Title: Roméite-Group Minerals Review: New Crystal Chemical and Raman Data of Fluorcalcioroméite and Hydroxycalcioroméite

Abstract: The roméite-group is part of the pyrochlore-supergroup and comprises cubic oxides of A2B2X6Y formula in which Sb5+ predominates in the B-site. The A and Y main occupants determine different minerals in the group and are important for the discovery of new mineral species. Two different roméite-group mineral samples were analysed by electron microprobe analysis (EMPA), Raman spectroscopy and single-crystal X-ray diffraction (XRD). The first sample is from Prabornaz Mine (locality of the original roméite), Saint Marcel, Valle d’Aosta, Italy, whereas the other one occurs in Kalugeri Hill, Babuna Valley, Jakupica Mountains, Nezilovo, Veles, Macedonia. Sample 1 was identified as fluorcalcioroméite, and sample 2 as hydroxycalcioroméite. Both samples belong to the cubic crystal system, space group Fd3¯m, Z = 8, where a = 10.2881(13) Å, V = 1088.9(4) Å3 for sample 1, and a = 10.2970(13) Å, V = 1091.8(4) Å3 for sample 2. The crystal structure refinements converged to (1) R1 = 0.016, wR2 = 0.042; and (2) R1 = 0.023, wR2 = 0.049. Bond-valence calculations validated the crystal structure refinements determining the correct valences at each crystallographic site. Discrepancies observed in the Sb5+ bond-valence calculations were solved with the use of the proper bond valence parameters. The resulting structural formulas are (Ca1.29Na0.55□0.11Pb0.05)Σ=2.00(Sb1.71Ti0.29)Σ=2.00[O5.73(OH)0.27]Σ=6.00[F0.77O0.21(OH)0.02]Σ=1.00 for sample 1, and (Ca1.30Ce0.51□0.19)Σ=2.00(Sb1.08Ti0.92)Σ=2.00O6.00[(OH)0.61O0.21F0.18]Σ=1.00 for sample 2. The Raman spectra of the samples exhibited the characteristic bands of roméite-group minerals, the most evident corresponding to the Sb-O stretching at around 510 cm−1.

Authors: Gerson Lopes, Daniel Atencio, Javier Ellena, Marcelo Andrade

Title: A simple alternative to prodrug: The hydrochloride salt monohydrate of the prostate anticancer drug abiraterone

Abstract: Abiraterone acetate is a first choice prodrug to treat prostate cancer. New higher-solubility multicomponent crystal forms of the active compound abiraterone could substitute for the commonly used acetate prodrug. Here we prepare abiraterone hydrochloride monohydrate, which is the first multicomponent crystal form of this striking prostate anticancer agent. Its solid state characterization by single-crystal X-ray diffraction (SCXRD), infrared (IR) spectroscopy and thermogravimetry (TG) was performed. The only conformational difference in the molecular backbone common to the literature related crystal forms (abiraterone acetate and the free base abiraterone) and our salt resides in the 3-pyridil rotation upon protonation. If the neutral molecules found in the two literature structures are taken as references, this motif is rotated by almost exactly 180° in our protonated abiraterone. Crystal packing also follows the protonation pattern. While in both prodrug and free base there is formation of head-to-tail fashioned one-dimensional chains as the main supramolecular entities, hydrogen bonded sheets are the main supramolecular motifs of abiraterone hydrochloride monohydrate. In addition, the IR spectrum and the TG thermogram of the hydrochloride salt monohydrate are present with characteristics absorption bands and thermal events, being therefore useful as analytical data for control quality purposes of this promising active pharmaceutical ingredient.

Authors: Rafael G. Silveira, Beatriz N. Cunha, Juan C. Tenório, Deborah Victória Alves de Aguiar, Patricia da Cruz Souza, Boniek Gontijo Vaz, Javier Ellena, Alzir A. Batista, Felipe Terra Martins

Title: Estudio estructural y supramolecular del ácido 2-E-((4-hidroxifenil) diazenil) benzoico

