Papers

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.

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

Abstract: Not Found

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

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

Abstract: Not Found

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

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

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

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

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

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

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

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

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

Title: NMR and X-ray diffraction conformational study of guanidines

Abstract: Leishmaniasis is a neglected disease that affects regions such as South Asia, South Africa, and Latin America, less developed regions. The research proposed the conformational study of brominated guanidine compounds with potential antileishmanial activity using Nuclear Magnetic Resonance (NMR) and X-ray diffraction (XRD) techniques. The present study involves the brominated molecules LQOF-G2, LQOF-G30, LQOF-G35 and LQOF-G35-Br. The latter was synthesized by the reaction of LQOF-G35 with NBS under IR irradiation at 120 Watts of potency and dichloromethane as solvent by 12 h of exposition. The obtained results demonstrated the efficiency of the bromination method, since two bromine atoms entered the molecule. Furthermore, NMR analysis showed a conformational change from Z to E when compound LQOF-G35 was brominated to LQOF-G35-Br. This behavior was confirmed by a comparative XRD study of the LQOF-G35 and LQOF-G35-Br compounds. The antileishmanial activity of LQOF-G2 e LQOF-G35 motivated the synthesis of new brominated compounds LQOF-G30 e LQOF-G35-Br.

Authors: Eduardo Henrique Zampieri, Luana Ribeiro dos Anjos, Pedro Henrique de Oliveira Santiago, Tainara Rosário da Silva Nascimento, Javier Ellena, Eduardo René Pérez González

Title: Innovative synthesis of Tm³⁺/Er³⁺-doped Yb-YGG single crystals for upconversion-based white light emission

Abstract: In recent years, there has been a growing interest in developing advanced materials for photonics applications, particularly for efficient white light emission, which is crucial for technologies like solid-state lighting and display devices. One interesting approach for emitting white light is Upconversion (UC) luminescence. This study focuses on synthesis, by a new and alternative method, and characterization of yttrium ytterbium gallium garnet (Yb-YGG) single crystals, specifically Y1.8Yb1.2Ga5O12, doped with various concentrations of Er3+ and Tm3+ ions. These crystals were studied intending to enhance UC luminescence properties for white light generation by modifying their respective emissions in the red, green, and blue (RGB) regions. Unlike traditional methods such as Czochralski, these crystals were produced by controlled nucleation and growth through gradual cooling of a specific glass mixture, leading to Yb-YGG single crystals doped with different concentrations of Yb3+, Er3+, and Tm3+ ions. By optimizing the Yb3+/Tm3+/Er3+ ratio, the study allowed to obtain micrometric single crystals that efficiently emit white light via UC. The crystals were characterized by X-ray diffraction, optical and electronic microscopies, EDS and luminescence spectroscopy.

Authors: Leonardo Vieira Albino, Agustín Delendatti, Fábio José Caixeta, Thiago Augusto Lodi, Douglas Faza Franco, Camila Batista Pinto, Javier Alcides Ellena, Marcelo Nalin

Title: Diastereoselective Synthesis of Highly Functionalized γ‐Lactams via Ugi Reaction/Michael Addition

Abstract: AbstractThe γ‐lactam ring is a prominent feature in medicinal chemistry, and its synthesis has garnered significant interest due to its valuable properties. Among the γ‐lactams, 2‐oxopyrrolidine‐3‐carbonitrile derivatives stand out as versatile synthons that can be readily transformed into a variety of other functional groups. In this work, we successfully synthesized highly functionalized 3‐cyano‐2‐pyrrolidinones with moderate to good overall yields using the Ugi reaction followed by intramolecular Michael addition. The process demonstrated excellent diastereoselectivity and showed good tolerance to a range of isonitriles and carbonyl compounds.

Authors: Herika D. A. Vidal, Paulo S. G. Nunes, Alice K. A. Martinez, Marcelo A. P. Januário, Pedro H. O. Santiago, Javier Ellena, Arlene G. Corrêa

Title: Synthesis, XRD structural analysis and theoretical studies of a potential inhibitor against rheumatoid arthritis (RA)

Abstract: This work focused on analyzing the properties of N-(5-nitrothiazol-2-yl)furan-2-carboxamide (C8H5N3O4S, NTFC) as a possible inhibitor of the rheumatoid arthritis process. The synthesis of NTFC was carried out and good-quality crystals were obtained and studied by NMR (1H and 13C), DEPT 135, UV–Vis, IR, MS and single-crystal X-ray diffraction. The structure of NTFC consists of two rings, thiazole and furan, and a central C—N—C(=O)—C segment, which appears to be planar. This central amide segment forms angles of 2.61 (10) and 7.97 (11)° with the planes of the thiazole and furan rings, respectively. The crystal structure of NTFC exhibits N—H...N, N—H...O and C—H...O hydrogen bonds, and C—H...π and π–π interactions that facilitate self-assembly and the formation of hydrogen-bonded dimers, which implies the appearance of R 2 2(8) graph-set motifs in this interaction. The stability of the dimeric unit is complemented by the formation of strong intramolecular C—S...O interactions of chalcogen character, with an S...O distance of 2.6040 (18) Å. Hirshfeld surface (HS) analysis revealed that O...H/H...O interactions were dominant, accounting for 36.8% of the total HS, and that N—H...N interactions were fundamental to the formation of the dimeric structure. The molecular electrostatic potential (MEP) map showed a maximum energy of 46.73 kcal mol−1 and a minimum of −36.06 kcal mol−1. The interaction energies of molecular pairs around NTFC are highest for those interactions linked by N—H hydrogen bonds. The properties of the NTFC ligand as a potential inhibitor of the DHODH (dihydroorotate dehydrogenase) enzyme were evaluated by molecular docking, showing coupling energies very close to those obtained with the control drug for rheumatoid arthritis, i.e. leflunomide.

Authors: Kevin Monge-Hoyos, Rodolfo Moreno-Fuquen, Kevin Arango-Daraviña, Javier Ellena, Pedro H. O. Santiago

Title: Reactivity of the p‐Cymene‐Ruthenium Complex with Two Phenylamines for Metathesis Polymerization of Norbornene Compared to the Reactivity of Complexes with a Single Benzylamine or Dibenzylamine

Abstract: AbstractThe complexes [RuCl(Cy)(NH2Ph)2]Cl (1), [RuCl2(Cy)(NH2Bz)] (2), and [RuCl2(Cy)(NHBz2)] (3) were synthesized under identical conditions from [RuCl2(Cy)]2, where Cy=η6‐p‐cymene, Ph=phenyl, and Bz=benzyl. X‐ray crystallography revealed an additional NH2Ph ligand in 1, distinguishing it from the neutral mono‐amine complexes 2 and 3. The number of amines in these complexes did not correlate clearly with the σ‐donor character or steric hindrance of the amines. Different reactivities were observed for the ROMP of norbornene (NBE), as measured by batch reactions and kinetic studies using Raman and 1H NMR spectroscopy. Semiquantitative conversions reached up to 90 % with complex 1 and around 40 % with complexes 2 and 3. DFT calculations supported the hypothesis that the reaction for complex 1 involves the release of an amine through a dissociative mechanism, whereas complexes 2 and 3 react through an associative mechanism involving amine loss. The presence of an amine in the propagation species of complex 1 suggests the participation of the amine as an ancillary ligand. All carbene species are of the η2‐p‐cymene type, and the catalytic cycle follows a 14–16‐14 electron counting mechanism.

Authors: Eliada A. Silva, Pedro H. O. Santiago, Javier A. Ellena, Antônio G. S. Oliveira‐Filho, Ana Paula de Lima Batista, Benedito S. Lima‐Neto