Pesquisa e desenvolvimento no LaMuCrEs

Utilizando a expertise acumulada ao longo de muitos anos, o LaMuCrEs possui múltiplos interesses e linhas de pesquisa, como Mineralogia, Insumos farmacêuticos e Compostos de Coordenação.

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Title: Structural, supramolecular analysis, and photoluminescence properties of a new hydroxybenzohydrazide Schiff base

Abstract: This work presents the synthesis, spectroscopic characterization, and structural analysis of N'-((1Z,2E)-1,3-diphenylallylidene)-2-hydroxybenzohydrazide (DAHH). Comprehensive spectroscopic characterization was performed using ¹H and ¹³C NMR, MS, FT-IR, and optical spectroscopy. Single crystal X-ray diffraction analysis shows that the new benzohydrazide derivative crystallizes in the monoclinic space group P21/c with one molecule per asymmetric unit and general formula C22H18N2O2. The structural data enabled supramolecular analysis, showing that crystalline packing is formed by N-H···O and O-H···O hydrogen interactions. It also features weak T-shape C-H···π (edge-to-face) and C=C···π interactions. These results were corroborated and quantified using Hirshfeld surface and fingerprint plot analysis. The most abundant interaction is H···H dispersion (50.2%), followed by C···H (28%) and O···H (10.1%). Lattice energies and energy frameworks for the DAHH compound were also calculated. Finally, the luminescence properties of DAHH were studied.

Authors: David Oliveros Garavito, Andrea Pastrana-Dávila, Javier Ellena, Pedro H.O. Santiago, Oscar Rojas, Dominik Pentlehner, Luis A. Illicachi, Richard D’Vries

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Title: Reactions of ketosulfoxonium ylides with allylic carbocations: stereoselective and direct access to highly-substituted cyclo-propanes and α-alkylated ylides

Abstract: The reaction of ketosulfoxonium ylides and allylic carbocations is described. Depending on the nature of the sulfoxonium ylide employed, highly substituted cyclopropanes or α-alkylated sulfoxonium ylides are obtained.

Authors: Viktor S. Camara, Marcio Hayashi, Alex S. Moraes, Pedro H. O. Santiago, Javier Ellena, Marco A. B. Ferreira, Antonio C. B. Burtoloso

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Title: New Naphthoquinone‐Based Manganese (II) Complexes: Synthesis, Characterization, and Cytotoxicity

Abstract: Abstract We have synthesized and characterized two new complexes of stilbenes‐quinone hybrids with a manganese(II) center, Mn1 [Mn(NQ1) 2 (EtOH) 2 ] and Mn2 ([Mn(NQ2) 2 (EtOH) 2 ], where NQ1 and NQ2 are the 2‐hydroxy‐3‐styryl‐1,4‐naphthoquinone and 2‐hydroxy‐3‐(4‐chlorostyryl)‐1,4‐naphthoquinone in their deprotonated forms. FTIR and UV–vis spectroscopy analyses were used to verify changes in characteristic bands upon the coordination to a manganese center. Single‐crystal X‐ray diffraction analysis allowed the structural elucidation of Mn1 as cis ‐[Mn(NQ1) 2 (EtOH) 2 ] and Mn2 as cis ‐[Mn(NQ2) 2 (EtOH) 2 ] isomers. The charge distribution, dipole moments, and Gibbs free energy of the complexes were also calculated. The in vitro cytotoxicity results revealed that the coordination of quinone nucleus into a metal center improved their cytotoxicity, highlighting the effect of the manganese complexes on ovarian cancer cells. Mn1 , the promising candidate, was able to change the morphology and inhibit the colony formation in A2780 cells. Further, based on circular dichroism and fluorescence results, this manganese complex interacts with DNA via minor groove binding. In light of these results, Mn1 displays a promising skeleton for the development of more cytotoxic and selective manganese‐based compounds against ovarian cancer.

