Drug-Inclusive Inorganic–Organic Hybrid Systems for the Controlled Release of the Osteoporosis Drug Zoledronate

Bisphosphonates (BPs) are common pharmaceutical treatments used for calcium- and bone-related disorders, the principal one being osteoporosis. Their antiresorptive action is related to their high affinity for hydroxyapatite, the main inorganic substituent of bone. On the other hand, the phosphonate groups on their backbone make them excellent ligands for metal ions. The combination of these properties finds potential application in the utilization of such systems as controlled drug release systems (CRSs). In this work, the third generation BP drug zoledronate (ZOL) was combined with alkaline earth metal ions (e.g., Sr2+ and Ba2+) in an effort to synthesize new materials. These metal–ZOL compounds can operate as CRSs when exposed to appropriate experimental conditions, such as the low pH of the human stomach, thus releasing the active drug ZOL. CRS networks containing Sr2+ or Ba2 and ZOL were physicochemically and structurally characterized and were evaluated for their ability to release the free ZOL drug during an acid-driven hydrolysis process. Various release and kinetic parameters were determined, such as initial rates and release plateau values. Based on the drug release results of this study, there was an attempt to correlate the ZOL release efficiency with the structural features of these CRSs.Hellenic Foundation for Research and Innovation (HFRI) 258MCIU/AEI/FEDER, UE PGC2018-102047-B-I0

Variable behaviour of a flexible bispyrazole ligand: A Co(II) polymer and a unique Cu(II) penta-coordinated dimer

Hoping to highlight the flexibility of a bispyrazole ligand possessing an ether chain including a weak spot (1,2-bis([4-(3,5- dimethyl -1 H - pyrazol -1- yl )-2- oxabutyl ]benzene ( L )), its reactivity against coordinatively flexible metal centres has been assayed. Thus Co(II) and Cu(II) coordination complexes of L have been synthesized and fully characterized by analytical and spectroscopical methods. Their X-ray crystal struc- ture elucidation has allowed to ascertain that while the Co(II) compound {[C o ( L )C l 2 ] ·1/2H 2 O} n ( 1 ) pos- sesses a polymeric structure, much like its Zn(II), Cd(II) and Hg(II) analogues, the Cu(II) compound [Cu 2 L Cl 4 ] ( 2 ) displays a completely unexpected dimeric architecture. The previously unreported coordi- nation mode of the ligand in the Cu(II) compound causes dramatical changes in the morphology of the resulting complexes. Their crystal structures are discussed in deep, and the causes behind their differing architectures are examined through comparison with bibliographical referencesLa Caixa Foundation CB615921 CB616406Generalitat de Catalunya 2017/SGR/1687Universitat Autonoma de Barcelon

Water soluble organometallic small molecules as promising antibacterial agents: synthesis, physical–chemical properties and biological evaluation to tackle bacterial infections