Abstract: La estructura cristalina del compuesto ácido 2-E-((4-hidroxifenil) diazenil) benzóico se resolvió por medio del método de fase intrínseca usando datos de difracción de rayos X de monocristal, encontrando que la molécula cristaliza en el sistema cristalino ortorrómbico con grupo espacial Pbca. Dentro de su celda unidad hay cuatro moléculas por unidad asimétrica que son confórmeros moleculares. Estos confórmeros forman hélices beta a lo largo de la dirección [010]. A partir de los datos estructurales se realizó el cálculo de superficies de Hirshfeld determinando, a partir de ellas, sus correspondientes diagramas de huellas dactilares bidimensionales, lo que permitió estudiar las interacciones intermoleculares que más contribuyen al empaquetamiento cristalino. Así, se pudo determinar que la principal contribución a la superficie general está dada por los contactos H···H (34,8%), seguida de interacciones O···H/H···O (27%) y C···H/H···C (18,6%). También fueron calculadas las redes energéticas de interacción con un nivel de teoría DFT/B3LYP/6-31G(d,p), permitiendo cuantificar los valores de cada componente que aportan a la energía total, siendo las interacciones de dispersión (-57,5 kJ/mol) las que más contribuyen en la formación del empaquetamiento cristalino para este compuesto.

Authors: Richard F. D’Vries, Camila A. García-Carreño, Camila Cardona-Restrepo, Elizabeth Castro-Giraldo, Oscar E. Rojas-Alvarez, Javier Ellena

Title: 5-Fluorocytosine/5-Fluorouracil Drug-Drug Cocrystal: a New Development Route Based on Mechanochemical Synthesis

Abstract: Purpose: Mechanochemistry is addressed here for the green formation of a 1:1 pharmaceutical cocrystal involving the antifungal prodrug 5-Fluorocytosine (5-FC) and the antineoplastic drug 5-Fluorouracil (5-FU). Crystalline material of this drug-drug cocrystal (DDC) was previously obtained by slow evaporation from solution (SES) and was then structurally analyzed. Method: In this paper, neat grinding and solvent-drop grinding (SDG) were applied in an attempt to achieve a route for the supramolecular synthesis of this cocrystal, exhibiting suitable yield and amount for solid characterization, which were not achieved via the SES method. Results: SDG provided the solid drug-drug cocrystal form. The resulting material had its physical stability monitored for 2 years and was then evaluated by a range of analytical technologies: X-ray powder diffraction, differential scanning calorimetry, hot-stage microscopy, thermogravimetric, and spectroscopic analysis. Conclusions: The new cocrystal proved to be stable for 6 months and in environments with high relative humidity. In this sense, it is believed that the new DDC is a potential model system which could be used as a base for further developments in the field, for other molecules or in relation to the feasibility of using this cocrystal therapeutically.

Authors: Cecilia C. P. da Silva, Cristiane C. de Melo, Matheus S. Souza, Luan F. Diniz, Renato L. Carneiro, Javier Ellena

Title: Ru(ii)–thyminate complexes: new metallodrug candidates against tumor cells

Abstract:

Herein, we used thymine (HThy) as a ligand to form two new ruthenium(ii) complexes with formula [Ru(PPh₃)₂(Thy)(bipy)]PF₆ (1) and [Ru(Thy)(bipy)(dppb)]PF₆ (2).

Authors: Rodrigo S. Correa, Vitória Freire, Marília I. F. Barbosa, Daniel P. Bezerra, Larissa M. Bomfim, Diogo R. M. Moreira, Milena B. P. Soares, Javier Ellena, Alzir A. Batista

Title: Highlighting Recent Crystalline Engineering Aspects of Luminescent Coordination Polymers Based on F-Elements and Ditopic Aliphatic Ligands

Abstract: Three principal factors may influence the final structure of coordination polymers (CPs): (i) the nature of the ligand, (ii) the type and coordination number of the metal center, and (iii) the reaction conditions. Further, flexible carboxylate aliphatic ligands have been widely employed as building blocks for designing and synthesizing CPs, resulting in a diverse array of materials with exciting architectures, porosities, dimensionalities, and topologies as well as an increasing number of properties and applications. These ligands show different structural features, such as torsion angles, carbon backbone number, and coordination modes, which affect the desired products and so enable the generation of polymorphs or crystalline phases. Additionally, due to their large coordination numbers, using 4f and 5f metals as coordination centers combined with aliphatic ligands increases the possibility of obtaining different crystal phases. Additionally, by varying the synthetic conditions, we may control the production of a specific solid phase by understanding the thermodynamic and kinetic factors that influence the self-assembly process. This revision highlights the relationship between the structural variety of CPs based on flexible carboxylate aliphatic ligands and f-elements (lanthanide and actinides) and their outstanding luminescent properties such as solid-state emissions, sensing, and photocatalysis. In this sense, we present a structural analysis of the CPs reported with the oxalate ligand, as the one rigid ligand of the family, and other flexible dicarboxylate linkers with –CH2– spacers. Additionally, the nature of the luminescence properties of the 4f or 5f-CPs is analyzed, and finally, we present a novel set of CPs using a glutarate-derived ligand and samarium, with the formula [2,2′-bipyH][Sm(HFG)2 (2,2′-bipy) (H2O)2]•(2,2′-bipy) (α-Sm) and [2,2′-bipyH][Sm(HFG)2 (2,2′-bipy) (H2O)2] (β-Sm).

