Showing: 10 from total: 35 publications
1. Thermal Study of Two Benzotriazole Derivatives
Lima, ACMO ; Silva, ALR ; da Silva, MDMCR
in U.Porto Journal of Engineering, 2022, ISSN: 2183-6493,  Volume: 8, 
Article,  Indexed in: crossref, scopus 
Abstract An experimental study based on the thermal analysis of 5-methyl-1H-benzotriazole and 5,6-dimethyl-1H-benzotriazole was developed, by using differential scanning calorimetry. Additionally, a summary of the experimental techniques and computational methodology being performed, in order to complement the energetic study of both compounds, is described. The knowledge of the thermochemical, thermophysical and structural properties of functionalized benzotriazoles is relevant for the evaluation of their chemical behaviour, as well as in the prediction of the reactivity of similar compounds that have not been thermodynamically characterized. © 2022, Universidade do Porto - Faculdade de Engenharia. All rights reserved.

2. Thermodynamic properties of 2-mercapto-, 2,5-dimethyl- and 2-mercapto-5-methyl-1,3,4-thiadiazole
Silva, ALR ; Goncalves, JM ; Morais, VMF ; da Silva, MDMCR
in JOURNAL OF CHEMICAL THERMODYNAMICS, 2022, ISSN: 0021-9614,  Volume: 165, 
Article,  Indexed in: crossref, scopus, wos 
Abstract The focus of this work is the establishment of energetic-structural correlations of compounds containing a pentagonal heterocyclic ring with different substituents, and consequent contribution on the assessment of their thermodynamic stability and a thorough insight on the thiol-thione tautomeric equilibrium. In this work we report an experimental and computational thermochemical study of three mercaptothiadiazoles: 2-mercapto-1,3,4-thiadiazole, 2-mercapto-5-methyl-1,3,4-thiadiazole and 2,5-dimethyl1,3,4-thiadiazole. The experimental data were determined mainly from calorimetric techniques and from effusion method. Thermochemical properties such as the enthalpies of formation, both in crystalline and gaseous phases, the enthalpies of fusion and of sublimation of each compound, as well as the Gibbs energies of formation were derived. Thus, the methyl-substituted thiadiazole is the more stable species in both gaseous and crystalline phases. In addition, quantum chemical calculations were carried out for those isolated molecules. This approach confirms the thione form as the predominant tautomer for the mercaptothiadiazoles. Finally, the activation energies of the tautomeric equilibrium of the mercaptothiadiazoles were calculated in the gas-phase, aqueous and dimethylsulfoxide solutions, showing that the thiol ? thione single hydrogen transfers are quite unfavourable reactions in gas phase and in a presence of polar solvents. (c) 2021 Elsevier Ltd.

3. Metal-ligand binding energies in copper (II) and nickel (II) complexes with tetradentate N2O2 Schiff base ligands
Silva, ALR ; Oliveira, PCFC ; Goncalves, JM ; Morais, VMF ; da Silva, MDMCR
in INORGANICA CHIMICA ACTA, 2022, ISSN: 0020-1693,  Volume: 535, 
Article,  Indexed in: crossref, scopus, wos 
Abstract This work constitutes a new contribution for understanding the relationship between the metal-ligand bonding and, indirectly, the inherent reactivity of metallic complexes with tetradentate N2O2 Schiff base ligands, being reported the energetic characterization of two transition metal complexes - (N,AT c -bis(salicylaldehydo)tetramethylenediiminate)nickel(II) and (N,N' -bis(salicylaldehydo)propylenediiminate)copper(II). The standard molar enthalpies of formation of these complexes were determined by solution-reaction calorimetry measurements. Their standard molar enthalpies of sublimation, at T = 298.15 K, were obtained by an effusion method. From these studies, the gas-phase enthalpies of formation of Ni(II) and Cu(II) complexes, at T = 298.15 K, were derived. Differences between the metal-ligand and mean hydrogen-ligand bond dissociation enthalpies were derived and discussed in structural terms, in comparison with identical parameters for complexes of the same metals with analogous tetradentate Schiff bases. High-level quantum chemical calculations have also been conducted, complementing the results obtained experimentally.

