFR-2 tyrosine kinase activity. In addition, T.14 improves the effect of the experimental drug BMS-8 in the inhibition of PD-L1 and c-Myc proteins

Synthesis, In Silico Studies, Antiprotozoal and Cytotoxic Activities of Quinoline‐Biphenyl Hybrids

This is the pre-peer reviewed version of the following article: Synthesis, In Silico Studies, Antiprotozoal and Cytotoxic Activities of Quinoline‐Biphenyl Hybrids, which has been published in final form at https://doi.org/10.1002/slct.201903835. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsThe synthesis, in silico studies, antiprotozoal and cytotoxic activities of eleven quinoline‐biphenyl hybrids are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against Plasmodium falciparum, and amastigotes forms both Leishmania (V) panamensis and Trypanosoma cruzi. Cytotoxicity was evaluated against human U‐937 macrophages. 8‐phenylquinoline (4 a) showed similar activity than meglumine antimoniate and 4‐(quinolin‐8‐yl)phenol (4 b) exhibited an activity similar to that of benznidazole. 8‐(3,4‐dimethoxyphenyl) quinoline (4 k) showed the best activity against P. falciparum. Although these compounds were toxic for mammalian U‐937 cells, however they may still have potential to be considered as candidates for drug development because of their antiparasite activity. Molecular docking was used to determine the in silico inhibition of some of the designed compounds against PfLDH and cruzipain, two important pharmacological targets involved in antiparasitic diseases. All hybrids were docked to the three‐dimensional structures of PfLDH and T. cruzi cruzipain as enzymes using AutoDock Vina. Notably, the docking results showed that the most active compounds 4‐(quinolin‐8‐yl)phenol (4 b, CE50: 11.33 μg/mL for T. cruzi) and 8‐(3,4‐dimethoxyphenyl) quinoline (4 k, CE50: 8.84 μg/mL for P. falciparum) exhibited the highest scoring pose (−7.5 and −7.7 kcal/mol, respectively). This result shows a good correlation between the predicted scores with the experimental data profile, suggesting that these ligands could act as competitive inhibitors of PfLDH or T. cruzi cruzipain enzymes, respectively. Finally, in silico ADME studies of the quinoline hybrids showed that these novel compounds have suitable drug‐like properties, making them potentially promising agents for antiprotozoal therapy

Synthesis and biological evaluation of carbamates derived from aminocombretastatin A-4 as vascular disrupting agents

A series of t wenty-six carbamates derived from aminocombretastatin A- 4 (AmCA-4 ) were syn thesized and evaluated for their capacity to affect cell proliferation, tubulin polymerization, mitotic cell arrest, microtubule network organization, apoptos is and endothelial tubular structures in vitro. The anti- pro liferative activity of the synthetic carbamates was measured on several human tumor cell lines (i.e. HT-29, MCF-7, HeLa, A-549, MDA-MB-231, H L-60) as well as on the endothelial cell line HMEC-1 and the non-tumor cell line H EK-293. The compounds showed anti-proliferative activity in the nanomolar range thereby exceeding by far the activity of combretastatin A-4 (CA-4 ) and, in some cases, the activity of AmCA-4. The most active compounds proved to be the carbamates bearing chloro, bromo or methoxy groups in the meta position of the phenyl ring. Moreover, all carbamates inhibited in vitro tubulin polymerization, in a similar manne r to that of CA-4 and Am CA-4 by interacting with the colchicine binding site in tubulin. The synthetic carbamates proved as active as AmCA-4 in causing mitotic arrest, as asses sed in A549 human lung cancer cells, and disruption of the microtubule ce llular network. Some selected carbamates induced apoptosis at concentrations as low as 10 nM, being more active than AmCA-4. Final ly, these selected carbamates displayed a vascular disrupting activity on endothelial cells in a dose-dependent manner. In conclusion, our data indicate that carbamates derived from aminocombretastatin A-4 represent interesting lead compounds for the design of vascular dis- rupting agent

Synthesis and biological evaluation of simplified pironetin analogues with modifications in the side chain and the lactone ring

The preparation of several new analogues of the natural dihydropyrone pironetin is described. They differ from the natural product mainly in the nature of the side chain and the lactone ring. Their cytotoxic activity has been measured. In addition, their interaction with tubulin, their ability to inhibit the secretion of the vascular endothelial growth factor (VEGF) and the expression of angiogenesis and telomeraserelated genes have been determined. Unexpectedly, and unlike pironetin, the lactones studied in this work do not interact with tubulin. Two of the compounds have been found to downregulate the expression of the hTERT and VEGF genes. Furthermore, one of them causes an appreciably decrease in the secretion of the VEGF protein

Synthesis and in-vitro evaluation of s-allyl cysteine ester-caffeic acid amide hybrids as potential anticancer agents

