Publications by authors named "Javier Ellena"

129 Publications

Electrochemical, mechanistic, and DFT studies of amine derived diphosphines containing Ru(II)-cymene complexes with potent cytotoxic activity against HeLa and triple-negative breast cancer cells MDA-MB-231.

Dalton Trans 2020 Nov;49(45):16498-16514

Departamento de Química, Universidade Federal do Paraná, Centro Politécnico, CP 19081, CEP 81531-980, Curitiba, PR, Brazil.

Complexes with general formula [RuCl(η6-p-cymene)(P-NR-P)]X (R = CH2Py (Py = pyridine) - [1a]+, CH2Ph (Ph = phenyl) - [1b]+, Ph - [1c] and p-tol (p-tol = p-tolyl) - [1d]+; X = PF6- or BF4-) were evaluated as cytotoxic agents against two cancer cell lines (HeLa and MDA-MB-231). All metal complexes are active in the range of concentrations tested (up to 100 μmol L-1). The IC50 (μmol L-1) values for the metal complexes are lower than that found for cisplatin. The activities are up to 6- and 15-fold higher than cisplatin for HeLa and MDA-MB-231 cancer cell lines, respectively. Studies of DNA binding and DNA cleavage were performed. DNA binding studies revealed a modest hypochromic shift in the metal complexes electronic spectra, indicating a weak interaction with Kb values in the range of 1.7 × 103-1.6 × 104. Although the cleavage tests revealed that in the dark DNA is not a biological target for these metal complexes, upon blue light irradiation they are activated causing DNA cleavage. Electrochemical studies showed the presence of two independent redox processes, one attributed to the oxidation process of Ru2+ → Ru3+ (EC process) and the other one to the reduction of Ru2+ → Ru1+, which is further reduced to Ru0 (ECE mechanism). In both processes, coupled chemical reactions were observed. DFT calculations were performed to support the electrochemical/chemical behavior of the complexes. The reactivity of complex [1b]BF4 with CH3CN was evaluated and two complexes were isolated [2b]BF4 and [3b]BF4. The complex mer-[RuCl(CH3CN)3(P-NCH2Ph-P)]BF4 ([2b]BF4) was isolated after refluxing the precursor [1b]BF4 in CH3CN. Isomerization of [2b]BF4 in CH3CN resulted in the formation of fac-[RuCl(CH3CN)3(P-NCH2Ph-P)]BF4. An attempt to isolate the fac-isomer by adding diethyl ether was unsuccessful, and the complex [3b]BF4 was observed as the major component. The complex [Ru2(μ-Cl3)(CH3CN)2(P-NCH2Ph-P)2]BF4 ([3b]BF4) proved to be very stable and can be obtained from both the mer- and the fac-isomers. The molecular structures of [1b]BF4 and [3b]BF4 were solved by single-crystal X-ray diffraction.
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http://dx.doi.org/10.1039/d0dt02500cDOI Listing
November 2020

A giant hybrid organic-inorganic octahedron from a narrow rim carboxylate calixarene.

Chem Commun (Camb) 2020 Dec;56(95):15024-15027

Institute of Chemistry, Federal University of Goias, CP 131, Goiania, 74001-970, GO, Brazil.

Here we discovered an unprecedented giant octahedral coordination compound bearing 16 Zn2+, 12 Na+, 8 O2-, 4 OH-, 13 H2O and 6 L4- ligands [L4- = fully deprotonated tetra(carboxymethoxy)calix[4]arene]. Its structure was elucidated by single-crystal X-ray diffraction, wavelength-dispersive X-ray spectroscopy and MALDI-TOF mass spectrometry. This compound, Zn8Na6L6⊃Zn8Na6O8(OH)4(H2O)13 (external⊃internal), has eight tetrahedral zinc ions forming the coordination vertices of an outermost cube where carboxylate groups from the sodium calixarenes are anchored. Its core consists of eight Zn2+, six Na+, eight O2-, and four OH- distributed over three layers, besides thirteen coordinated H2O molecules.
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http://dx.doi.org/10.1039/d0cc07043bDOI Listing
December 2020

Silver(I) complexes of 3-methoxy-4-hydroxybenzaldehyde thiosemicarbazones and triphenylphosphine: structural, cytotoxicity, and apoptotic studies.

Dalton Trans 2020 Nov;49(45):16474-16487

Department of General and Inorganic Chemistry, Department of Analytical Chemistry, UNESP - São Paulo State University, Institute of Chemistry, CEP 14800-060 Araraquara, SP, Brazil.

Novel silver(i) complexes of the type [AgCl(PPh3)2(L)] {PPh3 = triphenylphosphine; L = VTSC = 3-methoxy-4-hydroxybenzaldehyde thiosemicarbazone (1); VMTSC = 3-methoxy-4-[2-(morpholine-1-yl)ethoxy]benzaldehyde thiosemicarbazone (2); VPTSC = 3-methoxy-4-[2-(piperidine-1-yl)ethoxy]benzaldehyde thiosemicarbazone (3)} were synthesized and fully characterized by spectroscopic techniques. The molecular structures of complexes 2 and 3 were determined by single crystal X-ray diffraction. Compounds 1-3 exhibited appreciable cytotoxic activity against human tumor cells (lung A549, breast MDA-MB-231 and MCF-7) with IC50 values in 48 h of incubation ranging from 5.6 to 18 μM. Cellular uptake studies showed that complexes 1-3 were efficiently internalized after 3 hours of treatment in MDA-MB-231 cells. The effects of complex 1 on the cell morphology, cell cycle, induction of apoptosis, mitochondrial membrane potential (Δψm), and reactive oxygen species (ROS) production have been evaluated in triple negative breast cancer (TNBC) cells MDA-MB-231. Our results showed that complex 1 induced typical morphological alterations of cell death, an increase in cells at the sub-G1 phase, apoptosis, and mitochondrial membrane depolarization. Furthermore, DNA binding studies evidenced that 1 can bind to ct-DNA and does so without modifying the B-structure of the DNA, but that the binding is weak compared to that of Hoechst 33258.
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http://dx.doi.org/10.1039/d0dt01134gDOI Listing
November 2020

Biotransformation of Ethinylestradiol by Whole Cells of Brazilian Marine-Derived Fungus Penicillium oxalicum CBMAI 1996.

