28 research outputs found
SĂntese, avaliação biolĂłgica e docking de novos derivados 2,3-substituĂdos-1,4-naftoquinĂŽnicos contendo nitrogĂȘnio, oxigĂȘnio e enxofre com atividade anticĂąncer
O cĂąncer Ă© uma das doenças que mais causam temor na sociedade, por ter se tornado um estigma de mortalidade e dor. Estatisticamente, em pesquisa realizada pela Organização Mundial de SaĂșde (WHO), o cĂąncer Ă© a segunda causa de Ăłbitos no mundo com 13%, matando cerca de 6,0 milhĂ”es de pessoas por ano. Acredita-se que em 2015 o cĂąncer seja responsĂĄvel por 9 milhĂ”es de mortes no mundo. Os avanços verificados nas Ășltimas dĂ©cadas, na ĂĄrea da quimioterapia antineoplĂĄsica, tĂȘm facilitado consideravelmente a aplicação de outros tipos de tratamento de cĂąncer e permitido maior nĂșmero de curas. Entretanto, muitos tipos de cĂąncer sĂŁo intrinsecamente resistentes a quimioterĂĄpicos, enquanto outros inicialmente respondem ao tratamento, porĂ©m adquirem resistĂȘncia aos fĂĄrmacos. A resistĂȘncia mĂșltipla ao fĂĄrmaco (MDR), o quadro mais grave, ocorre quando culturas de cĂ©lulas in vitro e in vivo mostram resistĂȘncia simultĂąnea a diferentes fĂĄrmacos. Portanto, apesar do grande nĂșmero de compostos que compĂ”em o arsenal quimioterĂĄpico de combate ao cĂąncer, o problema de resistĂȘncia requer a busca constante por novos fĂĄrmacos eficazes no combate ao cĂąncer, doença que afeta milhĂ”es de pessoas.
Em estudos farmacolĂłgicos com diversas quinonas foi evidenciado que esta classe de substĂąncia mostram variadas atividades farmacodinĂąmicas, dentre elas, as propriedades citotĂłxicas e inibidoras de sistemas celulares reparadores, processos nos quais atuam de diferentes formas. Como exemplo, destaca-se o estresse oxidativo que provocam ao induzirem a formação deletĂ©ria endĂłgena de espĂ©cies bioativas derivadas do oxigĂȘnio (ROS). Outra atividade marcante destas substĂąncias, descoberta recentemente, Ă© a inibição da enzima topoisomerase II, ação que provoca o desencadeamento da apoptose celular.
Neste trabalho foram sintetizados em rendimentos que variaram de 52 a 89% onze derivados 1,4-naftoquinĂŽnicos contendo grupos oxigenados, nitrogenados e sulfurados nas posiçÔes 2 e/ou 3 do nĂșcleo naftoquinĂŽnico. Posteriormente estes compostos tiveram as suas citotoxidades avaliadas nas linhagens de cĂąncer humano de pulmĂŁo (H460), mama triplo-negativo (MDA-MB-231) e ovĂĄrio (A2780). Os compostos 25f e 44, 25c e 44, e 25g e 44 apresentaram uma significativa atividade anticĂąncer in vitro para as linhagens de cĂąncer de pulmĂŁo H460, mama triplo-negativos MDA-MB-231 e ovĂĄrio A2780, respectivamente, demostrando um grande potencial como compostos protĂłtipos para o desenvolvimento de novos agentes
antineoplĂĄsicos.
Efetuou-se tambĂ©m estudos de docking dos quatro compostos mais ativos com os alvos terapĂȘuticos PI3K e topoisomerase II. Os estudos mostraram que um possĂvel alvo terapĂȘutico das subtĂąncias sintetizadas Ă© a enzima topoisomerase II, resultado das interaçÔes estabilizadoras observadas no complexo enzima/ligante.Cancer is one of the most feared disease in society, which have become a
stigma of death and pain. Statistically, a survey conducted by the World Health
Organization (WHO), cancer is the second cause of death in the world with 13%,
killing about 6.0 million people per year. It is believed that in 2015 cancer will be
responsible for over 9 million deaths worldwide. The advances achieved in recent
decades in cancer chemotherapy research have greatly facilitated the
implementation of other types of cancer treatment and allowed a greater number of
cures. However, many cancers are intrinsically resistant to chemotherapy, while
others respond to initial treatment, but it acquires drug resistance. The multiple drug
resistance (MDR), the most severe case, occurs when in vitro and in vivo cell
cultures show simultaneous resistance to different drugs. Therefore, despite the large
number of compounds that make up the arsenal of anti-cancer chemotherapy, the
resistance problem requires a constant search for effective new drugs in fighting
cancer, a disease that affects millions of people.
In pharmacological studies with various quinones was evidenced that these
substances show different pharmacodynamic activities, among them, cytotoxic
properties and inhibiting cellular systems repairers, processes in which they act in
different ways. As an example, there is oxidative stress that cause deleterious by
inducing formation of endogenous bioactive oxygen species derived (ROS). Another
remarkable activity of these substances, recently discovered, is the inhibition of the
enzyme topoisomerase II, an action that triggers the onset of cellular apoptosis.