Authors: R. L. Machado, W. T. G. Novato, R. S. Silva, F. C. Demidoff, S. H. M. Abe, M. V. Palmeira‐Mello, J. H. A. Neto, J. A. Ellena, A. A. Batista, C. D. Netto, M. S. Schultz

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Title: Manganese‐Induced Production of Antioxidant Polyene Steroids in the Extremophile Fungus Talaromyces fuscoviridis Isolated From Copper‐Mine Soil

Abstract: ABSTRACT The fungus Talaromyces fuscoviridis was isolated from soil collected in a copper‐mine tailings basin in Pará State, Brazil, an extreme environment that can induce the production of bioactive secondary metabolites. Extracts and fractions obtained after cultivation were analyzed by liquid chromatography coupled to high‐resolution mass spectrometry (LC–HRMS) and compared using Global Natural Products Social molecular networking (GNPS), which revealed a family of seven putative polyunsaturated steroids. Isolation led to the characterization of two major steroids: the known Ergosta‐3(4),5(6),7(8),14(15),22(23)‐pentaene (1a) and a previously unreported metabolite, Ergosta‐5(6),7(8),14(15),22(23)‐tetraen‐3‐ol (2a). Their structures were elucidated through comprehensive spectroscopic and spectrometric methods (e.g., UV–Vis, NMR, and high‐resolution mass spectrometric [HRMS]), with the structure of steroid 2a being unequivocally confirmed by single‐crystal x‐ray diffraction (SCXRD). Notably, the biosynthesis of these steroids was significantly enhanced when the cultivation medium was supplemented with manganese chloride (MnCl 2 ). Furthermore, the steroids were tested for their in vitro antioxidant activity against the 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) free radical using an adapted UHPLC–DAD method, showing over 80% of the scavenging capacity of β‐carotene at the lowest tested concentrations.

Authors: Mauricio Augusto Pinto Moreno da Silva Alves, Alef dos Santos, Eduardo Jorge Pilau, Pedro Henrique de Oliveira Santiago, Javier Alcides Ellena, Marilene Nunes Oliveira, Edson Rodrigues Filho

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Title: Use of computational techniques in Raman spectra analysis

Abstract: Not Found

Authors: Tulio Santana Ramos, Alfredo A. A. Exposito de Queiroz, Marcelo B. Andrade, Javier Ellena

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Title: Ascorbyl Radicals as Reducing Agents in Copper-Catalyzed Redox Reactions

Abstract: Radical-based redox reactions are greatly influenced by their surrounding environment, with the solvent playing a pivotal yet sometimes underestimated role. In this study, we examined how copper catalysts and the choice of solvent impact the reductive power of ascorbyl radicals. Our study used the reduction of 4-nitrophenyl azide as a model and further extended it to other azides and aldehydes. The results reveal a striking difference in radical stability and reductive efficiency, with higher conversions in methanolic solutions compared to acetonitrile. This difference was attributed to the formation and persistence of ascorbyl radicals in methanolic solutions as in acetonitrile; the copper complexes were fully reduced to their copper(I) forms, and the ascorbyl radicals were barely detectable via EPR spectroscopy. Conversely, in methanol, DMPO-trapped ascorbyl radicals persisted for extended periods, indicating that these radicals were the primary reducing agents. Theoretical calculations supported this hypothesis, indicating that these findings suggest that optimizing solvent and copper catalyst selection is crucial for enhancing the reductive power of ascorbyl radicals, with implications for other metal-mediated reductions.

Authors: Caio Bezerra de Castro, Gabrielle Conciani, Everton M. da Silva, Joao Honorato, Walber Gonçalves Guimarães Júnior, André Farias de Moura, Javier Ellena, Arlene G. Corrêa, Otaciro Rangel Nascimento, Caterina G.C. Marques Netto

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Title: The Vortex-Slurry Implementation: A Cheap, Easy, and Ultrafast Mechanochemical Tool to Synthesize/Screen Pharmaceutical Salts and Cocrystals

Abstract: The vortex-slurry implementation is a combination of the best insights taken from multiple solid-state methods using accessible tools to improve the physical scenario, mainly designed for the supramolecular synthesis of new multicomponent pharmaceutical solid forms by coupling mechanochemistry and slurry techniques within a vortex mixer. The proposal of the vortex-slurry implementation is to provide a totally different experimental ambient capable of reaching new 3D thermodynamic states, not allowed in the current commercial mechanochemistry methods (1D mixer mill and 2D planetary mill). The obtained compounds could be easily scaled from milligrams to grams, thus opening the door for the possibility of an industrial scaling approach. The improvements achieved by this new implementation were validated by resynthesizing already reported salts and cocrystals and by presenting a new solid form for the antiviral drug Stavudine (DT4), which is an orally administered second-line drug in HIV treatment. Theoretical studies revealed that this implementation enhances the activation energy of the system due to the ball bearings’ helical movements. It is expected that this implementation can spread to the scientific community, allowing manufacturability of new drug candidates and generating improvements in the quality of life of patients.

