The triazole heterocycle is a privileged scaffold in medicinal chemistry, since its structure is present in a large number of biologically active molecules, including several drugs currently in the ...market. Due to their vast applications, a wide variety of methods are described for their preparation, such as the 1,3‐dipolar cycloaddition and processes involving diazo compounds and diazo transfer reactions. Considering the significant number of contributions from our research group to this chemistry in recent decades, in this account we discuss both the development of new methods for the synthesis of 1,2,3‐triazoles and the preparation of new triazole‐functionalized biologically active molecules using classical approaches.
This review paper discusses both the development of new methods for the synthesis of 1,2,3‐triazoles and the preparation of new triazole‐functionalized biologically active molecules using classical approaches, and focuses on the contributions of the Ferreira's group throughout the last decades.
Arboviruses have become a major public health concern in Brazil, especially after Zika virus (ZIKV) and Chikungunya virus (CHIKV) introduction, leading to massive epidemics. We conducted an ...investigation of arboviruses in patients with acute febrile illness for less than five days in Mato Grosso state (MT) during the period of ZIKV and CHIKV dissemination in Brazil. To achieve that, 453 human serum samples of patients suspected of Dengue (DENV), Yellow Fever (YFV), ZIKV or CHIKV collected in health units of 31 cities of MT were subjected to RT-PCR protocols for 10 flaviviruses, 5 alphaviruses and orthobunyaviruses from Simbu serogroup, nucleotide sequencing and viral isolation. Regarding flaviviruses, five (1.1%) patients were infected with DENV-1 genotype V, 22 (4.4%) with DENV-4 genotype II, 3 (0.7%) with YFV South American genotype II and five (1.1%) with ZIKV Asian genotype. The first human case of ZIKV in MT was detected in this study during August, 2015 in Tapurah. Alphaviruses were detected in 2 (0.4%) patients infected with CHIKV genotype ECSA, 1 (0.2%) with Madariaga (EEEV) lineage III and 34 (7.5%) with Mayaro (MAYV) genotype L. Four (11.4%) patients presented dual infections with DENV-1/ZIKV, DENV-1/DENV4, DENV-4/MAYV and ZIKV/MAYV. The majority - 13/34 positive for MAYV, one for Madariaga virus - are residents in Várzea Grande (VG), metropolitan region of Cuiabá, capital of MT. The first CHIKV infection in MT was detected in this study in Mirassol D’Oeste, during July, 2015. In addition, 20 (4.4%) patients were positive for OROV Segment S genotype IA. These results reinforce the variation in arboviruses frequency and distribution during outbreaks, highlinghing the importance of differential diagnosis to identify agents silently co-circulating with major health problem arboviruses.
Cholinergic α7 nicotinic receptors encoded by the
gene are ligand-gated ion channels directly related to memory and immunomodulation. Exons 5-7 in
can be duplicated and fused to exons A-E of
, ...resulting in a hybrid gene known as
, unique to humans. Its product, denoted herein as Dupα7, is a truncated subunit where the N-terminal 146 residues of the ligand binding domain of the α7 receptor have been replaced by 27 residues from FAM7. Dupα7 negatively affects the functioning of α7 receptors associated with neurological disorders, including Alzheimer's diseases and schizophrenia. However, the stoichiometry for the α7 nicotinic receptor containing dupα7 monomers remains unknown. In this work, we developed computational models of all possible combinations of wild-type α7 and dupα7 pentamers and evaluated their stability via atomistic molecular dynamics and coarse-grain simulations. We assessed the effect of dupα7 subunits on the Ca
conductance using free energy calculations. We showed that receptors comprising of four or more dupα7 subunits are not stable enough to constitute a functional ion channel. We also showed that models with dupα7/α7 interfaces are more stable and are less detrimental for the ion conductance in comparison to dupα7/dupα7 interfaces. Based on these models, we used protein-protein docking to evaluate how such interfaces would interact with an antagonist, α-bungarotoxin, and amyloid Aβ
. Our findings show that the optimal stoichiometry of dupα7/α7 functional pentamers should be no more than three dupα7 monomers, in favour of a dupα7/α7 interface in comparison to a homodimer dupα7/dupα7 interface. We also showed that receptors bearing dupα7 subunits are less sensitive to Aβ
effects, which may shed light on the translational gap reported for strategies focused on nicotinic receptors in 'Alzheimer's disease research.
The emergence of observable properties from the organisation of the underlying potential energy landscape is analysed, spanning a full range of complexity from self-organising to glassy and jammed ...systems. The examples include atomic and molecular clusters, a β-barrel protein, the GNNQQNY peptide dimer, and models of condensed matter that exhibit structural glass formation and jamming. We have considered measures based on several different properties, namely, the Shannon entropy, an equilibrium thermodynamic measure that uses a sample of local minima, and indices that require additional information about the connections between local minima in the form of transition states. A frustration index is defined that correlates directly with key properties that distinguish relaxation behaviour within this diverse set. The index uses the ratio of the energy barrier to the energy difference with reference to the global minimum. The contributions for each local minimum are weighted by the equilibrium occupation probabilities. Hence we obtain fundamental insight into the connections and distinctions between systems that cover the continuum from efficient structure-seekers to landscapes that exhibit broken ergodicity and rare event dynamics.