4. Experimental and Theoretical Investigation on the Thermochemistry of 3-Methyl-2-benzoxazolinone and 6-Nitro-2-benzoxazolinone
Silva, ALR ; Costa, VMS ; da Silva, MDMCR
in MOLECULES, 2022, Volume: 27, 
Article,  Indexed in: crossref, scopus, wos 
Abstract The determination of the reliable thermodynamic properties of 2-benzoxazolinone derivatives is the main goal of this work. Some correlations are established between the energetic properties determined and the structural characteristics of the title compounds, and the reactivity of this class of compounds is also evaluated. Static-bomb combustion calorimetry and high-temperature Calvet microcalorimetry were used to determine, respectively, the standard molar enthalpies of formation in the solid state and the standard molar enthalpies of sublimation, both at T = 298.15 K. Using the results obtained for each compound, the respective gas-phase standard molar enthalpy of formation was derived. High-level quantum chemical calculations were performed to estimate the same property and the results evidence good accordance. Moreover, the gas-phase relative thermodynamic stability of 2-benzoxazolinone derivatives was also evaluated using the respective gas-phase standard molar Gibbs energy of formation. In addition, the relationship between the energetic and structural characteristics of the benzoxazolinones is presented, evidencing the enthalpic increments associated with the presence of a methyl and a nitro groups in the molecule, and this effect is compared with similar ones in other structurally related compounds.

5. Adherens Junction Integrity Is a Critical Determinant of Sodium Iodide Symporter Residency at the Plasma Membrane of Thyroid Cells
Faria, M ; Vareda, J ; Miranda, M ; Bugalho, MJ ; Silva, AL ; Matos, P
in CANCERS, 2022, ISSN: 2072-6694,  Volume: 14, 
Article,  Indexed in: scopus, wos 
Abstract Simple Summary Most cases of differentiated thyroid carcinoma (DTC) are associated with a good prognosis. However, a significant number progress to advanced disease exhibiting aggressive clinical characteristics. These cases have a poorer prognosis because they become resistant to radioactive iodine (RAI) treatment. One of the causes for this resistance is the reduction of the channel responsible for iodide uptake (NIS-the sodium iodide symporter) at the plasma membrane (PM) of metastatic thyroid cancer cells. Here we describe that cell-cell adhesion is a key determinant for NIS residency at the PM, suggesting that loss of cell-cell adhesion during metastization contributes to RAI treatment resistance in advanced TC. Our findings indicate that successful resensitization therapies might require the use of agents that improve epithelial cell-cell adhesion in refractory TC cells. While most cases of differentiated thyroid carcinoma (DTC) are associated with a good prognosis, a significant number progress to advanced disease exhibiting aggressive clinical characteristics and often becoming refractory to radioactive iodine (RAI) treatment, the current gold-standard therapeutic option for metastatic disease. RAI-refractoriness is caused by defective functional expression of the sodium-iodide symporter (NIS), which is responsible for the active transport of iodide across the plasma membrane (PM) into thyroid follicles. NIS deficiency in these tumors often reflects a transcriptional impairment, but also its defective targeting and retention at the cells' PM. Using proteomics, we previously characterized an intracellular signaling pathway derived from SRC kinase that acts through the small GTPase RAC1 to recruit and bind the actin-anchoring adaptor EZRIN to NIS, regulating its retention at the PM of both non-transformed and cancer thyroid cells. Here, we describe how by reanalyzing the proteomics data, we identified cell-cell adhesion as the molecular event upstream the pathway involved in the anchoring and retention at the PM. We show that by interacting with NIS at the PM, adherens junction (AJ)-associated P120-catenin recruits and is phosphorylated by SRC, allowing it to recruit RAC1 to the complex. This enables SRC-phosphorylated VAV2 exchange factor to activate RAC1 GTPase, inducing NIS retention at the PM, thus increasing its abundance and function at the surface of thyroid cells. Our findings indicate that the loss of epithelial cell-cell adhesion may contribute to RAI refractoriness, indicating that in addition to stimulating NIS expression, successful resensitization therapies might require the employment of agents that improve cell-cell adhesion and NIS PM retention in refractory TC cells.

6. Energetics of tetradentate N2O2 schiff bases containing different alkyldiimine brigdes
Silva, ALR ; Goncalves, JM ; Morais, VMF ; da Silva, MDMCR
in THERMOCHIMICA ACTA, 2021, ISSN: 0040-6031,  Volume: 695, 
Article,  Indexed in: crossref, scopus, wos 
Abstract This work is part of a comprehensive study of the thermal properties of several molecules of tetradentate Schiff bases, obtained as condensation products of salicylaldehyde with alkyldiamines. Herein, we report an experimental thermochemical study of SALPN (N,N'-bis(salicylaldehydo)propylenediimine) and a computational thermochemical study of SALEN (N,N' -bis(salicylaldehydo)dimethylenediimine), SALPN and SALBUTEN (N,N'-bis(salicylaldehydo)tetramethylenediimine) ligands. The standard (p degrees =0.1 MPa) molar enthalpy of formation of crystalline SALPN, at T = 298.15 K, was determined using the static-bomb calorimetry technique. Also, the enthalpy of fusion of this ligand has been determined by differential scanning calorimetry. Additionally, using quantum chemical calculations at the CCSD(T) level of theory, we have calculated the gas-phase standard molar enthalpies of formation of three Schiff base ligands, SALEN, SALPN and SALBUTEN. Moreover, a computational study of the molecular structures of the ligands has been carried out.