Mar Biotechnol (NY) 2020 Oct 24;22(5):673-682. Epub 2020 Aug 24.

Laboratório de Química Orgânica e Biocatálise, Instituto de Química de São Carlos, Universidade de São Paulo, Av. João Dagnone, 1100, Ed. Química Ambiental, Santa Angelina, São Carlos, SP, 13563-120, Brazil.

In this study, we report our contribution to the application of whole cells of Brazilian marine-derived fungi in the biotransformation of ethinylestradiol 1. A preliminary screening with twelve marine-derived fungi strains revealed that the fungus Penicillium oxalicum CBMAI 1996 promoted the biotransformation of ethinylestradiol 1. Then, P. oxalicum CBMAI 1996 was employed in the reactions in decaplicate in order to purify and characterize the main biotransformation products of ethinylestradiol 1. Compounds 1b and 1c were characterized by NMR, HRMS, [α] and mp. Compound 1b was also characterized by single crystal X-ray diffraction. In addition, kinetic monitoring of the biotransformation of ethinylestradiol 1 by P. oxalicum CBMAI 1996 was evaluated in this study in order to obtain high yields of compounds 1b and 1c with a reduction of the reaction time. In this work, we proposed a biotransformation pathway of ethinylestradiol 1, which suggests the presence of several enzymes such as phenol oxidases, monooxygenases, and ene-reductases in the fungus P. oxalicum CBMAI 1996. In summary, the rapid biodegradation of ethinylestradiol 1 and compounds 1b and 1c also has an environmental relevance, since ethinylestradiol 1 and other steroidal compounds are improperly discarded in the environment, and part of these compounds are displaced into the oceans.
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http://dx.doi.org/10.1007/s10126-020-09989-wDOI Listing
October 2020

Synthesis and structural characterization of a series of ternary copper(II)-L-dipeptide-neocuproine complexes. Study of their cytotoxicity against cancer cells including MDA-MB-231, triple negative breast cancer cells.

J Inorg Biochem 2020 02 18;203:110930. Epub 2019 Nov 18.

Facultad de Química, Universidad de la República, Av. General Flores 2124, Montevideo, Uruguay. Electronic address:

This work presents the synthesis and characterization of eight copper complexes [Cu(L-dipeptide)(neo)]·nHO (neo = neocuproine) and their cytotoxic activities against tumor cell lines. The crystalline structure of [Cu(gly-val)(neo)]·3HO, [Cu(gly-leu)(neo)]·HO, [Cu(ala-gly)(neo)]·4HO, [Cu(val-phe)(neo)]·4.5HO and [Cu(phe-phe)(neo)]·3HO were determined by single crystal X-ray diffraction. In all of them, the Cu(II) is pentacoordinated, in a square pyramidal environment. The coordination observed in solid state was retained in the major species in aqueous solution, as suggested by Electronic Paramagnet Resonance and UV-vis spectroscopies. The complexes were shown to have affinity for isolated DNA, as determined by Circular Dichroism experiments. Furthermore, biological experiments showed that all the complexes present high cytotoxic activity against the cell lines: MDA-MB-231, MCF-7 (human metastatic breast adenocarcinomas, the first triple negative), MCF-10A (human normal breast cells), A549 (human lung epithelial carcinoma) and MRC-5 (human lung epithelial cells). Together, these results suggest that these compounds are promising steps towards new effective drugs to treat cancer.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110930DOI Listing
February 2020

Synthesis, spectroscopic (FT-IR and UV-Vis), crystallographic and theoretical studies, and a molecular docking simulation of an imatinib-like template.

Acta Crystallogr C Struct Chem 2019 12 26;75(Pt 12):1681-1689. Epub 2019 Nov 26.

Instituto de Física de São Carlos, IFSC, Universidade de São Paulo, USP, São Carlos, SP, Brazil.

The aim of the present study was to report the crystal structure and spectroscopic, electronic, supramolecular and electrostatic properties of a new polymorph of 4-(pyridin-2-yl)pyrimidin-2-amine (CHN). The compound was synthesized under microwave irradiation. The single-crystal X-ray structure analysis revealed an angle of 13.36 (8)° between the planes of the rings, as well as molecules linked by Nsp-H...N hydrogen bonds forming dimers along the crystal. The material was analyzed by FT-IR vibrational spectroscopy, while a computational approach was used to elucidate the vibrational frequency couplings. The existence of Nsp-H...N hydrogen bonds in the crystal was confirmed spectroscopically by the IR peaks from the N-H stretching vibration shifting to lower wavenumbers in the solid state relative to those in the gas phase. The supramolecular studies confirmed the formation of centrosymmetric R(8) rings, which correspond to the formation of dimers that stack parallel to the b direction. Other weak C-H...π interactions, essential for crystal growth, were found. The UV-Vis spectroscopic analysis showed a donor-acceptor process, where the amino group acts as a donor and the pyridine and pyrimidine rings act as acceptors. The reactive sites of the molecule were identified and their quantitative values were defined using the electrostatic potential model proposed in the multifunctional wave function analyzer multiwfn. The calculated interaction energies between pairs of molecules were used to visualize the electrostatic terms as the leading factors against the dispersion factors in the crystal-growth process. The docking results showed that the amino group of the pyrimidine moiety was simultaneously anchored by hydrogen-bonding interactions with the Asp427 and His407 protein residues. This compound could be key for the realization of a series of syntheses of molecules that could be used as possible inhibitors of chronic myelogenous leukemia.
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http://dx.doi.org/10.1107/S2053229619015523DOI Listing
December 2019

Crystal structures of two Cu compounds: -poly[[chlorido-copper(II)]-μ--[eth-oxy(pyridin-2-yl)methyl-idene]-'-[oxido(pyridin-3-yl)methyl-idene]hydrazine-κ,',:''] and di-μ-chlorido-1:4κ:-2:3κ:-di-chlorido-2κ,4κ-bis[μ-eth-oxy(pyridin-2-yl)methano-lato-1:2:3κ:,:;1:3:4κ::,]bis-[μ-eth-oxy(pyridin-2-yl)methano-lato-1:2κ,:;3:4κ,:]tetracopper(II).

Acta Crystallogr E Crystallogr Commun 2019 Jul 28;75(Pt 7):1069-1075. Epub 2019 Jun 28.