Authors: Richard F. D’Vries, Germán E. Gomez, Javier Ellena

Title: Molecular Structure Studies on Allyl Sulfonamides: Synthesis, Theoretical Treatment and Evaluation of Biological Activity

Abstract: Two series of allyl sulfonamides, prepared from Morita-Baylis-Hillman adducts and primary aromatic sulfonamides, were fully characterized. The Z configuration for the products derived from 2-[hydroxy(phenyl)methyl]acrylonitrile (1) and E configuration for those derived from methyl 2-[hydroxy(phenyl)methyl]acrylate (2) were confirmed by X-ray diffraction for one compound of each series (1e, 2f). Density functional theory calculations for all allyl sulfonamides agreed with the X-ray crystallographic data. X-ray diffraction studies indicate that these compounds form dimers in their crystal structures. Fingerprint plots show that compound 1e is stabilized by H⋯H, C⋯H/H⋯C, O⋯H/H⋯O and N⋯H/H⋯N interactions, while the compound 2f has no N⋯H/H⋯N contacts. Hirshfeld surface analyses were performed to gain insight into the behavior of these interactions. Calculated frontier orbitals showed that their highest occupied and lowest unoccupied molecular orbitals are antibonding orbitals. The allyl sulfonamides 1e and 2f are among the most active compounds in each series, inhibiting approximately 60% of the mycelial growth of Botrytis cinerea at 3 mmol L-1.

Authors: Anderson Rabello, Mayura Rubinger, Rafael Souza, Silvana Guilardi, Guilherme de Lima, Eder Tavares, Édipo Zanon, Giovanna Silva, Laércio Zambolim, Javier Ellena

Title: Synthesis and X-ray crystal structures of polyfunctionalized 4H-chromene derivatives via tricomponent reaction with Knoevenagel adducts as intermediates in aqueous medium

Abstract: Chromenes and their derivatives are an important class of compounds known for their biological properties. In this study, synthetic methodologies were described to obtain 4H-chromene derivatives. Two routes were investigated, the first being a bicomponent reaction using Knoevenagel adducts as reagents and the second using one-pot tricomponent reactions, both under microwave irradiation, using H2O as solvent and triethylamine as catalyst. Twenty 4H-chromene derivatives were synthesized with 50–95% yields from aromatic aldehydes, 5,5-dimethyl-1,3-cyclohexadione and malononitrile or methyl cyanoacetate, being further characterized by Fourier Transform Infrared and Nuclear Magnetic Resonance. We also report three crystal structures from the synthesized chromene derivatives, by single-crystal X-ray diffraction, showing the main supramolecular features of each structure – a poorly unexplored approach involving this class of compounds so far.

Authors: Lucas Lima Zanin, David Esteban Quintero Jimenez, Matheus Pereira de Jesus, Luan Farinelli Diniz, Javier Ellena, André Luiz Meleiro Porto

Title: Synthesis, Characterization and Structural Analysis of Two New Biguanide Complexes

Abstract: This study reports on the synthesis and characterization of two new coordination compounds of the active pharmaceutical ingredient metformin and transition metals. The cobalt compound with the formula [Co(Met)3][CoCl4]Cl·3H2O is a complex salt formed by a cationic Co(III) octahedral and anionic Co(II) tetrahedral subunits. The Cu(II) complex is represented by the formula [(Cu(Met)Cl)2-μ-Cl2] and is a dimeric compound with two chloride anions acting as a bridge, forming shared-edge square pyramidal units. Both compounds were characterized by single crystal X-ray diffraction, FT-IR spectroscopy and thermal analysis.