The androgen receptor (AR) is an important drug target in prostate cancer and a driver of castration-resistant prostate cancer (CRPC). A significant challenge in designing effective drugs lies in ...targeting constitutively active AR variants and, most importantly, nearly all AR variants lacking the ligand-binding domain (LBD). Recent findings show that an AR's constitutive activity may occur in the presence of somatic DNA mutations within non-coding regions, but the role of these mutations remains elusive. The discovery of new drugs targeting CRPC is hampered by the limited molecular understanding of how AR binds mutated DNA sequences, frequently observed in prostate cancer, and how mutations within the protein and DNA regulate AR-DNA interactions. Using atomistic molecular dynamics (MD) simulations and quantum mechanical calculations, we focused our efforts on (i) rationalising the role of several activating DBD mutations linked to prostate cancer, and (ii) DBD interactions in the presence of abasic DNA lesions, which frequently occur in CRPC. Our results elucidate the role of mutations within DBD through their modulation of the intrinsic dynamics of the DBD-DNA ternary complex. Furthermore, our results indicate that the DNA apurinic lesions occurring in the androgen-responsive element (ARE) enhance direct AR-DNA interactions and stabilise the DBD homodimerisation interface. Moreover, our results strongly suggest that those abasic lesions may form reversible covalent crosslinks between DNA and lysine residues of an AR via a Schiff base. In addition to providing an atomistic model explaining how protein mutations within the AR DNA-binding domain affect AR dimerisation and AR-DNA interactions, our findings provide insight into how somatic mutations occurring in DNA non-coding regions may activate ARs. These mutations are frequently observed in prostate cancer and may contribute to disease progression by enhancing direct AR-DNA interactions.
Plant species of the Brazilian Caatinga experience seasonal wet and dry extremes, requiring seasonally different leaf characteristics for optimizing water availability. We investigated if Croton ...blanchetianus Baill exhibits leaf morphoanatomical traits across seasons and positioning in sunlight/natural shade. Leaves of ten 1-3 m tall plants in full sunlight and ten in natural shade were assessed in May, July (wet season), October and December (dry season) 2015 for gas exchange, leaf size, lamina and midrib cross sections (14 parameters), and chloroplast structure (5 parameters). Net photosynthesis was greater during the wet season (21.6 µm
s
) compared to the dry season (5.8 µm
s
) and was strongly correlated with almost all measured parameters (p < 0.01). Shaded leaves in the wet season had higher specific leaf area (19.9 m
kg
in full-sun and 23.1 m
kg
in shade), but in the dry season they did not differ from those in full sun (7.5 m
kg
and 7.2 m
kg
). In the wet season, the expansion of the adaxial epidermis and mesophyll lead to larger and thicker photosynthetic area of leaves. Furthermore, chloroplast thickness, length and area were also significantly larger in full sunlight (2.1 μm, 5.1 μm, 15.2 μm
; respectively) and shaded plants (2.0 μm, 5.2 μm, 14.8 μm
; respectively) during wetter months. Croton blanchetianus exhibits seasonal plasticity in leaf structure, presumably to optimize water use efficiency during seasons of water abundance and deficit. These results suggest that the species is adaptable to the increased drought stress projected by climate change scenarios.
6-Nitrodopamine is a novel catecholamine released by vascular tissues, heart, and vas deferens. The aim of this study was to investigate whether 6-nitrodopamine is released from the thoracic aorta ...and pulmonary artery rings of marmosets (Callithrix spp.) and to evaluate the relaxing and anti-contractile actions of this catecholamine. Release of 6-nitrodopamine, dopamine, noradrenaline, and adrenaline was assessed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The relaxations induced by 6-nitrodopamine and by the selective dopamine D2 receptor antagonist L-741,626 were evaluated on U-46619 (3 nM)-pre-contracted vessels. The effects of 6-nitrodopamine and L-741,626 on the contractions induced by electric-field stimulation (EFS), dopamine, noradrenaline, and adrenaline were also investigated. Both aorta and pulmonary artery rings exhibited endothelium-dependent release of 6-nitrodopamine, which was significantly reduced by the NO synthesis inhibitor L-NAME. Addition of 6-nitrodopamine or L-741,626 caused concentration-dependent relaxations of both vascular tissues, which were almost abolished by endothelium removal, whereas L-NAME and the soluble guanylate cyclase inhibitor ODQ had no effect on 6-nitrodopamine-induced relaxations. Additionally, pre-incubation with 6-nitrodopamine antagonized the dopamine-induced contractions, without affecting the noradrenaline- and adrenaline-induced contractions. Pre-incubation with L-741,626 antagonized the contractions induced by all catecholamines. The EFS-induced contractions were significantly increased by L-NAME, but unaffected by ODQ. Immunohistochemical assays showed no immunostaining of the neural tissue markers S-100 and calretinin in either vascular tissue. The results indicated that 6-nitrodopamine is the major catecholamine released by marmoset vascular tissues, and it acts as a potent and selective antagonist of dopamine D2-like receptors. 6-nitrodopamine release may be the major mechanism by which NO causes vasodilatation.
PDF