Instituto de Física de São Carlos, Universidade de São Paulo, CP 369, 13.560-970 - São Carlos, SP, Brazil.

Two Cu complexes [Cu(CHNO)Cl] , , and [Cu(CHNO)Cl] , , have been synthesized. In the structure of the mononuclear complex , each ligand is coordinated to two metal centers. The basal plane around the Cu cation is formed by one chloride anion, one oxygen atom, one imino and one pyridine nitro-gen atom. The apical position of the distorted square-pyramidal geometry is occupied by a pyridine nitro-gen atom from a neighbouring unit, leading to infinite one-dimensional polymeric chains along the axis direction. Each chain is connected to adjacent chains by inter-molecular C-H⋯O and C-H⋯Cl inter-actions, leading to a three-dimensional network structure. The tetra-nuclear complex lies about a crystallographic inversion centre and has one core in which two Cu metal centers are mutually inter-connected two enolato oxygen atoms while the other two Cu cations are linked by a chloride anion and an enolato oxygen. An open-cube structure is generated in which the two open-cube units, with seven vertices each, share a side composed of two Cu ions bridged by two enolato oxygen atoms acting in a μ-mode. The Cu atoms in each of the two CuONCl units are connected by one μ-O and two μ-O atoms from deprotonated hydroxyl groups and one chloride anion to the three other Cu centres. Each of the penta-coordinated Cu cations has a distorted NOCl square-pyramidal environment. The Cu atoms in each of the two CuONCl units are connected by μ-O and μ-O atoms from deprotonated alcohol hy-droxy groups and one chloride anion to two other Cu ions. Each of the penta-coordinated Cu cations has a distorted NOCl square-pyramidal environment. In the crystal, a series of intra-molecular C-H⋯O and C-H⋯Cl hydrogen bonds are observed in each tetra-nuclear monomeric unit, which is connected to four tetra-nuclear monomeric units by inter-molecular C-H⋯O hydrogen bonds, thus forming a planar two-dimensional structure in the (01) plane.
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http://dx.doi.org/10.1107/S2056989019008922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659337PMC
July 2019

Ru(II) complexes containing uracil nucleobase analogs with cytotoxicity against tumor cells.

J Inorg Biochem 2019 09 9;198:110751. Epub 2019 Jun 9.

Departamento de Química, Universidade Federal de São Carlos - UFSCar, Rodovia Washington Luiz, KM 235 CP 676, CEP 13561-901 São Carlos, SP, Brazil; Instituto de Química, Universidade Federal de Goiás - UFG, CEP 74690-900 Goiânia, GO, Brazil. Electronic address:

We report on chemistry and cytotoxic studies of four new ruthenium (II) complexes containing uracil derivatives. All compounds are neutral, presenting the formula [Ru(PPh)(2TU)] (1), [Ru(PPh)(6m2TU)] (2), [Ru(dppb)(2TU)] (3) and [Ru(dppb)(6m2TU)] (4), where PPh = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane, 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil. They were characterized using NMR, UV-vis and IR spectroscopies, microanalytical analysis and mass spectrometry. Furthermore, the crystal structures of 1-4 were determined by single-crystal X-ray diffraction. The coordination of 2-thiouracil derivatives with ruthenium increases regions able to carry out hydrogen bonds with the biological targets, such as DNA. We evaluated the interaction of the complexes with DNA by UV/Vis spectrophotometric titration, and as a result, the values of DNA-binding constants are in the range of 0.8-1.8 × 10 M. Moreover, the interaction of the complexes with BSA was investigated. In vitro, activities against B16-F10 (mouse melanoma), HepG2 (human hepatocellular carcinoma), HL-60 (human promyelocytic leukemia) and K562 (human chronic myelocytic leukemia) and non-tumor cells: PBMC (human peripheral blood mononuclear cells activated with concanavalin A - human lymphoblast) were carried out. Cytotoxicity assays revealed that complexes (2) and (4) present biological activity against tumor cells comparable with oxaliplatin, the reference platinum drug, revealing that they are promising molecules for developing new antitumor compounds.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110751DOI Listing
September 2019

Picraviane A and B: Nortriterpenes with limonoid-like skeletons containing a heptanolide E-ring system from Picramnia glazioviana.

Phytochemistry 2019 Jul 16;163:38-45. Epub 2019 Apr 16.

Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100, Copenhagen, Denmark. Electronic address:

Two highly oxygenated nortriterpenes, picraviane A and B, were isolated from the ethanolic extract of Picramnia glazioviana Engl. The structures were determined by analysis of HRMS and 2D NMR spectroscopic data. Single-crystal X-ray diffraction data was also obtained for picraviane B. The absolute configuration of both compounds were assigned by comparison of experimental and calculated vibrational and electronic circular dichroism spectroscopy, respectively. Picraviane A showed a moderate cytotoxic activity against the triple negative MDA-MB-231 breast cancer cell line. These compounds represent an undescribed class of natural products with limonoid-like skeletons containing a heptanolide as the E-ring.
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http://dx.doi.org/10.1016/j.phytochem.2019.03.024DOI Listing
July 2019

In vitro cytotoxicity and in vivo zebrafish toxicity evaluation of Ru(ii)/2-mercaptopyrimidine complexes.

Dalton Trans 2019 May;48(18):6026-6039

Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goias-UFG, CEP 74690-900 Goiania, Goias, Brazil.