In this work were synthesized eleven 1,4-naphthoquinone derivatives containing
functional groups, nitrogen and sulfur in positions 2 and/or 3 naphthoquinone core in
yields ranging 52-89%. Subsequently these compounds had their cytotoxicity
evaluated in strains of human lung cancer (H460), triple-negative breast (MDA-MB-
231) and ovarian (A2780). Compounds 25f and 44, 44 and 25c, and 25g and 44
showed a significant anticancer in vitro activity for the strains of lung cancer H460,
triple-negative breast MDA-MB-231 and ovarian A2780, respectively, showing a great
potential as lead compounds for the development of new anticancer agents.
Docking studies of the four most active compounds with therapeutic targets
PI3K and topoisomerase II were performed. Those studies have shown that a
16
possible therapeutic target of synthesized compounds is topoisomerase II enzyme
because of the observed enzyme/binder complex stabilizing interactions
Cation-doping strategies for tuning of zirconia acid?base properties
The role of Y-, Ca- and Ce-doping of cubic zirconia (c-ZrO2) (111) surface on its acidity, basicity and the interplay between surface acidâbase pairs is investigated by computational methods. The most stable surface structures for this investigation were initially determined based on previous studies of Y-doped c-ZrO2 (111) and by a detailed exploration of the most stable configuration for Ca-doped c-ZrO2 (111) and Ce-doped c-ZrO2 (111). Next, surface mapping by basic probe molecules (NH3 and pyridine) revealed a general reduction of the acidity of the surface sites, although a few exceptions were observed for zirconium ions at next nearest neighbour (NNN) positions to the oxygen vacancy and at the nearest neighbour (NN) position to the dopants. Adsorption of CO2 over basic sites revealed a cooperative interplay between acidâbase groups. In this case, the overall effect observed was the decrease of the calculated adsorption energies when compared with the pristine surface. Moreover, spontaneous formation of η3-CO2 systems from initial η2-CO2 configurations indicates a decrease in the required energy for forming oxygen vacancies in the doped ZrO2 systems at NNN positions or further away from the existing vacancy site
Modelling the bulk properties of ambient pressure polymorphs of zirconia
We report a detailed survey of the calculated bulk properties of zirconia using GGA and meta-GGA functionals (PBE, PBEsol, RPBE, and TPSS), dispersion (Grimme's D2 and D3 approach), and on-site Coulomb repulsion correction (U = 2â8 eV). Structural, elastic, mechanical, and dielectric properties, as well as energetics, electronic structure, and phonon dispersion curves were computed and compared to previous investigations to identify the best DFT approach for a consistent in silico description of zirconia polymorphs. In general, inclusion of dispersion corrections led to only small changes in the calculated properties, whereas DFT+U (U = 2 or 4 eV) reduced the deviations of calculated properties from the experimental results, although deterioration of the structure and relative stabilities may be observed in some cases. Standard PBEsol, RPBE+U, and PBE+U were the best methodologies for a simultaneous description of the three polymorphs of ZrO2. RPBE+U, however, was the only functional to conserve the distinct structures and stabilities of c-, t-, and m-ZrO2 when U = 4 eV was used, resulting in the best in silico replication of the band gaps of ZrO2, whilst outperforming the other methodologies in the description of elastic, mechanical, and dielectric properties of this material. Overall, these results provide insight into the most appropriate DFT methodology for in silico investigations of ZrO2, and show that simultaneous description of all three ambient pressure zirconia polymorphs by DFT techniques with acceptable levels of accuracy can be achieved only when the correct choice of methodology is applied
Design of CO2 hydrogenation catalysts based on phosphane/borane frustrated Lewis pairs and xanthene-derived scaffolds
UK Catalysis Hub is kindly thanked for resources and support provided via our membership of the UK Catalysis Hub Consortium and funded by EPSRC grant: EP/R026939/1, EP/R026815/1, EP/R026645/1, EP/R027129/1, and EP/M013219/1. J.W.M.C. acknowledges financial support from FAPERJ (grants E-26/203.001/2017, E-26/010.101118/2018, and E-26010.001424/2019) and CNPq (grants 309080/2015-0 and 434955/2018-3). M.B. thanks the School of Chemistry in St Andrews and EaStCHEM for support.New naphtho[2,1,8,7-klmn]xanthene and benzo[kl]xanthene-based intramolecular phosphaneâborane frustrated Lewis pairs (FLPs) were investigated in catalyzed H2 activation and CO2 hydrogenation processes. According to DFT predictions at the B3LYP-D3 level, the presence of rigid scaffolds and increased P···B distances in the investigated FLPs lead to a remarkable drop in the energy barrier for CO2 hydrogenation (by up to 19.2âŻkcalâŻmolâ1, compared to the parent dimethylxanthene-based FLP). Furthermore, the energy differences between the transition states for H2 activation and CO2 hydrogenation are significantly reduced, making both processes feasible under relatively mild experimental conditions.Publisher PDFPeer reviewe
