14 research outputs found
Integrated stacking motifs of TTF-like donors and cyclic trinuclear acceptor complexes of monovalent coinage metals: Supramolecular structures, magneto-opto electronic properties
No full textIntegrated stacking motifs of
TTF-like donors and cyclic trinuclear
acceptor complexes of monovalent
coinage metals: Supramolecular
structures, magento-opto-electronic
properties and potential
apps. M.M. Ghimire, O. Camille
Simon, V.N. Nesterov, A. Macchioni,
C. Zuccaccia, R. Galassi, M.A. Omar
Spectroscopic studies on the interaction between poly-phosphane gold(I) complexes and dihydrofolate reductase: an interplay with nicotinamide adenine dinucleotide cofactor
No full textSpectroscopic studies on the interaction between poly-phosphane gold(I) complexes and dihydrofolate reductase: an interplay with nicotinamide adenine dinucleotide cofactor.
Lorenzo Luciani1, Stefania Pucciarelli2, Oumarou Camille Simon1, Alfredo Burini1, Annateresa Ramadori1, Silvia Vincenzetti2, and Rossana Galassi1.
1. School of Science and Technology, University of Camerino, Via Sant’Agostino, 1, Camerino 62032
2. School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, Camerino 62032.
Abstract
A class of gold (I) phosphane complexes have been identified as inhibitors of dihydrofolate reductase (DHFR), an enzyme that catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), using NADPH as a coenzyme [1]. Since DHFR does not contain seleno-cysteines either cysteines in the active site, which are the most favorable sites of attack of Au(I) moieties, exploiting the nature of the interaction at the base of these effects could add new insights about the mechanisms by which these compounds exert their action. In this work, the interactions of bis and tris(4- or 2-benzoic-diphenyl)phosphane acid gold(I) chloride compounds [((4-COOH Ph)Ph2P)3AuCl], [((4-COOH Ph)Ph2P)3AuTf], Tf = triflate, [((2-COOH Ph)Ph2P)3AuCl], [(4COOHPh-Ph2P)2AuCl], [(2COOHPh-Ph2P)2AuCl], and [(PPh3)2AuCl] with DHFR from E. coli have been studied by emission spectroscopy and spectrophotometric assay. By elucidating the energetic aspects of the binding event, we have attempted to dissect the role played by the phosphine/protein interactions, in the gold (I) phosphane complexes inhibitory activity. The effect of the carboxylic polar group in one phenyl ring of the triphenyl-phosphine and the interplay with the cofactor NADPH have been investigated. By analyzing the temperature dependence of the dissociation constants obtained by quenching of Trp fluorescence, through the van’t Hoff equation, the enthalpy and entropy contributions to the energetics of binding have been evaluated. In this study, the presence of the carboxylic group in the phenyl ring of [((4-COOH Ph)Ph2P)3AuCl] did not produce a higher affinity for the enzyme, neither a stronger inhibition; nevertheless, an exothermic enthalpy change and a positive entropic contribution (H° = -5.04 ± 0.08 kcal/mol and S° = 7.34 ± 0.005 cal/mol·K) was associated to its interaction with the enzyme. The negative enthalpy value can be associated with hydrogen bonds and van der Waals forces occurring between the functional groups of the gold complex and DHFR. The increase of entropy is mainly due to the hydrophobic effect, related to the increase of the degree of freedom of the water molecules released from the solvation shells of both protein and gold complexes [2]. The not covalent binding between the enzyme and the gold complex yields an enzyme fluorescence quenching, the inhibition of its activity and a hyperchromic effect of the intrinsic complex fluorescence.