This work was supported by the Spanish Ministerio de Economia y Competitividad (PID2019-106832RB-100, and SAF2017-82261-P grant cofounded by the European Regional Development Fund) and the Generalitat de Catalunya (2017SGR1720). J. A. M. Xavier acknowledges DOC-FAM program under the Marie Sklodowska-Curie grant agreement N degrees 754397. A. B. Buades, M. Nuez and J. A. M. Xavier are enrolled in the PhD program of the UAB.The Na[3,3’-Fe(8-I-1,2-C2B9H10)2] and Na[2,2’-M(1,7-C2B9H11)] (M = Co3+, Fe3+) small molecules are synthesized and the X-ray structures of [(H3O)(H2O)5][2,2’-Co(1,7-C2B9H11)2] and [Cs(MeCN)][8,8’-I2-Fe(1,2 C2B9H10)2], both displaying a transoid conformation of the [M(C2B9)2]− framework, are reported. Importantly, the supramolecular structure of [(H3O)(H2O)5][2,2’-Co(1,7-C2B9H11)2] presents 2D layers leading to a lamellar arrangement of the anions while the cation layers form polymeric water rings made of six- and fourmembered rings of water molecules connected via OH⋯H hydrogen bonds; B–H⋯O contacts connect the cationic and anionic layers. Herein, we highlight the influence of the ligand isomers (ortho-/meta-), the metal effect (Co3+/Fe3+) on the same isomer, as well as the influence of the presence of the iodine atoms on the physical–chemical and biological properties of these molecules as antimicrobial agents to tackle antibioticresistant bacteria, which were tested with four Gram-positive bacteria, five Gram-negative bacteria, and three Candida albicans strains that have been responsible for human infections. We have demonstrated an antimicrobial effect against Candida species (MIC of 2 and 3 nM for Na[3,3’-Co(8-I-1,2-C2B9H10)2] and Na[2,2’-Co (1,7-C2B9H11)2], respectively), and against Gram-positive and Gram-negative bacteria, including multiresistant MRSA strains (MIC of 6 nM for Na[3,3’-Co(8-I-1,2-C2B9H10)2]). The selectivity index for antimicrobial activity of Na[3,3’-Co(1,2-C2B9H11)2] and Na[3,3’-Co(8-I-1,2-C2B9H10)2] compounds is very high (165 and 1180, respectively), which reveals that these small anionic metallacarborane molecules may be useful to tackle antibioticresistant bacteria. Moreover, we have demonstrated that the outer membrane of Gram-negative bacteria constitutes an impermeable barrier for the majority of these compounds. Nonetheless, the addition of two iodine groups in the structure of the parent Na[3,3’-Co(1,2-C2B9H11)2] had an improved effect (3–7 times) against Gram-negative bacteria. Possibly the changes in their physical–chemical properties make the meta-isomers and the ortho-di-iodinated small molecules more permeable for crossing this barrier. It should be emphasized that the most active metallabis(dicarbollide) small molecules are both transoid conformers in contrast to the ortho- [3,3’-Co(1,2-C2B9H11)2]− that is cisoid. The fact that these small molecules cross the mammalian membrane and have antimicrobial properties but low toxicity for mammalian cells (high selectivity index, SI) represents a promising tool to treat infectious intracellular bacteria. Since there is an urgent need for antibiotic discovery and development, this study represents a relevant advance in the field.Spanish Government PID2019-106832RB-100 SAF2017-82261-PGeneralitat de CatalunyaGeneral Electric 2017SGR1720DOC-FAM program under the Marie Sklodowska-Curie grant 75439

Role of hydrazone substituents in determining the nuclearity and antibacterial activity of Zn(II) complexes with pyrazolone-based hydrazones

Hydrazones and their metal derivatives are very important compounds in medicinal chemistry due to their reported variety of biological activities, such as antibacterial, antifungal and anticancer action. Five hydrazone- pyrazolone ligands H2Ln (n = 1–5) were prepared and fully characterized and their tautomerism was investigated in the solid state and solution. Five zinc(II) complexes 1–5 of composition [Zn(HLn)2] (n = 1 and 2), [Zn(HLn)2(H2O)2] (n = 3 and 5) and [Zn(HL4)2]n were synthesized and characterized by elemental analysis, IR, 1H, 19F, 13C, and 15N NMR spectroscopy, and ESI mass spectrometry. In addition, the structures of two ligands and three complexes were determined by single-crystal X-ray diffraction. The ligands H2L2 and H2L4 exist both in the NH,NH tautomeric form. Complexes 1 and 2 are mononuclear compounds, while complex 4 is a one-dimensional coordination compound. Density functional theory (DFT) calculations were carried out on proligands, their anions and all zinc complexes, confirming the experimental results, supporting IR and NMR assignments and giving proofs of the mononuclear diaqua structure of complexes 3 and 5. The antibacterial activity of the free ligands and the Zn(II) complexes was established against Escherichia coli and Staphylococcus aureus, and a strong efficiency has been found for Zn(II) complexes, particularly for the polynuclear 4 and the mononuclear diaqua complex 5, the latter containing a ligand with aliphatic and fluorinated substituents able to compromise the permeability of and disrupt the bacterial cell membrane.University of Camerino (Italy)European Commission PRIMA19_00246Ministry of Education, Universities and Research (MIUR)POR Marche FSEInstituto de Salud Carlos IIISpanish Government PGC2018-093443-B-I0

H(N3)dap (Hdap = 2,6-Diaminopurine) Recognition by Cu2(EGTA): Structure, Physical Properties, and Density Functional Theory Calculations of [Cu4( -EGTA)2( -H(N3)dap)2(H2O)2] 7H2O