Authors: Andrea Pastrana-Dávila, Gianella Minotta, Javier Ellena, Pedro H. O. Santiago, Richard F. D’Vries

Title: “Half-Sandwich”/RuII Anticancer Complexes Containing Triphenylphosphine and p-Substituted Benzoic Acids

Abstract: Mononuclear and binuclear RuII/arene/triphenylphosphine complexes with p-substituted benzoic acid derivatives were prepared and characterized. These monocationic complexes of type [Ru(η6-p-cymene)(PPh3)L] (L = benzoic acid (1), p-hydroxybenzoic acid (2), p-nitrobenzoic acid (3) and terephthalic acid (4)) were characterized using various techniques, such as nuclear magnetic resonance (NMR) and matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry, and the crystal structure of 1, 3 and 4 were determined by X-ray diffraction analysis. The cytotoxicity of the complexes was evaluated, in vitro, against tumorigenic [MDA-MB-231, MCF-7 (breast), A549 (lung) and DU-145 (prostate)] and non-tumorigenic [MCF-10A (breast), MRC-5 (lung) and PNT-2 (prostate)] cells. The binuclear complex (4) was inactive due to its low solubility. Complexes 1, 2 and 3 showed similar cytotoxicity, however, complex 1 presented better selectivity index against MDA-MB-231 than compounds 2 and 3. Cellular ruthenium absorption was explored by inductively coupled plasma mass spectrometry (ICP-MS) analyzing the whole cells and the culture medium. Complementary studies showed that complex 1 inhibited colony formation, induced morphology changes in cells and promoted cell cycle arrest in the Sub-G1 phase for the MDA-MB-231 cells.

Authors: João Honorato, Katia Oliveira, Celisnolia Leite, Legna Colina-Vegas, Joaquim Nóbrega, Eduardo Castellano, Javier Ellena, Rodrigo Correa, Alzir Batista

Title: Molecular structure of Ru(II)/diphosphine/4,6-dimethyl-2-pyrimidinethiol complexes: A combined experimental and density functional theory study

Abstract: Reactions of cis-[RuCl2(P-P)(bipy)] precursors with the SpymMe2 ligand (4,6-dimethyl-2-pyrimidinethiol) yielded complexes of the [Ru(SpymMe2)(P-P)(bipy)]PF6 type, where P-P = 1,2-bis(diphenylphosphino)ethane (dppe - for complex 1), 1,3-bis(diphenylphosphino)propane (dppp - for complex 2) and 1,1’-bis(diphenylphosphino)ferrocene (dppf - for complex 3) and bipy = 2,2’-bipyridine. The new compounds were obtained by displacing the chlorido ligands from the precursors and coordination of one monoanionic 4,6-dimethyl-2-pyrimidinethiol ligand. All complexes were characterized by spectroscopic, electrochemical and elemental analysis techniques, as well as single-crystal X-ray diffraction, where the structures of complexes 1, 2 and 3 showed that the SpymMe2 ligand coordinates to the ruthenium(II) center as bidentated, yielding complexes with the sulfur atom trans positioned to the nitrogen atom from the bipy ligand. A theoretical study of the structures of the complexes was performed using the DFT/B3LYP method. Distances and angles of optimized structures agree with X-ray experimental data. Furthermore, the calculated IR and UV-Vis spectra are compatible with experimental data. Charge decomposition analysis (CDA) and NBO (natural bond orbitals) charges showed that there was an overall charge transfer from bipy and P-P ligands to the ruthenium centers. Higher electrochemical stability and 1H and 31P{1H} NMR shifts of 1, 2 and 3 compared with precursors could be explained by the lower values of calculated molecular orbital energies, NBO charge on atoms and CDA data. Finally, the structure of the isomers of complexes 1, 2 and 3, considering the sulfur atom trans positioned to the phosphorus atom, were optimized, showing that they are slightly less stable, presenting total energy higher, 10.4, 31.5 and 60.5 kJ/mol than 1, 2 and 3, where nitrogen is trans to the phosphorus atom.