References:
1. Galassi R. et al. Dalton Trans., 2015, 44, 3043
2. Breiten B. et al, J. Am. Chem. Soc., 2013, 135 (41), 1557
Columnar stacking materials based on donor/acceptor complexes of tetrathiofulvalene/coinage-metal metallocycles
No full textColumnar stacking materials based on donor/acceptor complexes of tetrathiofulvalene/coinage-metal metallocycles
Rossana Galassi1, Oumarou Camille Simon1, Vladimir Nesterov2, Alceo Macchioni3, Cristiano Zuccaccia3, Mohammad A. Omary2
Tetrathiofulvalene and dibenzotetrathiofulvalene, TTF and DBTTF respectively, are strong one- or two-electron donors,[1] whereas a class of cyclic trinuclear coinage complexes, in which the bridging ligand is a 3,5-pyrazolate disubstituted with electron-withdrawing groups, are known to be electron-acceptors.[2] Recently, we have proved the electrophilic behavior of the [Ag(3,5-(NO2)2pz)]3 cyclotrimer towards small volatile organic or inorganic molecules (e.g., NH3, acetone, acetonitrile, pyridine, and dimethylsulfide). This behavior was compared to that of [Ag(3,5-(CF3)2pz)]3 and rationalized in terms of inter-trimer bonding energies.[3] Moreover, electron-rich trinuclear metallocycles were observed to react with electron-poor organic counterparts, such as TCNQ (7,7’,8,8’-tetracyanoquinodimethane). In order to obtain new classes of materials with potentially-interesting conductive properties, reactions between reactants having these opposite donor/acceptor characteristics have been carried out and reported herein. By mixing solutions of the corresponding Au, Ag or Cu trinuclear derivatives and TTF or DBTTF, the formation of the relative adducts was observed. The compounds were characterized by elemental analysis, IR, ESI-MS, and 1H NMR spectroscopy. Moreover, the X ray diffraction structure determination was performed on suitable crystals of the [Cu(3,5-(CF3)2pz)]3 . DBTTF complex. This compound is mostly stable both in the solid state and in solution as highlighted by 1H and 19F NMR, and by UV/visible spectroscopies. The [Ag(3,5-(CF3)2pz)]3 . DBTTF and [Au(3,5-(CF3)2pz)]3 . DBTTF analogs have been isolated and their characterizations suggest similar structures in the solid state, but less stability in solution. The [Ag(3,5-(NO2)2pz)]3 metallocycle shows a stronger interaction with both TTF and DBTTF, readily attaining highly-colored precipitates, albeit with too low solubility for single-crystal XRD analysis.
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[1] J. Ferrari et al., J. Am. Chem. Soc., 1973, 95 (3), pp 948–949; T.J. Emge et al., Molecular Crystals and Liquid Crystals, 1982, 87 (1-2), pp 137-161
[2] M. A. Omary et al., J. Am. Chem. Soc., 2008, (130), pp 1669–949
[3] R. Galassi et al., Inorg. Chem., 2013, 52, pp 14124 -1413
Homo- and Heterotrinuclear cyclic complexes of the 11th group metal ions: fifteen years of a golden chemistry
No full textHomo- and Heterotrinuclear cyclic complexes of the 11th group metal ions: fifteen years of a golden chemistry
Alfredo Burini1, Vladimir Nesterov2, Mohammad A. Omary2, Oumarou Camille Simon1, Rossana Galassi1
1School of Science and Technology - Chemistry Division, Camerino University, via S. Agostino 1, 62032 Camerino, Italy, e-mail:[email protected]
2 University of North Texas, Department of Chemistry, TX 76203, Denton, USA
In the last fifteen years our group has given an important contribution to the development of the synthesis of cyclic trinuclear complexes (CTC) of the 11th group metal ions. Our pioneering studies showed that trinuclear cyclic gold(I) complexes with bridging imidazolate or carbeniate ligands can act as π-Lewis base. The interaction of these substrates with metal ions, organometallic compounds or organic molecules showing some Lewis acidity, yield polymeric supramolecular structures showing amazing photoemissive properties. [1] [2] The CTCs can also act as π-Lewis acids: this inversion of the acid/base properties depends on both the ligand and the metal present in the complex; in fact, by using a pyrazolate ligand bearing withdrawing groups (such as NO2), and silver(I) ions as connecting metal, we obtained a silver CTC that interact with small molecules having donor atoms in their structure such as acetone, acetonitrile, pyridine etc.. and it stacks with naphtalene [3] Moreover, some years ago we found a synthetic route to obtain the first heteronuclear CTCs. By using different stoichiometry, Au2I/AgI and AuI/Ag2I CTCs were isolated and structurally characterized. [4] This strategy was applied to yield new heteronuclear AuI/CuI CTCs. The crystal structure of [Au2(μ-C2,N3-BzIm)2Cu(μ-3,5-(CF3)2Pz)], and of [Au2(μ-C2,N3-MeIm)2Cu(μ-3,5-(CF3)2Pz)] are reported and the crystal packing indicates the formation of a dimer of heterobimetallic trimers linked by quite long Au-Cu metallophilic bonds with distances of 3.317 Å (Au2···Cu1B) and 3.232 Å (Au2···Cu1B), respectively. In this case, on the contrary of what already observed in the case of Ag/Au heterobimetallic complexes, the exchange of ligands occurs too. Their formation passes through a likely - acid base interaction, affording to stable stacking products only in the case of {Au(μ-C2,N3-BzIm)}3{Cu(μ-3,5-(CF3)2Pz)}3. These complexes exhibit fascinating and sophisticated photophysical properties that are dependent on the excitation wavelength and on the temperature.
