Development of novel Cu(I) compounds with vitamin B1 derivative and their potential application as anticancer drugs

The synthesis and crystal structure of two new copper(I) compounds with molecular formula of {Cu4[(µ3-thiocrome)2Cl4]∙2(H2O)}n 1, and Cu2[(µ2-thiocrome)2Cl2] 2 are reported. The crystal structure of compounds 1 and 2 are solved by single crystal X-ray diffraction. The reaction of Cu(II) with thiamine chloride in water at room temperature produces Cu(I) thiochrome compounds 1 and 2. Compound 1 shows a 1D chain structure based on the linkage of two crystallographic different copper centers and thiochrome ligand through the N(1), N(2) and N(3) nitrogen atoms. Compound 2 is a 0D dimeric copper structure assembled by two thiochrome ligands. For both compounds, the copper(I) centers exhibits a distorted trigonal pyramidal geometry. The antitumor capacity of both compounds was tested in vitro against a human cancer cell line, the colorectal adenocarcinoma (Caco-2) cell line, by determining their effect on cell viability. The two compounds showed similar IC50 values, and were slightly more potent than cisplatin, against the same cell line.publishe

Locking the GFP Fluorophore to Enhance Its Emission Intensity

Funding Information: Thanks are due to the University of Aveiro, FCT/MEC, Centro 2020 and Portugal2020, the COMPETE program, and the European Union (FEDER program) via the financial support to the LAQV-REQUIMTE (UIDB/50006/2020 and UIDP/50006/2020), to the CICECO-Aveiro Institute of Materials (UID/CTM/50011/2019, UIDB/50011/2020 and UIDP/50011/2020), financed by national funds through the FCT/MCTES, to the Portuguese NMR Network. SG is supported by national funds (OE), through FCT, I.P., in the scope of the framework contract foreseen in the numbers 4, 5, and 6 of the article 23, of the Decree-Law 57/2016, of August 29, changed by Law 57/2017, of July 19. JRMF. Thanks FCT and ESF (European Social Fund) through POCH (Programa Operacional Capital Humano) for her PhD grant (UI/BD/151272/2021). Publisher Copyright: © 2022 by the authors.The Green Fluorescent Protein (GFP) and its analogues have been widely used as fluorescent biomarkers in cell biology. Yet, the chromophore responsible for the fluorescence of the GFP is not emissive when isolated in solution, outside the protein environment. The most accepted explanation is that the quenching of the fluorescence results from the rotation of the aryl–alkene bond and from the Z/E isomerization. Over the years, many efforts have been performed to block these torsional rotations, mimicking the environment inside the protein β-barrel, to restore the emission intensity. Molecule rigidification through chemical modifications or complexation, or through crystallization, is one of the strategies used. This review presents an overview of the strategies developed to achieve highly emissive GFP chromophore by hindering the torsional rotations.publishersversionpublishe

Synthesis and luminescence properties of analogues of the green fluorescent protein chromophore

The green fluorescent protein (GFP) is extensively used as a biomarker for fluorescence biological imaging. The chromophore in GFP is only fluorescent when confined into the β–barrel of the protein. Similarly, synthetic analogues of the fluorophore of GFP are usually non-emissive in solution, due to free rotation around the aryl-alkene bond and (Z/E)-isomerization of the double bond. Here, the synthesis and characterization of three analogues of the fluorophore of GFP are reported. The introduction of more electron donating substituents induces a red-shift in the absorption and emission. The fluorophores are more emissive in the solid state than in solution, and a study of their crystal structure reveals that the (Z/E)-isomerization is efficiently blocked in the crystals.publishe

Synthesis of Unsymmetrical Methylenebisphenol Derivatives

A simple and efficient route towards unsymmetrical methylenebisphenol derivatives is reported. This straightforward strategy avoids the use of harmful or dangerous chemicals, allowing the synthesis of highly functionalized bisphenyls with no need of protecting groups. The alkylation of the phenyl ring is selective for the para position of the hydroxyl substituent. All methylenebisphenols were obtained in a completely regioselective manner and isolated in high yields

Dimethyl 5,5′-methyl­enebis(2-hy­droxy­benzoate)

In the title compound, C17H16O6, the two methyl salicylate moieties are related by crystallographic twofold rotational symmetry with the two benzene rings close to being perpendicular [inter-ring dihedral angle = 86.6 (8)°]. Intra­molecular phenolic O—H⋯O hydrogen bonds with carboxyl O-atom acceptors are present, with these groups also involved in centrosymmetric cyclic inter­molecular O—H⋯O hydrogen-bonding associations [graph set R 2 2(4)], giving infinite chains extending across (101)

Steroid–quinoline hybrids for disruption and reversion of protein aggregation processes