A DFT study on the mechanism for polymerization of ÎŽ-valerolactone initiated by N-heterocyclic carbene (NHC) catalysts
Polymerization reactions using renewable raw material as substrate (namely, ÎŽ-valerolactone) and N-heterocyclic carbenes (NHC) as organocatalysts to form polyesters were investigated by computational approaches. Two routes were investigated for the reaction, either with the NHC acting as a BrĂžnsted base and activating an alcohol used as co-initiator or by direct nucleophilic attack of the NHC on the carbonyl carbon of the lactone, forming a zwitterionic intermediate. In agreement with previous studies, the lowest energy pathway leading to polymerization is that where the NHC activates the alcohol co-initiator, yielding a partially charged alkoxide that then performs a nucleophilic attack on the lactone. The proton affinity of the NHCs shows a high correlation with the activation enthalpy for the first reaction step. Thus, NHCs with high proton affinity stabilize the first intermediate and make the lactone ring-opening the rate-determining step for the reaction
The conundrum of α- and ÎČ-lapachone isomerization in acidic media : insights from experimental and implicit/explicit solvation approaches
The authors are grateful to CAPES (Coordenação de Aperfeiçoamento de Pessoal de NĂvel Superior), CNPq (Conselho Nacional de Desenvolvimento CientĂfico e TecnolĂłgico), and FAPERJ (Fundação Carlos Chagas Filho de Amparo Ă Pesquisa do Estado do Rio de Janeiro) for funding this research project.Combined experimental and mixed implicit/explicit solvation approaches were employed to gain insights into the origin of switchable regioselectivity of acidâcatalyzed lapachol cyclization and αâ/ÎČâlapachone isomerization. It was found that solvating species under distinct experimental conditions stabilized αâ and ÎČâlapachone differently, thus altering the identity of the thermodynamic product. The energy profile for lapachol cyclization revealed that this process can occur with low freeâenergy barriers (lower than 8.0â
kcalâmolâ1). For α/ÎČ isomerization in a dilute medium, the computed enthalpic barriers are 15.1â
kcalâmolâ1 (αâÎČ) and 14.2â
kcalâmolâ1 (ÎČâα). These barriers are lowered in concentrated medium to 11.5 and 12.6â
kcalâmolâ1, respectively. Experimental determination of isomers ratio was quantified by HPLC and NMR measurements. These findings provide insights into the chemical behavior of lapachol and lapachone derivatives in more complex environments.PostprintPeer reviewe
Synthesis and evaluation of corrosion inhibiting activity of new molecular hybrids containing the morpholine, 1,4-naphthoquinone, 7-chloroquinoline and 1,3,5-triazine cores
Three molecules containing morpholine, 1,4-naphthoquinone, 7-chloroquinoline and 1,3,5-triazine cores, scaffolds with recognized anti-corrosive activity, were synthesized and had their anticorrosive activity evaluated through potentiodynamic polarization and electrochemical impedance studies. Both studies were conducted in a simulated production water medium containing 150,000 mg·L-1 Cl- and 5 mg·L-1 S2-. Corrosion inhibition efficiency ranged from 67% - 86%, amongst which the naphthoquinone-containing derivative (compound 1) was the most effective. These compounds act through formation of a protective film on the surface of AISI 316 stainless steel. Investigation of the molecular properties of the prepared inhibitors by DFT calculations revealed that the LUMO energy and chemical hardness of the molecules can be directly correlated with their inhibition efficiency
A stereoselective, base-free, palladium-catalyzed heck coupling between 3-halo-1,4-naphthoquinones and vinyl-1H-1,2,3-triazoles
A stereoselective, base-free Heck coupling between 1,4-naphthoquinone and 1H-1,2,3-triazole derivatives was reported for the first time. This study shows that depending on the 1,4-naphthoquinone, the use of an additional base is unnecessary to produce the naphthoquinone-triazole conjugates. This is also the first example of a Heck coupling of these two cores without using a base as an additive. In this work, sixteen new naphthoquinone-triazole hybrids were stereoselectively synthetized in good to excellent yields. The reaction mechanism was discussed based on DFT CAMâB3LYP calculations. The first step is the coordination of the arene to the palladium catalyst to form a palladacycle intermediate. After reorganization in this intermediate, the double bond in the arene is restored to proceed with the coupling step and formation of the CâC bond in the rate determining step. The Kozuchi-Shaik span model was employed to rationalize substituent effects
Periodic density functional theory approaches for exploring metal oxides in catalysis
The following sections are included:
Introduction
Density Functional Theory in the Investigation of Oxides by Periodic Boundary Conditions
Theoretical Description of Bulk Properties of Metal Oxides: Effect of Different DFT Approaches
Summary
Glossary of Acronyms
Reference