7. MAPK Inhibition Requires Active RAC1 Signaling to Effectively Improve Iodide Uptake by Thyroid Follicular Cells
Faria, M ; Domingues, R ; Bugalho, MJ ; Matos, P ; Silva, AL
in CANCERS, 2021, Volume: 13, 
Article,  Indexed in: crossref, scopus, wos 
Abstract Simple Summary: The Sodium/Iodide Simulator (NIS) is responsible for the uptake of iodide in the thyroid follicular cells. NIS is present in most differentiated thyroid carcinomas (DTC), allowing radioactive iodine (RAI) to be used to destroy malignant cells. However, a significant proportion of DTCs stop picking up iodide and become resistant to RAI therapy. This is mainly due to the symporter no longer being produced or not being placed correctly at the cell's membrane. This has been associated with mechanisms linked to malignant transformation, namely the overactivation of the so-called MAPK pathway. Thus, several drugs have been developed to inhibit this pathway, attempting to increase NIS levels and iodide uptake. However, MAPK inhibitors have had only partial success in restoring NIS expression. We found that the activity of another protein, the small GTPase RAC1, has an important role in this process, determining the outcome of MAPK inhibitors. Thus, our findings open new opportunities to find effective therapeutic alternatives for DTC resistant to RAI. The Sodium/Iodide Symporter (NIS) is responsible for the active transport of iodide into thyroid follicular cells. Differentiated thyroid carcinomas (DTCs) usually preserve the functional expression of NIS, allowing the use of radioactive iodine (RAI) as the treatment of choice for metastatic disease. However, a significant proportion of patients with advanced forms of TC become refractory to RAI therapy and no effective therapeutic alternatives are available. Impaired iodide uptake is mainly caused by the defective functional expression of NIS, and this has been associated with several pathways linked to malignant transformation. MAPK signaling has emerged as one of the main pathways implicated in thyroid tumorigenesis, and its overactivation has been associated with the downregulation of NIS expression. Thus, several strategies have been developed to target the MAPK pathway attempting to increase iodide uptake in refractory DTC. However, MAPK inhibitors have had only partial success in restoring NIS expression and, in most cases, it remained insufficient to allow effective treatment with RAI. In a previous work, we have shown that the activity of the small GTPase RAC1 has a positive impact on TSH-induced NIS expression and iodide uptake in thyroid cells. RAC1 is a downstream effector of NRAS, but not of BRAF. Therefore, we hypothesized that the positive regulation induced by RAC1 on NIS could be a relevant signaling cue in the mechanism underlying the differential response to MEK inhibitors, observed between NRAS- and BRAF-mutant tumors. In the present study, we found that the recovery of NIS expression induced through MAPK pathway inhibition can be enhanced by potentiating RAC1 activity in thyroid cell systems. The negative impact on NIS expression induced by the MAPK-activating alterations, NRAS Q61R and BRAF V600E, was partially reversed by the presence of the MEK 1/2 inhibitors AZD6244 and CH5126766. Notably, the inhibition of RAC1 signaling partially blocked the positive impact of MEK inhibition on NIS expression in NRAS Q61R cells. Conversely, the presence of active RAC1 considerably improved the rescue of NIS expression in BRAF V600E thyroid cells treated with MEK inhibitors. Overall, our data support an important role for RAC1 signaling in enhancing MAPK inhibition in the context of RAI therapy in DTC, opening new opportunities for therapeutic intervention.

8. Effects of the functional groups amino and nitro on the reactivity of benzoxazoles and comparison with homologous benzothiazoles
Silva, ALR ; da Silva, MDMCR
in JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, 2021, ISSN: 0894-3230,  Volume: 34, 
Article,  Indexed in: crossref, scopus, wos 
DOI: 10.1002/poc.4118 P-00S-HM2
Abstract The energetic study of 2-aminobenzoxazole (ABO) and 2-methyl-6-nitrobenzoxazole (MNBO) has been developed using experimental and computational tools. The enthalpies of combustion, of fusion, and of sublimation of these compounds were measured by static-bomb combustion calorimetry, differential scanning calorimetry, and Calvet microcalorimetry drop-technique and/or the Knudsen-effusion method. Additionally, we calculated the gas-phase standard molar enthalpies of formation of these compounds, as well as of 2-methyl-6-nitrobenzothiazole (MNBT), through high level ab initio calculations, at the G3(MP2)//B3LYP level of theory. Furthermore, the energetic effects associated with the presence of the amino and nitro groups on the core of benzoxazole or benzothiazole molecules were also evaluated, as well as stabilizing electronic interactions occurring in the molecules. The latter were investigated through Natural Bonding Orbital (NBO) of the corresponding wave functions. Finally, the thermodynamic stability of the titled compounds was evaluated and a comparison with their sulfur heteroanalogs was achieved. In the gaseous phase, the oxygen derivatives exhibit the lowest tendency to decompose into their constituent elements at standard conditions.