Authors: Benedicto A.V. Lima, Jaldyr de J.G. Varela, Javier Ellena, Alzir A. Batista, Albérico B.F. da Silva, Rodrigo S. Correa

Title: Glycosylated narciclasine alkaloid in Hippeastrum puniceum (Lam.) Kuntze

Abstract: The present work focused on the chemical study of the main alkaloid component in Brazilian indigenous Amaryllidaceae species Hippeastrum puniceum (Lam.) Kuntze. The strategy applied was based on a distinct partitioning process and chromatographic-purification steps using the crude methanolic extract as the starting material. In this way, the glycosylated derivative narciclasine-4-O-β-D-xylopyranoside was isolated from the ethyl acetate fraction of H. puniceum. Structural elucidation of the compound was performed through NMR (Nuclear Magnetic Resonance) analysis including mono- and bi-dimensional experiments. The absolute configuration was determined herein for the first time by means of X-Ray Crystallography. The compound was also evaluated as cytotoxic agent against colon (HCT 116) and breast (MCF-7) tumor cells, showing no significant activity at the tested concentrations of 10 and 50 μM.

Authors: Amanda Eiriz Feu, Jean Paulo de Andrade, Alejandro Pedro Ayala, Larissa Costa de Almeida, Leticia V. Costa-Lotufo, Jaume Bastida, Javier Ellena, Warley de Souza Borges

Title: Biguanide–transition metals complexes as potential drug for hyperglycemia treatment

Abstract:

Coordination compounds of Cu(ii), Ni(ii), Co(ii), and Zn(ii) with a type of biguanide were obtained and structurally characterized. The new metal-drugs present biological applications as potential drugs for diabetes and metabolic syndrome.

Authors: Stephanny Villamizar-Delgado, Laura M. Porras-Osorio, Octavio Piñeros, Javier Ellena, Norman Balcazar, Ruben E. Varela-Miranda, Richard F. D'Vries

Title: Synthesis, characterization and solubility of a new anthelmintic salt: Mebendazole nitrate

Abstract: Salt formation approach was taken to improve Mebendazole (MBZ) solubility. MBZ polymorph A was easily recrystallized as a 1:1 nitrate salt (MBZ N) in methanol. Single crystal X-ray diffraction data show that MBZ N crystallizes in the P1¯ space group. By strong intermolecular H-bonding interactions, MBZ is associated with a nitrate anion forming a supramolecular R22(8) synthon. Crystal packing is stabilized by these H-bonds, through which each nitrate connects two molecules of MBZ forming chains along the b axis. The vibrational behavior studied by micro FT-Raman and FT-IR spectroscopy is consistent with the crystal structure. Thermal analysis of the salt indicates that the compound is stable up to 150 °C, when an almost simultaneous elimination of HNO3 and CO2 occurs. MBZ N equilibrium solubility was evaluated in hydrochloric acid 0.1 M solution and compared with those of MBZ A and C. An improvement in a factor of 5 and 1.22 was found respectively.

Authors: Eduardo L. Gutiérrez, Matheus S. Souza, Luan F. Diniz, Javier Ellena

Title: Modulating the water solubility and thermal stability of the anti-tuberculosis drug Isoniazid via multicomponent crystal formation

Abstract: In this paper three novel salts of the anti-tuberculosis drug Isoniazid (INH) with the GRAS salt formers (oxalic, maleic and methanesulfonic acids) were supramolecularly synthesized by solvent evaporation method. Aiming to expand the diversity of supramolecular synthons of this drug as well as obtaining new solid forms with enhanced solubility and thermal stability, these salts namely oxalate (INH−OXA), maleate (INH−MAL) and mesylate (INH−MES) were fully characterized by X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR) and thermal (TGA, DSC, HSM) techniques. At the same time, salts' solubility was explored. Analysis of the crystal structures and packings were analyzed in details, showing that the INH salts exhibit layered structures stabilized by N–H⋯O, C–H⋯O and π···π interactions. The salt formations were confirmed from the FT-IR and FT-Raman spectra and their thermal behaviors indicate that INH−OXA and INH−MES are thermally more stable than the corresponding INH. The equilibrium solubilities of these salts, in different buffered media, were evaluated and both INH−MAL and INH−MES were found to be more soluble (∼3 fold) than INH. Therefore, the present study proved that salt formation is an efficient strategy to enhance solubility and thermal stability of INH.

Authors: Luan F. Diniz, Matheus S. Souza, Paulo S. Carvalho, Charlane C. Correa, Javier Ellena