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[1] A. Burini et al., Inorg. Chem. 39 (2000) p. 3158-3165.
[2] A. Burini et al., J. Am. Chem. Soc., 122 (2000) p.11264-11265.
[3] R. Galassi et al., Inorg. Chem., 52 (2013) pp 14124–14137.
[4] A. Burini et al., Inorg. Chem., 45 (2006) pp 7770-7776
Copper (II) metallocycles as anions receptors. Further studies on their synthesis, spectroscopic and spectrometric characterization in solution
No full textCopper (II) metallocycles as anions receptors.
Further studies on their synthesis, spectroscopic and spectrometric characterization in solution
Rossana Galassia, Camille S. Oumaroua, Alfredo Burinia, Massimiliano Lupacchinia, Stefania Pucciarellib
a School of Science and Technology, Università di Camerino, Via Sant’Agostino 1, 62032, Camerino, Italia
b School of Biosciences and Biotechnology, University of Camerino, Via Gentile III da Varano, 1, 62032 Camerino, Italy
[email protected]
Halide-centered hexanuclear, anionic copper (II) pyrazolate complexes [trans-Cu6{(3,5-CF3)2pz}6(OH)6X]-, X= Cl, Br, I can be isolated in a good yield from the redox reaction of the trinuclear copper(I) pyrazolate complex [μ-Cu3{(3,5-CF3)2pz}3] with a halide source such as Ph3PAuCl, [Bu4N]X, X= Cl, Br or I or PPN(NO2) where PPN is bis(triphenylphosphoranylidene)ammonium [1]. We reported in this work a new route for the synthesis of the [trans-Cu6{(3,5-CF3)2pz}6(OH)6X] starting from the neutral 3,5-(CF3)2pzH. The reactions showed lower yields but fast conversion to the corresponding halide centered metallocycles. A water centered metallocycle was obtained too. The nature of the molecule inside the cavity was discussed by IR spectroscopy, X-ray structural data and by determining the rate constant of the water exchange reaction in acetone solution. The mechanism likely involves the formation of pyrazoles self-aggregates by intermolecular hydrogen bonding. From data analysis, we can assume that the cavity is very affine for chloride and bromide but scarcely selective, while is slightly less affine for iodide.
[1] A. A. Mohamed, S. Ricci, A. Burini, R. Galassi Inorg. Chem. 2011, 50, 1014-1020
Catalytic activity of Copper(I) and Copper(II) 3,5-dinitro- or 3,5-bis(trifluoromethyl)-pyrazolate derivatives
No full textCatalytic activity of Copper(I) and Copper(II) 3,5-dinitro- or 3,5-bis(trifluoromethyl)-pyrazolate derivatives.
Rossana Galassi,a Oumarou Camille Simon,a* Claudia Graiff,b M. Fátima C. Guedes da Silva,c Nuno M. R. Martins,c Luísa M. D. R. S. Martins,c,d Armando J. L. Pombeiroc
a School of Science and Technology, Via S. Agostino 1, 62032 Camerino (MC), Italy, *[email protected]
b Dipartimento di Chimica, Parco Area delle Scienze 17/A, Parma, Italy
c Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Universidade de Lisboa, Portugal.
d Chemical Engineering Departament, Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa, Portugal.