Authors: Paulo N. de Souza, Lucas V. C. Militão, Pollyana P. Firmino, Pedro H. de O. Santiago, João H. de Araujo-Neto, Javier Ellena, Cecilia C. P. da Silva

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Title: A supersaturated glass-melt approach for growing micrometer-sized TGG single crystals

Abstract: Terbium gallium garnet (TGG, Tb3Ga5O12) is an important material used as Faraday rotator in telecommunication, in interferometric facilities and in other important technological and photonic applications. TGG can be synthesized using different methodologies, however obtaining single crystals on a large scale is still a challenge. In this paper, for the first time, micrometric cubic single crystals were obtained from rare earths supersaturated melted heavy metal oxide glass compositions. A systematic study of the glass composition allied to the control of cooling parameters allowed the synthesis of micro-scale single crystals. A chemical route is proposed to isolate the crystals from the parent glass without compromising their properties. A series of structural and spectroscopic techniques was employed to characterize the crystals, which crystallize in the Ia 3‾ d space group. XRD, Raman and EDS measurements demonstrate the formation of the Tb3Ga5O12 crystalline phase and the microscopy images show the presence of microcrystals with a perfect cubic shape and size between 50 and 100 μm. Luminescence analysis indicates a green emission between 530 and 560 nm characteristic of the 5D4 → 7F5 transitions of Tb3+ ions and the presence of Stark components as well resolved multiplets and perfectly coherent with the Stark components of the TGG crystal. Finally, SQUID measurements were performed on glass samples containing crystals and on isolated crystals after removal of the glass and both presented paramagnetic behavior. The effective magnetic moment obtained for the TGG microcrystals between 50 and 70 μm removed from the glass was 9.7 μB, the same value as the theoretical effective magnetic moment for Tb3+ ions. This achievement represents an advance in the methodologies for obtaining TGG cubes in the micro-scale range, opening the possibility of mass production of such crystal and its uses in different technological photonic applications.

Authors: Juliane Resges Orives, Thiago Augusto Lodi, Lia Mara Silva Marcondes, Camila Batista Pinto, Victória Mamelli, Antonio Eduardo Souza, Fabricio Benedito Destro, Juliani Caland, Javier Alcides Ellena, Thierry Cardinal, Marc Dussauze, Jorlandio Felix, Marcelo Nalin

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Title: Enhanced Anticancer Potential of Pd(II)-Thiosemicarbazone Complexes: Selectivity, Mechanisms, and 3D Models

Abstract: Background/Objectives: Cancer remains a major global health challenge, driving the search for novel chemotherapeutic agents. This study aimed to evaluate the structural and biological properties of a series of Pd(II) complexes containing triphenylphosphine and thiosemicarbazone ligands, in order to assess their potential as anticancer agents. Methods: Six Pd(II) complexes with the general formula [PdCl(PPh3)(TSC)] were synthesized and fully characterized by NMR (1H, 1³C, ³1P), FTIR, mass spectrometry, and X-ray diffraction. Their cytotoxic effects were investigated through in vitro assays using 2D and 3D cancer cell models, including clonogenic, wound healing, cell cycle, and apoptosis assays via flow cytometry. Results: Complexes from the B family demonstrated significantly higher cytotoxicity than those from the C family, particularly against ovarian (IC50 < 1 µM) and breast (IC50~2 µM) cancer cell lines. These compounds exhibited superior potency and selectivity compared to cisplatin, with high selectivity indices toward non-tumor cells. Mechanistic studies revealed both cytotoxic and cytostatic effects depending on structural variations, with apoptosis identified as the primary mechanism of cell death. PdB1, in particular, induced a marked increase in late apoptotic populations and maintained its cytotoxic activity in 3D spheroid models by promoting disintegration, loss of cell adhesion, and nuclear fragmentation. Conclusions: The findings underscore the therapeutic promise of Pd(II) complexes, especially PdB1, as potent and selective antineoplastic agents capable of acting effectively in complex tumor environments and potentially overcoming chemoresistance.

Authors: Mauro A. Lima, Tamara Teixeira, Dario B. Fortaleza, George B. S. Pereira, Amos O. Akinyemi, Carlos André Ferreira Moraes, Moacir R. Forim, Alzir A. Batista, Jocely L. Dutra, João H. Araujo-Neto, Javier A. Ellena, Fillipe V. Rocha

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Title: A nickel glutamate metal biomolecule framework

Abstract: The first solved supramolecular crystal structure for the combination of glutamic acid and Ni(ii) ions.