Reactions inwater between the Cu2( -EGTA) chelate (EGTA= ethylene-bis(oxyethyleneimino) tetraacetate(4-) ion) and Hdap in molar ratios 1:1 and 1:2 yield only blue crystals of the ternary compound [Cu4( -EGTA)2( -H(N3)dap)2(H2O)2] 7H2O (1), which has been studied via single-crystal X-ray diffraction and various physical methods (thermal stability, spectral and magnetic properties), as well as DFT theoretical calculations. In the crystal, uncoordinated water is disordered. The tetranuclear complex molecule also has some irrelevant disorder in an EGTA-ethylene moiety. In the complex molecule, both bridging organic molecules act as binucleating ligands. There are two distorted five- and two six-coordinated Cu(II) centers. Each half of EGTA acts as a tripodal tetradentate Cu(II) chelator, with a mer-NO2 + O(ether, distal) conformation. Hdap exhibits the tautomer H(N3)dap, with the dissociable H-atom on its less basic N-heterocyclic atom. These features favor the efficient cooperation between Cu-N7 or Cu-N9 bonds with appropriate O-EGTA atoms, as N6-H O or N3-H O interligand interactions, respectively. The bridging role of both organics determines the tetranuclear dimensionality of the complex. In this crystal, such molecules associate in zig-zag chains built by alternating – interactions between the five- or six-atom rings of Hdap ligands of adjacent molecules. DFT theoretical calculations (using two different theoretical models and characterized by the quantum theory of “atoms in molecules”) reveal the importance of these – interactions between Hdap ligands, as well as those corresponding to the referred hydrogen bonds in the contributed tetranuclear moleculeMICIU/AEI of Spain project PID2020-115637GB-I00 FEDER, MICINN of Spain project PGC2018-102047-B-I00Project B-FQM-478-UGR20 (FEDER-Universidad de Granada, Spain)FQM-283 (Junta de Andalucía, Spain

Bis-Citrullinato Copper(II) Complex: Synthesis, Crystal Structure, and Non-Covalent Interactions

Citrulline (C6H13N3O3) is a non-protein amino acid found in watermelon. In physiological conditions, it is almost entirely present as a zwitterion, so its carboxylic and amine groups can act as Lewis donors, chelating metallic cations. In addition, Citrulline possesses a terminal ureide group of the aliphatic chain, which appears to be non-innocent. Although Citrulline is similar to other classical amino acids, only one coordination complex has been reported in the Cambridge Crystallographic Database. As part of our search for Casiopeina® analogs, we synthesized and characterized the copper bis-citrullinato complex, [Cu(Citr)2]n. The compound was described using UV-Vis, Infrared, and Raman spectroscopy, together with single-crystal X-ray diffraction. Computational tools were also used. The optimized structure, MEP map, IR and Raman spectra, and 1H and 13C chemical shifts were obtained with functional mPW1PW91 using 6-31G(d) basis set for N, O, C, and H atoms, and LANL2DZ basis set and ECP=LANL2DZ for the Cu atom. TD-mPW1PW91 calculations generated the UV-Vis spectrum. Finally, AIM and Hirshfeld surface analysis were used to examine noncovalent interactions. Previous investigations suggest Casiopeina®-like complexes can interact with DNA/RNA, creating potential anticancer chemicals. The [Cu(Citr)2]n complex’s polymeric nature and insolubility make it difficult for such purposes. However, the facile synthesis of D-Citrulline could be a novel way to find new applications for this interesting amino acid.PRODEP Academic Group (SEP, Mexico) BUAP-CA-263Ministerio de Universidades and Next Generation for the Margarita Salas contract (Spain) 401 100108444-VIEP 100256733-VIEP 100233622-VIE

Easy Handling and Cost-Efficient Processing of a Tb3+-MOF: The Emissive Capacity of the Membrane-Immobilized Material, Water Vapour Adsorption and Proton Conductivity

The development of convenient, non-complicated, and cost-efficient processing techniques for packing low-density MOF powders for industry implementation is essential nowadays. To increase MOFs’ availability in industrial settings, we propose the synthesis of a novel 3D Tb-MOF (1) and a simple and non-expensive method for its immobilization in the form of pellets and membranes in polymethacrylate (PMMA) and polysulphone (PSF). The photoluminescent properties of the processed materials were investigated. To simulate industrial conditions, stability towards temperature and humidity have been explored in the pelletized material. Water-adsorption studies have been carried out in bulk and processed materials, and because of the considerable capacity to adsorb water, proton-conduction studies have been investigated for 1.University of the Basque Country GIU 20/028Portuguese Foundation for Science and Technology UIDB/50011/2020 UIDP/50011/2020 LA/P/0006/2020Spanish Government PGC2018-102052-A-C22 PGC2018-102052-B-C21 PID2019-108028GB-C21Basque Government IT1755-22 IT1310-19 IT1291-19Junta de Andalucia B-FQM-734-UGR20 ProyEx-cel_00386 FQM-39