The reaction of [μ-N,N-Cu-(3,5(CF3)2pz]3 (1) with halide sources led to the formation of Cu(II) hexanuclear derivatives such as [(Cu((CF3)2pz)6(OH)6) X][Bu4N] (2a)(Cl-), (2b) (Br-), (2c) (I-), (2d) (NO2-).[1] If the reaction occurs in the same conditions but without halides, a highly hydrated hexanuclear metallocycle [(Cu((CF3)2pz)6(OH)6) (H2O)n], (3), was isolated, ruling out the template action of the anions. By replacing the CF3 groups with NO2 groups in the pyrazole, neither the trinuclear nor the hexanuclear copper derivatives were obtained, and the dinuclear [Cu-(3,5-(NO2)2pz)(PPh3)]2 compound, (4), was the only Cu(I) derivative isolated in good yield. Even though CF3 and NO2 are both withdrawing groups, a pronounced different chemical behavior was already revealed in the case of similar pyrazolate silver(I) derivatives.[2] All compounds were characterized by elemental analysis, NMR, IR spectroscopy and ESI-MS spectrometry. In the case of compound 4 its crystal structure has been determined by X Ray diffraction analysis, evidencing its dinuclear nature, build up by two bridging ligands which coordinate two copper atoms through nitrogen donors, forming a six member ring with boat conformation. Compounds (3) and (4) act as catalysts towards the microwave (MW) assisted peroxidative oxidation of cyclohexane to cyclohexanol and cyclohexanone under mild conditions, which is of industrial significance for the synthesis of Nylon-6,6. High yield (up to 51% of oxygenated products) is obtained after 2h of MW irradiation, using a maximum of 0.2% molar ratio of 3 (the best catalyst) relatively to the substrate in the presence of TEMPO. The efficiency of the catalytic systems as well as the influence of various parameters, such as the reaction time, amount of catalyst, temperature and presence of different additives, are discussed. The work was partially supported by the Fundação para a Ciência e a Tecnologia (project UID/QUI/00100/2013)
[ ] Galassi, R.; Burini, A.; Ahmed, A. M. Eur. J. Inorg. Chem. 2012, 3257.
[2] Galassi, R.; Ricci, S., Burini, A., Macchioni A., Rocchiggiani, L., Marmottini, F., Tekarli, S. M., Nesterov, V. N. Omary M. A. Inorg. Chem., 2013, 52, 14124
Azolate gold(I) phosphane complexes as innovative therapies for the treatment of HER2-driven breast cancer
No full textGold(I) compounds have been known as cytotoxic agents since 30 years ago1. Lastly, the inhibition activity studies on compounds (such as LAuL’, where L is a phosphane and L’ a co-ligand) led to the individuation of a likely molecular target2, renewing the interest on the field of these metallodrugs. In the design of active gold compounds, the proper hydro / lipophilic balancing provides the lowering of the overall toxicity, maintaining both a good cellular uptake and anticancer properties. Imidazoles and pyrazoles as co-ligands afford to gold(I) phosphane compounds having cytotoxic activity, but enough polarity to be soluble in physiological media. Different azolate gold(I)phosphane complexes have been synthesized. They contain substituents on imidazole or pyrazole ligands such as R = NO2, CF3, CN, Cl, CH2OH) or substituents such as COOH or COONHEt3 in the phosphane moiety. Some of them have been already tested as antitumoral in some panels of cancer cells, resulting active3. In this work we present the study of the cytotoxic effects of several gold(I) compounds and a natural compound on an in vitro model of HER2-overexpressing breast cancer. We tested the effectiveness of these compounds as potential anticancer agents on SKBR-3 cell line, a human breast cancer cell line that overexpresses the HER2 (Neu/ErbB-2) gene product4. These cells display an epithelial morphology in tissue culture and are a useful preclinical model to screen for new therapeutic agents which could overcome the drawback of resistance to HER2-targeted therapies5. In order to screen the cytotoxic activity of these new compounds on SKBR-3 cells we performed different cell viability assays. As conclusion we observed a detrimental effect on the cytotoxicity for those compounds having an ionic structure or highly hydrophilic polar substituents on the azolate or phosphane ligands and a remarkable activity for those compounds having the Ph3PAu+ moiety and substituted imidazolate as co-ligands.