Authors: Élvio Antônio de Campos, Luana Thayline Casagrande Silva, Rodrigo Vieira Rodrigues, Ronan Farias Freire de Souza, Jeane Patrícia Cardozo dos Santos, Conceição de Fátima Alves Olguin, Cleide Viviane Buzanello, Javier Alcides Ellena, Pedro Henrique de Oliveira Santiago, Sílvia Denofre de Campos

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Title: Ru(II)-Fenamic-Based Complexes as Promising Human Ovarian Antitumor Agents: DNA Interaction, Cellular Uptake, and Three-Dimensional Spheroid Models

Abstract: Cancer resistance to chemotherapeutic agents such as cisplatin presents a significant challenge, leading to treatment failure and poor outcomes. Novel metal-based compounds offer a promising strategy to overcome drug resistance and to enhance efficacy. Four Ru(II) complexes with fenamic acid derivatives were synthesized and characterized: [Ru(L)(bipy)(dppp)]PF6, where L represents fenamic acid (HFen, complex 1), mefenamic acid (HMFen, complex 2), tolfenamic acid (HTFen, complex 3), and flufenamic acid (HFFen, complex 4). Their composition was supported by molar conductivity, elemental analysis, Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, mass spectrometry, and 31P{1H}, 1H, and 13C nuclear magnetic resonance, with the crystal structure of complex 1 confirmed via X-ray diffraction. Complexes 1-4 exhibited notable cytotoxicity against tested cell lines, particularly A2780 and A2780cisR (cisplatin-resistant ovarian tumors), compared to MDA-MB-231 (breast) and A549 (lung) lines. Mechanistic studies revealed weak DNA interactions through minor grooves or electrostatic binding. Cellular uptake assays showed effective internalization of complexes 1 (3.6%) and 2 (4.5%), correlating with potent IC50 values. These complexes also altered cell morphology, reduced cell density, and inhibited colony formation in the A2780 cells. Staining assays indicated induced cell death and organelle damage, highlighting their potential as promising antitumor agents.

Authors: Tamara Teixeira, Marcos V. Palmeira-Mello, Pedro Henrique Machado, Carlos A. F. Moraes, Camila Pinto, Rayane C. Costa, Wladimir Badaró, José A. Gomes Neto, Javier Ellena, Fillipe Vieira Rocha, Alzir A. Batista, Rodrigo S. Correa

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Title: Supramolecular assembly of mebendazolium and dihydrogen phosphate ions in a new anthelmintic salt

Abstract: A new mebendazolium dihydrogen phosphate phosphoric acid solid material was obtained and characterized by single-crystal X-ray diffraction and complementary solid-state techniques {systematic name: 5-benzoyl-2-[(methoxycarbonyl)amino]-1H-1,3-benzodiazol-3-ium dihydrogen phosphate–phosphoric acid (1/1), C16H14N3O3 +·H2PO4 −·H3PO4}. Structure solution confirmed proton transfer from phosphoric acid towards the basic imidazole ring of mebendazole. The mebendazolium cation and the dihydrogen phosphate anion assemble in the solid state in a cyclic hydrogen-bond-driven supramolecular motif, as observed in all mebendazolium/oxyanions structures reported in the literature. This salt crystallizes in the monoclinic P21/c (No. 14) space group. A detailed study of the crystal structure performed by atom-to-atom and global Hirshfeld surface analysis indicates that several hydrogen bonds act as the main intermolecular interactions stabillizing the material. The new material is stable up to 458 K.

Authors: Eduardo L. Gutiérrez, Marcos G. Russo, Griselda E. Narda, Elena V. Brusau, Alejandro P. Ayala, Javier Ellena

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Title: Ruthenium(II) Complex with 1-Hydroxy-9,10-Anthraquinone Inhibits Cell Cycle Progression at G0/G1 and Induces Apoptosis in Melanoma Cells