In this paper, four new ruthenium complexes, [Ru(N-S)(dppm)2]PF6 (1), [Ru(N-S)(dppe)2]PF6 (2), [Ru(N-S)2(dppp)] (3) and [Ru(N-S)2(PPh3)2] (4) [dppm = 1,1-bis(diphenylphosphino)methane, dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, PPh3 = triphenylphosphine and N-S = 2-mercaptopyrimidine anion] were synthesized and characterized using spectroscopy techniques, molar conductance, elemental analysis, electrochemical techniques and X-ray diffraction. The DNA binding studies were investigated using voltammetry and spectroscopy techniques. The results show that all complexes exhibit a weak interaction with DNA. HSA interaction with the complexes was studied using fluorescence emission spectroscopy, where the results indicate a spontaneous interaction between the species by a static quenching mechanism. The cytotoxicity of the complexes was evaluated against A549, MDA-MB-231 and HaCat cells by MTT assay. Complexes (1) and (2), which are very active against triple negative MDA-MB-231, were subjected to further biological tests with this cell line. The cytotoxic activity triggered by the complexes was confirmed by clonogenic assay. Cell cycle analyses demonstrated marked anti-proliferative effects, especially at the G0/G1 and S phases. The morphological detection of apoptosis and necrosis - HO/PI and Annexin V-FITC/PI assay, elucidated that the type of cell death triggered by these complexes was probably by apoptosis. The in vivo toxicological assessment performed on zebrafish embryos revealed that complexes (1) and (2) did not present embryotoxic or toxic effects during embryonic and larval development showing that they are promising new prototypes of safer and more effective drugs for triple negative breast cancer treatment.
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http://dx.doi.org/10.1039/c8dt03738hDOI Listing
May 2019

Ru(II)/N-N/PPh complexes as potential anticancer agents against MDA-MB-231 cancer cells (N-N = diimine or diamine).

J Inorg Biochem 2019 04 18;193:70-83. Epub 2019 Jan 18.

Universidade Federal de São Carlos, Departamento de Química, São Carlos, SP, Brazil. Electronic address:

The rational design of anticancer agents that acts in specific biological targets is one of the most effective strategies for developing chemotherapeutic agents. Aiming at obtaining new ruthenium (II) compounds with good cytotoxicity against tumor cells, a series of new complexes of general formula [RuCl(PPh)(Hdpa)(NN)]Cl [PPh = triphenylphosphine, N-N = 2,2'-dipyridylamine (Hdpa) (1), 1,2-diaminoethane (en) (2), 2,2'-bipyridine (bipy) (3), 5,5'-dimethyl-2,2'-bipyridine (dmbipy) (4), 1,10-phenanthroline (phen) (5) and 4,7-diphenyl-1,10-phenanthroline (dphphen) (6)] were synthesized. The complexes were characterized by elemental analysis and spectroscopic techniques (IR, UV/Visible, and 1D and 2D NMR) and three of their X-ray structures were determined: [RuCl(PPh)(Hdpa)]Cl, [RuCl(PPh)(Hdpa)(en)]Cl and [RuCl(PPh)(Hdpa)(dmbipy)]Cl. All the complexes are more cytotoxic against the cancer cell line than against the non-tumor cell line, highlighting complexes 1 and 5, which have an index selectivity of 18 and 15, respectively. The binding constants of compounds 1-6 with human serum albumin (HSA) were determined by tryptophan fluorescence quenching, indicating moderate to strong interactions. The binding mode of the complexes to calf thymus (CT) DNA was explored by several techniques, which reveal that only the dphphen compound 6 causes distortions in the secondary and tertiary structures of DNA. The studies demonstrated that the nature of the NN co-ligand and the presence of the PPh and Hdpa ligands are features that can influence the binding affinity of the complexes by the biomolecules and in the cytotoxic activity of the complexes. Overall, the complexes with diimine co-ligand are much more cytotoxic than compound 2 with the aliphatic diamine.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.01.006DOI Listing
April 2019

In vitro anti-Trypanosoma cruzi activity of ternary copper(II) complexes and in vivo evaluation of the most promising complex.

Biomed Pharmacother 2019 Jan 2;109:157-166. Epub 2018 Nov 2.

Instituto de Química, Universidade Federal de Uberlândia, Campus Santa Mônica, Uberlândia, MG, Brazil. Electronic address:

In order to improve the previously observed antichagasic activity of Cu(II) complexes containing 2-chlorobenzhydrazide (2-CH), we report herein the synthesis and anti-Trypanosoma cruzi activity of novel copper complexes containing 2-methoxybenzhydrazide (2-MH), 4-methoxybenzhydrazide (4-MH) and three α-diimine ligands, namely, 1,10-phenanthroline (phen), 2,2-bipyridine (bipy) and 4-4'-dimethoxy-2-2'-bipyridine (dmb). Two of these complexes showed higher in vitro anti-Trypanosoma cruzi activity when compared to benznidazole, the main drug used in Chagas disease treatment. One of them, the copper complex with 4-MH and dmb, [Cu(4-MH)(dmb)(ClO)], exhibited a higher selectivity index than that recommended for preclinical studies. Considering this observation, complex [Cu(4-MH)(dmb)(ClO)] was selected for preliminary in vivo assays, which verified that this compound was able to reduce parasitemia by 64% at the peak of infection. Further investigations were performed on all compounds. The Cu(II) complexes bind to ct-DNA with K values in the range of 10-10 M, with [Cu(4-MH)(dmb)(ClO)] showing the highest K value (1.45 × 10 M). Molecular docking simulations predicted that [Cu(4-MH)(dmb)(ClO)] binds in the minor groove of the double helix of ct-DNA and forms one hydrogen bond.
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http://dx.doi.org/10.1016/j.biopha.2018.10.057DOI Listing
January 2019

In vitro leishmanicidal activity and theoretical insights into biological action of ruthenium(II) organometallic complexes containing anti-inflammatories.

Biometals 2018 12 4;31(6):1003-1017. Epub 2018 Oct 4.

Instituto de Química, Universidade Federal de Uberlândia, Av. João Naves de Ávila, 2121, Uberlândia, MG, 38408-100, Brazil.

Leishmaniasis, a neglected tropical disease caused by protozoans of the genus Leishmania, kills around 20-30 thousand people in Africa, Asia, and Latin America annually and, despite its potential lethality, it can be treated and eventually cured. However, the current treatments are limited owing to severe side effects and resistance development by some Leishmania. These factors make it urgent to develop new leishmanicidal drugs. In the present study, three ruthenium(II) organometallic complexes containing as ligands the commercially available anti-inflammatories diclofenac (dic), ibuprofen (ibu), and naproxen (nap) were synthesized, characterized, and subjected to in vitro leishmanicidal activity. The in vitro cytotoxicity assays against Leishmania (L.) amazonensis and Leishmania (L.) infantum promastigotes have shown that complexes [RuCl(dic)(η-p-cymene)] (1) and [RuCl(nap)(η-p-cymene)] (3) were active against both Leishmania species. Complex [RuCl(ibu)(η-p-cymene)] (2) has exhibited no activity. The IC values for the two active complexes were respectively 7.42 and 23.55 μM, for L. (L.) amazonensis, and 8.57 and 42.25 μM, for L. (L.) infantum. Based on the toxicological results and computational analysis, we proposed a correlation between the complexes and their activity. Our results suggest both complexation to ruthenium(II) and ligands structure are key elements to leishmanicidal activity.
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http://dx.doi.org/10.1007/s10534-018-0145-zDOI Listing
December 2018

Rational Design of a Famotidine-Ibuprofen Coamorphous System: An Experimental and Theoretical Study.