1) Benoît Bertrand, and Angela Casini. Dalton Trans., 2014, 43, 4209. DOI: 10.1039/c3dt52524d
2) a) Peter J. Barnard, Susan J. Berners-Price. Coord. Chem. Rev. 2007, 251, 1889–1902. DOI:10.1016/j.ccr.2007.04.006. b) A. Bindoli, M. P. Rigobello, G. Scutari, C. Gabbiani, A. Casini, L. Messori, Coord. Chem. Rev., 2009, 253, 1692–1707. DOI: 10.1016/j.ccr.2009.02.026.
3) a) R. Galassi, A. Burini, S. Ricci, M. Pellei, M. P. Rigobello, A. Citta, A. Dolmella, V. Gandin, C Marzano. Dalton Trans., 2012, 41, 5307. DOI: 10.1039/c2dt11781a b)
4) Fogh J, Fogh JM, Orfeo T, 1977, One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. J Natl Cancer Inst. , 59(1):221-6. DOI: 10.1016/j.bmcl.2013.11.058.
5) Saturnino C, Sirignano E, Botta A, Sinicropi MS, Caruso A, Pisano A, Lappano R, Maggiolini M, Longo P, 2014, New titanocene derivatives with high antiproliferative activity against breast cancer cells. Bioorg Med Chem Lett., 1;24(1):136-40. DOI: 10.1016/j.bmcl.2013.11.058
IN VITRO AND IN VIVO STUDIES FOR THE TREATMENT OF BASAL LIKE BREAST CANCER (BLBC) WITH AZOLATE/PHOSPHANE GOLD(I) COMPOUNDS
No full textIN VITRO AND IN VIVO STUDIES FOR THE TREATMENT OF BASAL LIKE BREAST CANCER (BLBC) WITH AZOLATE/PHOSPHANE GOLD(I) COMPOUNDS
Rossana Galassia, Alfredo Burinia, Oumarou Camille Simona, Anna Teresa Ramadoria, Stefania Pucciarelli,b Albana Hisy,c Manuela Iezzi,c Valentina Gambini b, Martina Tiliob, Cristina Marchini b, Augusto Amicib
a School of Science and Technology, Chemistry Division, Camerino University, Via Sant’ Agostino, I-62032 Italy.
b Department of Biosciences and Veterinary, University of Camerino, Via Gentile III da Varano, I-62032, Italy
c Aging Research Centre, G. d’Annunzio University, Chieti, 66100, Italy
e-mail: [email protected]
Breast cancer is a heterogeneous disease classified into molecular subtypes with distinctive gene expression signatures. Of all the molecular subtypes, BLBC has the worst negative outcome and prognosis. BLBCs are generally estrogen receptor (ER-) and progesterone receptor (PR)-negative and also lack high expression/amplification of HER2, limiting targeted therapeutic options. Thus, to date, Cisplatin remains the only possible therapeutic choice in the adjuvant or metastatic setting in the BLBC. Considering also several and serious side effects, new therapies are therefore an urgent unmet medical need for this patient population. Azolate gold(I) phosphane compounds have become good candidate for anticancer applications.[1] It was highlighted that azolate gold(I) phosphane compounds were mostly very active in the regards of many panel of cancer cells, in addition to cis-platin resistant cells. They show a mechanism of action involving the inhibition of seleno dependent ThioredoxinaReductase (TrxR), but they inhibit with IC50 in the micromolar scale also many other enzymes such as DeHydroFolateReductase.[1][2] In order to study the effectiveness of these new azolate gold(I) phosphane compounds as potential anticancer agents, different cell viability assays (MTT assays) were performed on a human in vitro model of HER2-overexpressing breast cancer: SKBR-3 cells.[3] After this preliminary screening, the most promising and effective compounds were selected to extend the study on A17 cell line, a murine preclinical model of Basal Like Breast Cancer (BLBC).[4] Hence, their efficacy in suppressing BLBC growth in vivo was tested and IHC analysis on explanted tumors were carried on. Overall, in vitro assays demonstrated a remarkable activity for those compounds having the Ph3PAu+ moiety and substituted imidazolate as co-ligands. Concerning the in vivo study the compounds act significantly delaying tumor growth. Accordingly, IHC analysis revealed a remarkable anti-angiogenic activity associated with a lower expression of proliferative markers and a higher level of apoptotic markers in treated tumours in comparison with controls. Moreover, respect to cisplatin these compounds displayed a lower nephrotoxicity, although their liver toxicity was higher. These promising results open the way to further investigations in order to understand the mechanism of action of these new azolate gold (I) posphane complexes.