We have synthesized a series of S-allyl cysteine ester-caffeic acid amide hybrids and evaluated them in order to determine their possible anticancer activity and selectivity in colorectal cancer, which is still one of the leading causes of morbidity and mortality worldwide. All compounds were tested against SW480 human colon adenocarcinoma cells and the non-malignant CHO-K1 cell line. Among the tested compounds, hybrids 6e, 9a, 9b, 9c and 9e exhibited the highest effect on viability (IC50 SW480-48h= 0.18, 0.12, 0.12, 0.11 and 0.12 mM, respectively) and selectivity (SI= 10.3, 1.5, >83.33, >90.91 and >83.33, respectively) in a time- and concentration-dependent manner. Besides, our results were even better as regards lead compounds (S-allyl cysteine and caffeic acid) and the standard drug (5-FU). Additionally, these five compounds induced mitochondrial depolarization that could be related with an apoptotic process. Moreover, hybrids 6e, 9a and 9e induced cell cycle arrest in G2/M phase, and compound 9c in S- phase, which suggests that these hybrid compounds could have also a cytostatic effect in SW480 cell line. The SAR analysis showed that hydroxyl groups increased the activity, besides, there was not a clear relationship between the antitumor properties and the length of the alkyl chain. Since hybrid compounds were much more selective than the conventional drug (5-FU), this make them promising candidates for further studies against colorectal cancer

N-alpha-Aminoacyl Colchicines as Promising Anticancer Agents

Background: In the last years, many efforts have been made to find colchicine derivatives with reduced toxicity. Additionally, the deregulation of amino acid uptake by cancer cells provides an opportunity to improve anticancer drug effectiveness. Objective: To design new colchicine derivatives with reduced cytotoxicity and enhanced selectivity by means of introducing aminoacyl groups. Methods: 34 colchicine analogues bearing L- and D-amino acid pendants were synthetized and characterized by NMR, IR and MS techniques. Cytotoxicity and antimitotic properties were assessed by spectrophotometry and cell cycle assays. Oncogene downregulation was studied by RTqPCR whereas in vivo studies were performed in SCID mice. Results: Compounds exhibit high antiproliferative activities at the nanomolar level while being, in general, less cytotoxic than colchicine. Most compounds inhibit the polymerization of tubulin in a way similar to colchicine itself, with L-amino acid derivatives being the most active in the inhibition of tubulin polymerization. All selected compounds caused cell cycle arrest at the G2/M phase when tested at 1 μM. More specifically, Boc-L-proline derivative 6 arrested half of the population and showed one of the highest Selectivity Indexes. Derivatives 1 (Boc-glycine), 27 (D-leucine) and 31 (Boc-glycine-glycine) proved fairly active in downregulating the expression of the c-Myc, hTERT and VEGF oncogenes, with compound 6 (Boc-L-proline) having the highest activity. This compound was shown to exert a potent anti-tumor effect when administered intraperitoneally (LD50 > 100 mg/kg for 6, compared with 2.5 mg/kg for colchicine). Conclusion: Compound 6 offers an opportunity to be used in cancer therapy with less toxicity problems than colchicine

Furanchalcone–biphenyl hybrids: synthesis, in silico studies, antitrypanosomal and cytotoxic activities

The synthesis, antitrypanosomal, and cytotoxic activities of 17 furanchalcone derivatives are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against Trypanosoma cruzi, which is the pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Eleven compounds were active against amastigotes of T. cruzi with EC50 values lower than 40 µM. Hybrids 7b–7d and 8a–8g showed better activity than benznidazole. Structure activity relationship (SAR) showed that the presence of electron withdrawing groups, such as nitro or fluorine, increased the activity and that the degree of oxygenation is essential for activity. In addition, molecular docking was used to identify a possible protein target for the designed compounds. A spearman correlation of 0.608 between the predicted scores and the experimental data profile the enzyme cruzipain as a potential candidate. Finally, in silico ADMET studies of the arylfuranchalcones showed that these novel compounds have suitable drug-like properties, making them potentially promising agents for antichagasic therapy

Synthesis of combretastatin analogues with antineoplastic properties

This doctoral thesis belongs to the field of medicinal and pharmacological chemistry. Its aim is the synthesis, characterization and biological evaluation of three families of aminocombretastatin derivatives, compound with antimitotic and antiangiogenic properties. The first group contains a carbamate function in its structure. These derivatives have been studied as antimitotic and vascular disrupting agents. The second family has been designed from sorafenib drug, with the aim of studying its antiangiogenic effects. Regarding the third family, these have been designed as multitarget compounds, with both antiangiogenic and immunomodulatory properties. Finally, in vivo studies have been developed with the aim of knowing all the perspectives of a biological evaluation process. In conclusion, several compounds have been obtained from the same general structure, able to interact with different targets involved in cancer disease, thus improving the effect offered by aminocombretastatin.Esta tesis doctoral se enmarca en el campo de la química médica y farmacológica. Tiene como objetivo la síntesis, caracterización y evaluación biológica de tres familias de derivados de aminocombretastatina, compuesto con propiedades antimitóticas y antiangiogénicas. El primer grupo contiene una función carbamato en su estructura. Estos se han estudiado como agentes antimitóticos y disruptores de la vasculatura. La segunda familia se ha diseñado a partir del fármaco sorafenib, con el objetivo de estudiar sus efectos antiangiogénicos. Respecto a la tercera familia, se trata de compuestos multidiana, con propiedades antiangiogénicas e inmunomoduladoras. Finalmente, se han desarrollado estudios in vivo con el objetivo de conocer todas las perspectivas de un proceso de evaluación biológica. Como conclusión, destacar que a partir de una misma estructura general se han obtenido varios compuestos que interactúan con diferentes dianas involucradas en la enfermedad del cáncer, mejorando así pues el efecto ofrecido por la aminocombretastatina.Programa de Doctorat en Cièncie

Síntesis y evaluación biológica de potenciales agentes anticáncer

Treball Final del Màster Universitari en Química Aplicada i Farmacològica. Codi: SIM138. Curs acadèmic 2013-201