9. Energetic and Structural Studies of Two Biomass-Derived Compounds: 6-and 7-hydroxy-1-indanones
Ribeiro da Silva, ALR ; Ribeiro da Silva, MDMCR
in APPLIED SCIENCES-BASEL, 2020, ISSN: 2076-3417,  Volume: 10, 
Article,  Indexed in: crossref, scopus, wos 
Abstract Featured Application This is a contribution for enlarging the thermodynamic database of organic compounds and ketone derivatives. These data are very relevant to controlling experimental investigations to produce value-added chemical products from biomass. Moreover, the knowledge from such data can be used in the development of schemes for the prediction of homologous properties of related compounds, in particular, modeling studies for the prediction of bio-oil composition. The energetic study of 6-hydroxy-1-indanone and 7-hydroxy-1-indanone was performed using experimental techniques and computational calculations. The enthalpies of combustion and sublimation of the two compounds were determined and allowed to derive the corresponding gas-phase standard molar enthalpies of formation. For this purpose, static-bomb combustion calorimetry and drop-method Calvet microcalorimetry were the experimental techniques used. Further, the enthalpy of fusion of each compound was obtained from scanning differential calorimetry measurements. Additionally, the gas-phase standard molar enthalpies of formation of these compounds were calculated through high-level ab initio calculations. The computational study of the molecular structures of the indanones was carried out and two possible conformers were observed for 6-hydroxy-1-indanone. Furthermore, the energetic effects associated with the presence of one hydroxyl group as a substituent on the benzenic ring of 1-indanone were also evaluated. Both experimental and theoretical methods show that 7-hydroxy-1-indanone is thermodynamically more stable than the 6-isomer in the gaseous phase and these results provide evidence for the existence of a strong intramolecular H-bond in 7-hydroxy-1-indanone. Finally, the intramolecular proton transfer in 7-hydroxy-1-indanone has been evaluated and as expected, it is not energetically favorable.

10. TNF alpha-mediated activation of NF-kappa B downregulates sodium-iodide symporter expression in thyroid cells
Faria, M ; Domingues, R ; Paixao, F ; Bugalho, MJ ; Matos, P ; Silva, AL
in PLOS ONE, 2020, ISSN: 1932-6203,  Volume: 15, 
Article,  Indexed in: crossref, scopus, wos 
Abstract The sodium-iodide symporter (NIS) mediates transport of iodide across the basolateral membrane of thyroid cells. NIS expression in thyroid cancer (TC) cells allows the use of radioactive iodine (RAI) as a diagnostic and therapeutic tool, being RAI therapy the systemic treatment of choice for metastatic disease. Still, a significant proportion of patients with advanced TC lose the ability to respond to RAI therapy and no effective alternative therapies are available. Defective NIS expression is the main reason for impaired iodide uptake in TC and NIS downregulation has been associated with several pathways linked to malignant transformation. NF-kappa B signaling is one of the pathways associated with TC. Interestingly, NIS expression can be negatively regulated by TNF-alpha, a bona fide activator of NF-kappa B with a central role in thyroid autoimmunity. This prompted us to clarify NF-kappa B's role in this process. We confirmed that TNF-alpha leads to downregulation of TSH-induced NIS expression in non-neoplastic thyroid follicular cell-derived models. Notably, a similar effect was observed when NF-kappa B activation was triggered independently of ligand-receptor specificity, using phorbol-myristate-acetate (PMA). TNF-alpha and PMA downregulation of NIS expression was reverted when NF-kappa B-dependent transcription was blocked, demonstrating the requirement for NF-kappa B activity. Additionally, TNF-alpha and PMA were shown to have a negative impact on TSH-induced iodide uptake, consistent with the observed transcriptional downregulation of NIS. Our data support the involvement of NF-kappa B-directed transcription in the modulation of NIS expression, where up-or down-regulation of NIS depends on the combined output to NF-kappa B of several converging pathways. A better understanding of the mechanisms underlying NIS expression in the context of normal thyroid physiology may guide the development of pharmacological strategies to increase the efficiency of iodide uptake. Such strategies would be extremely useful in improving the response to RAI therapy in refractory-TC.