J Phys Chem B 2018 09 11;122(37):8772-8782. Epub 2018 Sep 11.

Departamento de Química, Facultad de Química, Bioquímica y Farmacia , Universidad Nacional de San Luis , Chacabuco 917 , D5700HOJ San Luis , Argentina.

Famotidine (FMT) and ibuprofen (IBU) were used as model drugs to obtain coamorphous systems, where the guanidine moiety of the antacid and the carboxylic group of the nonsteroidal anti-inflammatory drug could potentially participate in H-bonds leading to a given structural motif. The systems were prepared in 3:7, 1:1, and 7:3 FMT and IBU molar ratios, respectively. The latter two became amorphous after 180 min of comilling. FMT-IBU (1:1) exhibited a higher physical stability in assays at 4, 25, and 40 °C up to 60 days. Fourier transform infrared spectroscopy accounted for important modifications in the vibrational behavior of those functional groups, allowing us to ascribe the skill of 1:1 FMT-IBU for remaining amorphous to equimolar interactions between both components. Density functional theory calculations followed by quantum theory of atoms in molecules analysis were then conducted to support the presence of the expected FMT-IBU heterodimer with consequent formation of a R8 structural motif. The electron density (ρ) and its Laplacian (∇ρ) values suggested a high strength of the specific intermolecular interactions. Molecular dynamics simulations to build an amorphous assembly, followed by radial distribution function analysis on the modeled phase were further employed. The results demonstrate that it is a feasible rational design of a coamorphous system, satisfactorily stabilized by molecular-level interactions leading to the expected motif.
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http://dx.doi.org/10.1021/acs.jpcb.8b06105DOI Listing
September 2018

The use of variable temperature C solid-state MAS NMR and GIPAW DFT calculations to explore the dynamics of diethylcarbamazine citrate.

Magn Reson Chem 2019 05 15;57(5):200-210. Epub 2018 Oct 15.

Department of Physics, University of Warwick, Coventry, UK.

Experimental C solid-state magic-angle spinning (MAS) Nuclear Magnetic Resonance (NMR) as well as Density-Functional Theory (DFT) gauge-including projector augmented wave (GIPAW) calculations were used to probe disorder and local mobility in diethylcarbamazine citrate, (DEC) (citrate) . This compound has been used as the first option drug for the treatment of filariasis, a disease endemic in tropical countries and caused by adult worms of Wuchereria bancrofti, which is transmitted by mosquitoes. We firstly present 2D C─ H dipolar-coupling-mediated heteronuclear correlation spectra recorded at moderate spinning frequency, to explore the intermolecular interaction between DEC and citrate molecules. Secondly, we investigate the dynamic behavior of (DEC) (citrate) by varying the temperature and correlating the experimental MAS NMR results with DFT GIPAW calculations that consider two (DEC) conformers (in a 70:30 ratio) for crystal structures determined at 293 and 235 K. Solid-state NMR provides insights on slow exchange dynamics revealing conformational changes involving particularly the DEC ethyl groups.
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http://dx.doi.org/10.1002/mrc.4790DOI Listing
May 2019

{1-[1-(2-Hy-droxy-phen-yl)ethyl-idene]-2-(pyridin-2-yl-κ)hydrazine-κ',}{1-[1-(2-oxidophen-yl)ethyl-idene]-2-(pyridin-2-yl-κ)hydrazine-κ',}nickelate(II) nitrate hemihydrate.

Acta Crystallogr E Crystallogr Commun 2018 May 6;74(Pt 5):642-645. Epub 2018 Apr 6.

Instituto de Física de São Carlos, Universidade de São Paulo, CP 369, São Carlos, SP, Brazil.

The 2-hydrazino-pyridine precursor has been widely used to prepare ligands of various kinds by condensation with carbonyl compounds. These types of ligands are suitable for synthesizing novel transition metal (II) complexes with inter-esting magnetic properties. In this context we have synthesized the ligand 1-(2-hy-droxy-phenyl-2-ethyl-idene)-2-(pyridin-2-yl)hydrazine (H) which was used in the preparation of the mononuclear title complex, [Ni(CHNO)(CHNO)]NO·0.5HO. As a result of the presence of H and in the [{Ni(H)()}] unit, the complex appears to be a supramolecular dimer composed of the Δ(-) and Λ(-) optical isomers, which are linked by strong hydrogen-bonds. As well as the dimer generated by two mononuclear [{Ni(H)()}] cations, the asymmetric unit also contains two nitrate anions and one water mol-ecule. Each Ni atom is coordinated to two ligand mol-ecules by a nitro-gen atom of the pyridine ring, an imine nitro-gen atom and a phenolic oxygen atom of one of the ligand mol-ecules and a phenolate oxygen atom of the other organic mol-ecules. The environment around the cation is a distorted octa-hedron. The basal planes are defined by the two nitro-gen atoms of the pyridine rings and the two phenolic oxygen atoms of the ligand, the apical positions being occupied by the azomethine atoms. The O atoms of one of the nitrate ions are disordered over two sets of sites in a 0.745 (9):0.255 (9) ratio. In the crystal, the dimers are linked by numerous hydrogen bonds, forming a three-dimensional framework.
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http://dx.doi.org/10.1107/S2056989018005261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947478PMC
May 2018

Cytotoxic activity and structural features of Ru(II)/phosphine/amino acid complexes.

J Inorg Biochem 2018 05 23;182:48-60. Epub 2017 Dec 23.

Departamento de Química, Universidade Federal de São Carlos, C.P. 676, CEP 13565-905 São Carlos, (SP), Brazil.