Reversing protein aggregation within cells may be an important tool to fight protein-misfolding disorders such as Alzheimer’s, Parkinson’s, and cardiovascular diseases. Here we report the design and synthesis of a family of steroid−quinoline hybrid compounds based on the framework combination approach. This set of hybrid compounds effectively inhibited Aβ1−42 self-aggregation in vitro by delaying the exponential growth phase and/or reducing the quantity of fibrils in the steady state. Their disaggregation efficacy was further demonstrated against preaggregated Aβ1−42 peptides in cellular assays upon their endocytosis by neuroblastoma cells, as they reverted both the number and the average area of fibrils back to basal levels. The antiaggregation effect of these hybrids was further tested and demonstrated in a cellular model of general protein aggregation expressing a protein aggregation fluorescent sensor. Together, our results show that the new cholesterol−quinoline hybrids possess wide and marked disaggregation capacities and are therefore promising templates for the development of new drugs to deal with conformational disorders.Thanks are due to the University of Aveiro, FCT/MEC, Centro 2020 and Portugal2020, the COMPETE Program, and the European Union (FEDER Program) via the financial support to the research units LAQV-REQUIMTE (UIDB/50006/2020), IBiMED (UID/BIM/04501/2019) and CICECO- Aveiro Institute of Materials (UID/CTM/50011/2019), financed by national funds through the FCT/MCTES, to the Portuguese NMR Network, to the ThiMES Project (POCI-01- 0145-FEDER-016630), and to the PAGE Project “Protein Aggregation Across the Lifespan” (CENTRO-01-0145- FEDER-000003), including postdoctoral grants to H.M.T.A. (BPD/UI98/4861/2017) and R.N.d.S. (BPD/UI98/6327/2018). M.P. was supported by Ph.D. Grant SFRH/BD/135655/2018. A.R.S. and S.G. were supported by national funds (OE) through FCT, I.P., in the scope of the framework contract foreseen in numbers 4, 5, and 6 of Article 23 of the Decree-Law 57/2016 of August 29, changed by Law 57/2017 of July 19. Microphotographs were acquired in the LiM facility of iBiMED/UA, a member of the Portuguese Platform of BioImaging (PPBI) (POCI-01-0145-FEDER-022122).info:eu-repo/semantics/publishedVersio

Liprobe, a vital dye for lipid aggregates detection in imaging and high-content screens

Pathological lipid accumulation is a hallmark of several metabolic disorders, and detection of lipid aggregates is an essential step for initial diagnosis and drug screening purposes. However, low-cost, simple, and reliable detection fluorescent probes are not widely available. Here, six push-pull-push dyes were studied, and proved to be highly sensitive to the polarity of the medium, presenting potential to distinguish structures with different hydrophobic indexes. Importantly, in the presence of lipid aggregates their staining specificity highly increased and the fluorescence wavelength blue shifted. One of the compounds, named Liprobe, was physiologically inert in cells, as witnessed by mass-spectrometry and metabolic assays. Liprobe was not toxic to living zebrafish embryos, and differentially stained the muscle and bone tissues. In triglyceride solutions, a high correlation was observed between Liprobe’s 558 and 592 nm emissions and the 0–2.5 mg dl−1 triglyceride range. Confocal and cell-based high content screens revealed that this fluorophore was able to selectively detect lipid droplets and ceramide loads in normal and Farber’s disease human fibroblasts, respectively. Our results demonstrate that Liprobe is a suitable fluorescing probe for vital staining of lipid aggregates, compatible with a rapid and cheap high content screening assays for preliminary diagnosis of Farber’s disease and, potentially, of other lipidosis.publishe

Multicomponent Synthesis of Luminescent Iminoboronates

A family of iminoboronates was prepared through a one-pot multicomponent reaction, starting from boronic acid, anthranilic acid, and different salicylaldehydes. Their synthesis was straightforward and the complexes were obtained in good to excellent yields. Their photophysical properties were assessed in a diluted solution, and the complexes proved to be faintly luminescent. These chelates demonstrated remarkable Aggregation-Induced Emission Enhancement, which was rationalized using crystal structures

Synthèse de cyclodextrines multidifférenciées et mise en évidence de la chiralité de plateforme par la catalyse

Nous avons utilisé la méthode de déprotection sélective des éthers benzyliques au DIBAl-H pour synthétiser de nouvelles cyclodextrines possédant plusieurs groupements protecteurs différents sur leur couronne primaire, et notamment des motifs tétradifférenciés inaccessibles jusqu à présent. Ces molécules ont servi à la synthèse d alpha- et béta-cyclodextrines amino-acides hydrosolubles, ainsi qu à l élaboration de chromophores contraints. Nous avons ensuite étudié la relation entre deux motifs régioisomères présentant des plateformes énantiomères l une de l autre. Pour cela, nous avons synthétisé des ligands diphosphine à partir de ces motifs régioisomères, et les avons engagés en catalyse asymétrique. Les résultats ont permis de valider le concept de plateforme chirale, et d élucider la relation de pseudo-énantiomérie entre les deux motifs. Enfin, nous avons synthétisé un ligand alpha-cyclodextrine-tétraphosphine qui a été engagé dans des tests catalytiques préliminaires.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Supramolecular organization of bis(3-halo-4-dimethylaminobenzylidene)hydrazines

Bis(3-bromo-4-dimethylaminobenzylidene)hydrazine and bis(3-chloro-4-dimethylaminobenzylidene)hydrazine have been synthesized, and their monoclinic crystal structures solved in space group P2(1)/c. For the bromo derivative at 150 K, a = 10.4505(2), b = 8.0358(2), c = 11.3208(2) angstrom, beta = 102.56(2)degrees, Z = 2, V = 927(9) angstrom(3), Dx = 1.618 g cm(-3), refinement on 2217 reflections, R = 0.023. For the chloro derivative at 150K, a = 10.3416(8), b = 8.0605(5), c = 11.1573(8) angstrom, beta = 102.70(8)degrees, Z = 2, V = 907(3) angstrom(3), Dx = 1.330 g cm(-3), refinement on 2429 reflections, R = 0.038. The molecules are close to planar, the crystal packing shows Br center dot center dot center dot Br or Cl center dot center dot center dot Cl intermolecular halogen bonds, and some C-H center dot center dot center dot Br or Cl contacts. There are no Cl center dot center dot center dot N or Br center dot center dot center dot N interactions. (c) 2012 Elsevier B.V. All rights reserved