Abstract: Background: Melanoma is the most aggressive and lethal skin cancer that affects thousands of people worldwide. Ruthenium complexes have shown promising results as cancer chemotherapeutics, offering several advantages over platinum drugs, such as potent efficacy, low toxicity, and less drug resistance. Additionally, anthraquinone derivatives have broad therapeutic applications, including melanoma. Objectives: Thus, two new ruthenium complexes with 1-hydroxy-9,10-anthraquinone were obtained: trans-[Ru(HQ)(PPh3)2(bipy)]PF6 (1) and cis-[RuCl2(HQ)(dppb)] (2), where HQ = 1-hydroxy-9,10-anthraquinone, PPh3 = triphenylphospine, bipy = 2,2′-bipyridine, PF6 = hexafluorophosphate, and dppb = 1,4-bis(diphenylphosphine)butane. Methods: The complexes were characterized by infrared (IR), UV–vis, 1H, 13C{1H}, and 31P{1H} NMR spectroscopies, molar conductivity, cyclic voltammetry, and elemental analysis. Furthermore, density functional theory (DFT) calculations were performed. Results: Compound (2) was determined by single-crystal X-ray diffraction, which confirms the bidentate coordination mode of HQ through the carbonyl and phenolate oxygens. Additionally, DNA-binding experiments yielded constants of 105 M−1 (Kb = 6.93 × 105 for (1) and 1.60 × 105 for (2)) and demonstrate that both complexes can interact with DNA through intercalation, electrostatic attraction, or hydrogen bonding. Conclusions: The cytotoxicity profiles of the compounds were evaluated in human melanoma cell lines (SK-MEL-147, CHL-1, and WM1366), revealing greater cytotoxic activity for (1) on the CHL-1 cell line with an IC50 of 14.50 ± 1.09 µM. Subsequent studies showed that (1) inhibits the proliferation of CHL-1 cells and induces apoptosis, associated at least in part with the pro-oxidant effect and cell cycle arrest at the G1/S transition.

Authors: Júlia S. M. Dias, Guilherme A. Ferreira-Silva, Rommel B. Viana, João H. de Araujo Neto, Javier Ellena, Rodrigo S. Corrêa, Marília I. F. Barbosa, Marisa Ionta, Antônio C. Doriguetto

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Title: A novel imatinib analogue inhibitor of chronic myeloid leukaemia: design, synthesis and characterization—explanation of its folded conformation

Abstract: Chronic myeloid leukaemia (CML) is primarily treated using imatinib mesylate, a tyrosine kinase inhibitor (TKI) targeting the BCR::ABL1 oncoprotein. However, the development of drug resistance and adverse side effects necessitate the exploration of alternative therapeutic agents. This study presents the synthesis and characterization of a novel imatinib analogue, 3-chloro- N -(2-methyl-5-((4-(pyridin-2-yl)pyrimidin-2-yl)amino)phenyl)benzamide (PAPP1). The compound’s structure was elucidated using X-ray crystallography and spectroscopic techniques, including NMR, infrared and UV–visible. Crystallographic analysis reveals that PAPP1 consists of a phenyl–amino–pyridine–pyrimidine (PAPP) scaffold with substituted aromatic rings forming a nearly coplanar geometry. Additionally, supramolecular interactions in the crystal are mediated by hydrogen bonds and dispersion forces, forming dimers and layered structures. Molecular docking studies demonstrate strong binding affinity to the ABL1 enzyme, with PAPP1 showing comparable binding energy to imatinib, indicating its potential as a lead compound for further development. Computational studies, including molecular electrostatic potential and vibrational analysis, provide further support for the structural stability and bioactivity of PAPP1. These findings suggest that PAPP could be a promising scaffold for future CML drug design, offering a potential alternative to existing TKIs, and PAPP1 is a promising lead susceptible to optimization.

Authors: Rodolfo Moreno-Fuquen, Juan F. Avellaneda-Tamayo, Kevin Arango-Daraviña, Javier Ellena, Alan R. Kennedy

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Title: Enhancing physicochemical properties of hydrochlorothiazide with zwitterionic L-proline and 5-fluorocytosine cocrystals through mechanochemical synthesis

Abstract: Hydrochlorothiazide (HTZ) is a thiazide-type diuretic drug approved by the FDA in 1959 for treatment of hypertension and peripheral edema and has been used since. HTZ exhibits low solubility and low permeability, leading to variable oral bioavailability and limited intestinal drug permeability. For this reason, several attempts to improve HTZ physicochemical properties have been made during the past decades. In the broad frame of molecular crystal engineering, significant efforts and promising results in the quest for more effective solid/dosage forms of HTZ, including studies on polymorphism and cocrystals, are being developed. As part of these efforts, we report here two new cocrystals of HTZ with the zwitterionic L-proline and the prodrug 5-Fluorocytosine. Both cocrystals show improvement in solubility and permeability, suggesting that these new solid forms could be used as new drug candidates to deliver HTZ in the antihypertensive therapy.

Authors: Pollyana Pereira Firmino, Cecilia Carolina Pinheiro da Silva, Paulo Nunes, José Eduardo Gonçalves, Fabrizia Grepioni, Javier Ellena