Thirteen new ruthenium amino acid complexes were synthesized and characterized. They were obtained by the reaction of α-amino acids (AA) with [RuCl(P-P)(N-N)], where P-P=1,4-bis(diphenylphosphino)butane (dppb) or 1,3-bis(diphenylphosphino)propane (dppp) and N-N=4,4'-dimethyl-2,2'-bipyridine (4'-Mebipy), 5,5'-dimethyl-2,2'-bipyridine (5'-Mebipy) or 4,4'-Methoxy-2-2'-bipyridine (4'-MeObipy). This afforded a family of complexes formulated as [Ru(AA-H)(P-P)(N-N)]PF, where AA=glycine (Gly), L-alanine (Ala), L-valine (Val), L-tyrosine (Tyr), L-tryptophan (Trp), L-histidine (His) and L-methionine (Met). All compounds were characterized by elemental analysis, spectroscopic and electrochemical techniques. The [Ru(AA-H)(P-P)(N-N)]PF complexes are octahedral (the AA-H ligand binding involves N-amine and O-carboxylate), diamagnetic (low-spin d, S=0) and present bands due to electronic transitions in the visible region. H, C{H} and P{H} NMR spectra of the complexes indicate the presence of C symmetry, and the identification of diastereoisomers. In vitro cytotoxicity assays of the compounds and cisplatin were carried out using MDA-MB-231 (human breast) tumor cell line and a non-tumor breast cell line (MCF-10A). Most complexes present promising results with IC values comparable with the reference drug cisplatin and high selectivity indexes were found for the complexes containing L-Trp. The binding of two Ru-precursors of the type [RuCl(dppb)(NN)] (N-N=4'-MeObipy or 4'-Mebipy) to the blood transporter protein human serum albumin (HSA) was evaluated by fluorescence and circular dichroism spectroscopy. Both complexes bind HSA, probably in the hydrophobic pocket near Trp214, and the Ru-complex containing 4'-MeObipy shows higher affinity for HSA than the 4'-Mebipy one.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.12.010DOI Listing
May 2018

Cytotoxicity and anti-tumor effects of new ruthenium complexes on triple negative breast cancer cells.

PLoS One 2017 12;12(9):e0183275. Epub 2017 Sep 12.

Departmento de Gerontologia, Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru) complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1) [Ru(SO4)(dppb)(bipy)], (2) [Ru(CO3)(dppb)(bipy)], (3) [Ru(C2O4)(dppb)(bipy)] and (4) [Ru(CH3CO2)(dppb)(bipy)]PF6 [where dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine], on proliferation of TNBC (MDA-MB-231), estrogen-dependent breast tumor cells (MCF-7) and a non-tumor breast cell line (MCF-10A). Complex (4) was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4) was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4) was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4) should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183275PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595280PMC
October 2017

Ru(II)/diphenylphosphine/pyridine-6-thiolate complexes induce S-180 cell apoptosis through intrinsic mitochondrial pathway involving inhibition of Bcl-2 and p53/Bax activation.

Mol Cell Biochem 2018 Jan 9;438(1-2):199-217. Epub 2017 Aug 9.

Laboratório de Genética Molecular e Citogenética, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiânia, GO, 74690-900, Brazil.

The aim of this work was the synthesis, characterization, and cytotoxicity evaluation of three new Ru(II) complexes with a general formula [Ru(Spy)(bipy)(P-P)]PF [Spy = pyridine-6-thiolate; bipy = 2,2'-bipyridine; P-P = 1,2-bis(diphenylphosphine)ethane (1); 1,3-bis(diphenylphosphine) propane (2); and 1,1'-bis(diphenylphosphino)ferrocene] (4). Complex (3) with the 1,4-bis(diphenylphosphine)butane ligand, already known from the literature, was also synthesized, to be better studied here. The cytotoxicities of the complexes toward two kinds of cancerous cells (K562 and S-180 cells) were evaluated and compared to normal cells (L-929 and PBMC) by MTT assay. The complex [Ru(Spy)(bipy)(dppb)]PF (3) was selected to study both the cellular and molecular mechanisms underlying its promising anticancer action in S-180 cells. The results obtained from this study indicated that complex (3) induces cell cycle arrest in the G0/G1 phase in S-180 cells associated with a decrease in the number of cells in S phase. After 24 and 48 h of exposure to complex (3), the cell viability decreased when compared to the negative control. Complex (3) does not appear to be involved in the DNA damage, but induced changes in the mitochondrial membrane potential in S-180 cells. Furthermore, there was also an increase in the gene expression of Bax, Caspase 9, and Tp53. According to our results, complex (3) induces cell apoptosis through p53/Bax-dependent intrinsic pathway and suppresses the expression of active antiapoptotic Bcl-2 protein.
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http://dx.doi.org/10.1007/s11010-017-3129-3DOI Listing
January 2018

Photochemical studies of cis-[Ru(bpy)(4-bzpy)(CO)](PF) and cis-[Ru(bpy)(4-bzpy)(Cl)](PF): Blue light-induced nucleobase binding.

J Inorg Biochem 2017 08 15;173:144-151. Epub 2017 May 15.

Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Cx. Postal 12200, Campus do Pici s/n, CEP 60440-900 Fortaleza, CE, Brazil. Electronic address:

The ruthenium(II) compounds cis-[Ru(bpy)(4-bzpy)(CO)](PF) (I) and cis-[Ru(bpy)(4-bzpy)(Cl)](PF) (II) (4-bzpy=4-benzoylpyridine, bpy=2,2'-bipyridine) were synthesized and characterized by spectroscopic and electrochemical techniques. The crystal structure of II was determined by X-ray diffraction. The photochemical behavior of I in aqueous solution shows that irradiation with ultraviolet light (365nm) releases both CO and 4-bzpy leading to the formation of the cis-[Ru(bpy)(HO)] ion as identified by NMR and electronic spectroscopy. Carbon monoxide release was confirmed with the myoglobin method and by gas chromatographic analysis of the headspace. CO release was not observed when aqueous I was irradiated with blue light (453nm). Changes in the electronic and H NMR spectra indicate that I undergoes photoaquation of 4-bzpy to form cis-[Ru(bpy)(CO)(HO)]. Blue light irradiation of aqueous II released the coordinated 4-bzpy to give the cis-[Ru(bpy)(HO)(Cl)] ion. When the latter reaction was carried out in the presence of the nucleobase guanine, Ru-guanine adducts were formed, indicating that the metal containing photoproduct may also participate in biologically relevant reactions. The photochemical behavior of I indicates that it can release either CO or 4-bzpy depending on the wavelength chosen, a feature that may have therapeutic application.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.05.006DOI Listing
August 2017

Spectroscopic (far or terahertz, mid-infrared and Raman) investigation, thermal analysis and biological activity of piplartine.