References
[1] R. Galassi et al., Dalton Trans., 2012, (41), pp 5307-5318.
[2] R. Galassi et al., Dalton Trans., 2015, (44), pp 3043-3056.
[3] Fogh, J., Fogh J. M., Orfeo T, J Natl Cancer Inst. , 1977, (59), pp 221-6;
[4] M. Galiè et al., Carcinogenesis , 2005, (11), pp 1868-187
Studies on the Interaction between Poly-Phosphane Gold(I) Complexes and Dihydrofolate Reductase: An Interplay with Nicotinamide Adenine Dinucleotide Cofactor
No full textclass of gold(I) phosphane complexes have been identified as inhibitors of dihydrofolate reductase (DHFR) from E. coli, an enzyme that catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), using NADPH as a coenzyme. In this work, to comprehend the nature of the interaction at the basis of these inhibitory effects, the binding properties of bis- and tris-phosphane gold(I) chloride compounds in regards to DHFR have been studied by emission spectroscopy and spectrophotometric assays. The lack of cysteine and seleno-cysteine residues in the enzyme active site, the most favorable sites of attack of Au(I) moieties, makes this work noteworthy. The interaction with the gold compounds results into the quenching of the DHFR tryptophan’s emissions and in an enhancement of their intrinsic emission intensities. Moreover, a modulating action of NADPH is highlighted by means of an increase of the gold compound affinity toward the enzyme; in fact, the dissociation constants calculated for the interactions between DHFR and each gold compound in the presence of saturating NADPH were lower than the ones observed for the apo-enzyme. The fluorimetric data afforded to Kd values ranged from 2.22 ± 0.25 μM for (PPh3)2AuCl in the presence of NADPH to 21.4 ± 3.85 μM for 4L3AuTf in the absence of NADPH. By elucidating the energetic aspects of the binding events, we have attempted to dissect the role played by the gold phosphane/protein interactions in the inhibitory activity, resulting in an exothermic enthalpy change and a positive entropic contribution (ΔH° = −5.04 ± 0.08 kcal/mol and ΔS° = 7.34 ± 0.005 cal/mol·K)
A study on the inhibition of dihydrofolate reductase (DHFR) from Escherichia coli by gold(i) phosphane compounds. X-ray crystal structures of (4,5-dichloro-1H-imidazolate-1-yl)-triphenylphosphane-gold(i) and (4,5-dicyano-1H-imidazolate-1-yl)-triphenylphosphane-gold(i)
No full textAn unprecedented study on the inhibitory activities of a class of phosphane gold(I) complexes on E. coli dihydrofolate reductase (DHFR) is reported. The gold(I) complexes considered in this work consist of azolate or chloride ligands and phosphane as co-ligands. The ligands have been functionalized with polar groups (-COOH, -COO-, NO2, Cl, CN) to obtain better solubility in polar media. Neutral, anionic and cationic gold(I) complexes have been tested as DHFR inhibitors by means of a continuous direct spectrophotometric method. X-ray structural characterizations were performed on ((triphenylphosphine)-gold(I)-(4,5-dicyanoimidazolyl-1H-1yl) and on the analog (triphenylphosphine)-gold(I)-(4,5-dichloroimidazolyl-1H-1yl). The inhibition constants obtained from the enzyme tests range from 20 mu M to 63 nM (auranofin) and are conducive to promoting these compounds as potential DHFR inhibitors