Tris(2-Pyridylmethylamine)V(O)2 Complexes as Counter Ions of Diprotonated Decavanadate Anion: Potential Antineoplastic Activity

Projects funded this research: 100517029-VIEP2021 and 100233622-VIEP2021, and the PRODEP Academic Group BUAP-CA-263 (SEP, Mexico). Financial support was also provided by Junta de Andalusia (Spain), Project number FQM-394. NC, BM-V, and LN wish to thank CONACyT (Mexico) Ph.D. fellowship support numbers 390894, 593307, and 697889.The synthesis and theoretical-experimental characterization of a novel diprotanated decavanadate is presented here due to our search for novel anticancer metallodrugs. Tris(2-pyridylmethyl)amine (TPMA), which is also known to have anticancer activity in osteosarcoma cell lines, was introduced as a possible cationic species that could act as a counterpart for the decavanadate anion. However, the isolated compound contains the previously reported vanadium (V) dioxido-tpma moieties, and the decavanadate anion appears to be diprotonated. The structural characterization of the compound was performed by infrared spectroscopy and single-crystal X-ray diffraction. In addition, DFT calculations were used to analyze the reactive sites involved in the donoracceptor interactions from the molecular electrostatic potential maps. The level of theory mPW1PW91/6–31G(d)-LANL2DZ and ECP = LANL2DZ for the V atom was used. These insights about the compounds’ main interactions were supported by analyzing the noncovalent interactions utilizing the AIM and Hirshfeld surfaces approach. Molecular docking studies with small RNA fragments were used to assess the hypothesis that decavanadate’s anticancer activity could be attributed to its interaction with lncRNA molecules. Thus, a combination of three potentially beneficial components could be evaluated in various cancer cell lines.European CommissionPRODEP Academic Group (SEP, Mexico) BUAP-CA-263Junta de Andalusia (Spain) FQM-394Consejo Nacional de Ciencia y Tecnologia (CONACyT) 390894 593307 697889 SEP PRODEP BUAP-PTC_61

Biomimetic Citrate-Coated Luminescent Apatite Nanoplatforms for Diclofenac Delivery in Inflammatory Environments

This research was funded by Spanish Agencia Estatal de Investigacion (AEI) of the Ministerio de Ciencia e Innovacion (MCI) and co-funded with FEDER, UE, Project No. PGC2018-102047-B-I00 (MCIU/AEI/FEDER, UE). M.P. acknowledges the Progetto di Ricerca Fondi di Ateneo per la Ricerca-FAR 2018 "Development of innovative biological materials for the functional regeneration of cardiac tissue models".Luminescent nanoparticles are innovative tools for medicine, allowing the imaging of cells and tissues, and, at the same time, carrying and releasing different types of molecules. We explored and compared the loading/release ability of diclofenac (COX-2 antagonist), in both undoped- and luminescent Terbium(3+) (Tb3+)-doped citrate-coated carbonated apatite nanoparticles at different temperatures (25, 37, 40 degrees C) and pHs (7.4, 5.2). The cytocompatibility was evaluated on two osteosarcoma cell lines and primary human osteoblasts. Biological effects of diclofenac-loaded-nanoparticles were monitored in an in vitro osteoblast's cytokine-induced inflammation model by evaluating COX-2 mRNA expression and production of PGE(2). Adsorption isotherms fitted the multilayer Langmuir-Freundlich model. The maximum adsorbed amounts at 37 degrees C were higher than at 25 degrees C, and particularly when using the Tb3+ -doped particles. Diclofenac-release efficiencies were higher at pH 5.2, a condition simulating a local inflammation. The luminescence properties of diclofenac-loaded Tb3+ -doped particles were affected by pH, being the relative luminescence intensity higher at pH 5.2 and the luminescence lifetime higher at pH 7.4, but not influenced either by the temperature or by the diclofenac-loaded amount. Both undoped and Tb3+-doped nanoparticles were cytocompatible. In addition, diclofenac release increased COX-2 mRNA expression and decreased PGE(2) production in an in vitro inflammation model. These findings evidence the potential of these nanoparticles for osteo-localized delivery of anti-inflammatory drugs and the possibility to localize the inflammation, characterized by a decrease in pH, by changes in luminescence.Spanish Agencia Estatal de Investigacion (AEI) of the Ministerio de Ciencia e Innovacion (MCI)European Commission PGC2018-102047-B-I0