Spectrochim Acta A Mol Biomol Spectrosc 2017 Sep 5;184:368-381. Epub 2017 May 5.

Instituto de Física de São Carlos, Universidade de São Paulo, CP. 369, 13560-970, São Carlos, SP, Brazil.

Research in the field of medicinal plants including Piper species like long pepper (Piper longum L.- Piperaceae) is increasing all over the world due to its use in traditional and Ayurvedic medicine. Piplartine (piperlongumine, 5,6-dihydro-1-[(2E)-1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-2(1H)-pyridinone), a biologically active alkaloid/amide was isolated from the phytochemical investigations of Piper species, as long pepper. This alkaloid has cytotoxic, anti-fungal, anti-diabetic, anti-platelet aggregation, anti-tumoral, anxiolytic, anti-depressant, anti-leishmanial, and genotoxic activities, but, its anticancer property is the most promising and has been widely explored. The main purpose of the work is to present a solid state characterization of PPTN using thermal analysis and vibrational spectroscopy. Quantum mechanical calculations based on the density functional theory was also applied to investigate the molecular conformation and vibrational spectrum, which was compared with experimental results obtained by Raman scattering, far (terahertz) and mid-infrared adsorption spectroscopy. NBO analysis has been performed which predict that most intensive interactions in PPTN are the hyperconjugative interactions between n(1) N6 and π*(O1C7) having delocalization energy of 50.53kcal/mol, Topological parameters have been analyzed using 'AIM' analysis which governs the three bond critical points (BCPs), one di-hydrogen, and four ring critical points (RCPs). MEP surface has been plotted which forecast that the most negative region is associated with the electronegative oxygen atoms (sites for nucleophilic activity). Theoretically, to confirm that the title compound has anti-cancer, anti-diabetic and anti-platelet aggregation activities, it was analyzed by molecular docking interactions with the corresponding target receptors. The obtained values of H-bonding parameters and binding affinity prove that its anti-cancer activity is the more prominent than the other properties.
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http://dx.doi.org/10.1016/j.saa.2017.05.007DOI Listing
September 2017

Probing intermolecular interactions in a diethylcarbamazine citrate salt by fast MAS H solid-state NMR spectroscopy and GIPAW calculations.

Solid State Nucl Magn Reson 2017 10 2;87:73-79. Epub 2017 Mar 2.

Department of Physics, University of Warwick, Coventry CV4 7AL, UK.

Fast magic-angle spinning (MAS) NMR is used to probe intermolecular interactions in a diethylcarbamazine salt, that is widely used as a treatment against adult worms of Wuchereria bancrofti which cause a common disease in tropical countries named filariasis. Specifically, a dihydrogen citrate salt that has improved thermal stability and solubility as compared to the free form is studied. One-dimensional H, C and N and two-dimensional H-C and N-H heteronuclear correlation NMR experiments under moderate and fast MAS together with GIPAW (CASTEP) calculations enable the assignment of the H, C and N/N resonances. A two-dimensional H-H double-quantum (DQ) -single-quantum (SQ) MAS spectrum recorded with BaBa recoupling at 60kHz MAS identifies specific proton-proton proximities associated with citrate-citrate and citrate-diethylcarbamazine intermolecular interactions.
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http://dx.doi.org/10.1016/j.ssnmr.2017.02.006DOI Listing
October 2017

Copper(I)-Phosphine Polypyridyl Complexes: Synthesis, Characterization, DNA/HSA Binding Study, and Antiproliferative Activity.

Inorg Chem 2017 Apr 14;56(7):3781-3793. Epub 2017 Mar 14.

Diretoria de Metrologia Aplicada às Ciências da Vida, Instituto Nacional de Metrologia, Qualidade e Tecnologia , CEP 25250-020 Xerém, RJ, Brazil.

A series of copper(I)-phosphine polypyridyl complexes have been investigated as potential antitumor agents. The complexes [Cu(PPh)dpq]NO (2), [Cu(PPh)dppz]NO (3), [Cu(PPh)dppa]NO (4), and [Cu(PPh)dppme]NO (5) were synthesized by the reaction of [Cu(PPh)NO] with the respective planar ligand under mild conditions. These copper complexes were fully characterized by elemental analysis, molar conductivity, FAB-MS, and NMR, UV-vis, and IR spectroscopies. Interactions between these copper(I)-phosphine polypyridyl complexes and DNA have been investigated using various spectroscopic techniques and analytical methods, such as UV-vis titrations, thermal denaturation, circular dichroism, viscosity measurements, gel electrophoresis, and competitive fluorescent intercalator displacement assays. The results of our studies suggest that these copper(I) complexes interact with DNA in an intercalative way. Furthermore, their high protein binding affinities toward human serum albumin were determined by fluorescence studies. Additionally, cytotoxicity analyses of all complexes against several tumor cell lines (human breast, MCF-7; human lung, A549; and human prostate, DU-145) and non-tumor cell lines (Chinese hamster lung, V79-4; and human lung, MRC-5) were performed. The results revealed that copper(I)-phosphine polypyridyl complexes are more cytotoxic than the corresponding planar ligand and also showed to be more active than cisplatin. A good correlation was observed between the cytostatic activity and lipophilicity of the copper(I) complexes studied here.
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http://dx.doi.org/10.1021/acs.inorgchem.6b02419DOI Listing
April 2017

Centrosymmetric resonance-assisted intermolecular hydrogen bonding chains in the enol form of β-diketone: Crystal structure and theoretical study.

J Mol Graph Model 2016 07 25;68:106-113. Epub 2016 Jun 25.

Instituto de Física de São Carlos, Universidade de São Paulo, 13560-970 São Carlos, SP, Brazil.

Isobenzofuran-1(3H)-ones (phtalides) are heterocycles that present a benzene ring fused to a γ-lactone functionality. This structural motif is found in several natural and synthetic compounds that present relevant biological activities. In the present investigation, the 3-(2-hydroxy-4,4-dimethyl-6-oxocyclohexen-1-yl)isobenzofuran-1(3H)-one was characterized by single-crystal X-ray analysis. In the crystal structure, there are two molecules per asymmetric unit. One of them exhibits resonance assisted hydrogen bonds (RAHBs). Semi-empirical and DFT calculations were performed to obtain electronic structure and π-delocalization parameters, in order to better understand the energy stabilization of RAHBs in the crystal packing of the studied molecule. The structural parameters showed good agreement between theoretical and experimental data. The theoretical investigation revealed that the RAHBs stabilization energy is directly related to the electronic delocalization of the enol form fragment. In addition, RAHBs significantly affected the HOMO and charge distribution around the conjugated system.
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http://dx.doi.org/10.1016/j.jmgm.2016.06.004DOI Listing
July 2016

On the Thermal Stability of the Diethylcarbamazine-Fortified Table Salt Used in the Control of Lymphatic Filariasis.

J Pharm Sci 2016 08 7;105(8):2437-43. Epub 2016 Jul 7.

Departamento de Física, Universidade Federal do Ceará, C. P. 6030, Fortaleza, Ceará 60455-970, Brazil. Electronic address:

Diethylcarbamazine, administered as a water-soluble citrate salt, has been used for more than 50 years as the first-line drug in the treatment of lymphatic filariasis. Mass drug administration programs have been successful in reducing microfilaremia and providing important collateral deworming benefits. One of these initiatives is based on the addition of diethylcarbamazine citrate to table salt. The fortified salt retaining the efficacy of the drug in reducing microfilaremia, but there is little information about its behavior above room temperature. In this study, the thermal stability of diethylcarbamazine, as a free base and a citrate salt, was investigated by differential scanning calorimetry and thermogravimetry under different conditions. Diethylcarbamazine does not release hazardous degradation substances above its melting point. It was also confirmed that this drug is stable at normal cooking temperatures, even when dry heat cooking methods, such as baking or grilling, are considered. However, if the drug is formulated as a salt, as in the case of the citrate, special attention needs to be given to the degradation substances of the counter ion.
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http://dx.doi.org/10.1016/j.xphs.2016.06.003DOI Listing
August 2016

Diffractaic acid: Crystalline structure and physicochemical characterization.

Spectrochim Acta A Mol Biomol Spectrosc 2016 08 13;165:26-32. Epub 2016 Apr 13.

Department of Physics, Federal University of Ceará, Fortaleza, Ceará, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.saa.2016.04.030DOI Listing
August 2016

Solution and Solid State Nuclear Magnetic Resonance Spectroscopic Characterization of Efavirenz.

J Pharm Sci 2016 09 22;105(9):2656-2664. Epub 2016 Jan 22.

Universidade de São Paulo, Instituto de Física de São Carlos, CP 369, 13560-970 São Carlos, SP, Brazil.

Samples of efavirenz (EFZ) were evaluated to investigate the influence of the micronization process on EFZ stability. A combination of X-ray diffraction, thermal analysis, FTIR, observations of isotropic chemical shifts of (1)H in distinct solvents, their temperature dependence and spin-lattice relaxation time constants (T1), solution (1D and 2D) (13)C nuclear magnetic resonance (NMR), and solid-state (13)C NMR (CPMAS NMR) provides valuable structural information and structural elucidation of micronized EFZ and heptane-recrystallized polymorphs (EFZ/HEPT). This study revealed that the micronization process did not affect the EFZ crystalline structure. It was observed that the structure of EFZ/HEPT is in the same form as that obtained from ethyl acetate/hexane, as shown in the literature. A comparison of the solid-state NMR spectra revealed discrepancies regarding the assignments of some carbons published in the literature that have been resolved.
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http://dx.doi.org/10.1016/j.xphs.2015.10.006DOI Listing
September 2016

Crystal structure of 4-formyl-2-nitro-phenyl 4-chloro-2-nitro-benzoate.

Acta Crystallogr E Crystallogr Commun 2015 Dec 14;71(Pt 12):o940. Epub 2015 Nov 14.

Instituto de Física de São Carlos, IFSC, Universidade de São Paulo, USP, São Carlos, SP, Brazil.

In the title compound, C14H7ClN2O7, the central ester moiety is essentially planar, with an r.m.s. deviation of 0.0113 Å. The ester group is twisted away from the chloro- and formyl-substituted rings by 84.60 (9) and 88.55 (9)°, respectively. The crystal packing shows inter-molecular C-H⋯O inter-actions. These inter-actions generate R 2 (2)(20) and R 4 (4)(22) edge-fused rings parallel to (20-2).
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http://dx.doi.org/10.1107/S205698901502006XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719892PMC
December 2015

Looking for the interactions between omeprazole and amoxicillin in a disordered phase. An experimental and theoretical study.

Spectrochim Acta A Mol Biomol Spectrosc 2016 Mar 22;156:70-7. Epub 2015 Nov 22.

Inorganic Chemistry, INTEQUI, National University of San Luis, Chacabuco and Pedernera-5700, San Luis, Argentina. Electronic address:

In this paper, co-grinding mixtures of omeprazole-amoxicillin trihydrate (CGM samples) and omeprazole-anhydrous amoxicillin (CGMa samples) at 3:7, 1:1 and 7:3 molar ratios, respectively, were studied with the aim of obtaining a co-amorphous system and determining the potential intermolecular interactions. These systems were fully characterized by differential scanning calorimetry (DSC), FT-infrared spectroscopy (FTIR), X-ray powder diffraction (PXRD), scanning electron microscopy (SEM) and solid state Nuclear Magnetic Resonance (ssNMR). The co-grinding process was not useful to get a co-amorphous system but it led to obtaining the 1:1 CGMa disordered phase. Moreover, in this system both FTIR and ssNMR analysis strongly suggest intermolecular interactions between the sulfoxide group of omeprazole and the primary amine of amoxicillin anhydrous. The solubility measurements were performed in simulated gastric fluid (SGF) to prove the effect of the co-grinding process. Complementarily, we carried out density functional theory calculations (DFT) followed by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses in order to shed some light on the principles that guide the possible formation of heterodimers at the molecular level, which are supported by spectroscopic experimental findings.
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http://dx.doi.org/10.1016/j.saa.2015.11.021DOI Listing
March 2016