RESUMEN
The new ligand L2Ad, obtained by conjugating the bifunctional species bis(3,5-dimethylpyrazol-1-yl)-acetate and the drug amantadine, was used as a chelator for the synthesis of new Cu complexes 1-5. Their structures were investigated by synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), near-edge X-ray absorption fine structure (NEXAFS) spectroscopy, and by combining X-ray absorption fine structure (XAFS) spectroscopy techniques and DFT modeling. The structure of complex 3 was determined by single-crystal X-ray diffraction analysis. Tested on U87, T98, and U251 glioma cells, Cu(II) complex 3 and Cu(I) complex 5 decreased cell viability with IC50 values significantly lower than cisplatin, affecting cell growth, proliferation, and death. Their effects were prevented by treatment with the Cu chelator tetrathiomolybdate, suggesting the involvement of copper in their cytotoxic activity. Both complexes were able to increase ROS production, leading to DNA damage and death. Interestingly, nontoxic doses of 3 or 5 enhanced the chemosensitivity to Temozolomide.
Asunto(s)
Adamantano , Antineoplásicos , Complejos de Coordinación , Cobre , Glioblastoma , Humanos , Cobre/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/metabolismo , Ligandos , Adamantano/farmacología , Adamantano/química , Adamantano/síntesis química , Adamantano/análogos & derivados , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Supervivencia Celular/efectos de los fármacos , Teoría Funcional de la Densidad , Ensayos de Selección de Medicamentos Antitumorales , Especies Reactivas de Oxígeno/metabolismo , Estructura Molecular , Quelantes/química , Quelantes/farmacología , Quelantes/síntesis química , Relación Estructura-Actividad , Acetatos/química , Acetatos/farmacología , Acetatos/síntesis químicaRESUMEN
In the framework of the design, synthesis and testing of a library of copper complexes and nanostructured assemblies potentially endowed with antitumor and antiviral activity and useful for several applications, from drugs and related delivery systems to the development of biocidal nanomaterials, we present the detailed spectroscopic investigation of the molecular and electronic structure of copper-based coordination compounds and of a new conjugated system obtained by grafting Cu(I) complexes to gold nanorods. More in detail, the electronic and molecular structures of two Cu complexes and one AuNRs/Cu-complex adduct were investigated by X-ray photoelectron spectroscopy (XPS), synchrotron-induced XPS (SR-XPS) and near edge X-ray absorption spectroscopy (NEXAFS) in solid state, and the local structure around copper ion was assessed by X-ray absorption spectroscopy (XAS) both in solid state and water solution for the AuNRs/Cu-complex nanoparticles. The proposed multi-technique approach allowed to properly define the coordination geometry around the copper ion, as well as to ascertain the molecular structures of the coordination compounds, their stability and modifications upon interaction with gold nanoparticles, by comparing solid state and liquid phase data.
RESUMEN
The new 3-monosubstituted acetylacetone ligands, 3-(phenyl(1H-pyrazol-1-yl)methyl)pentane-2,4-dione (HLacPz) and 3-((3,5-dimethyl-1H-pyrazol-1-yl)(phenyl)methyl)pentane-2,4-dione (HLacPzMe), were synthesized and used as supporting ligands for new copper(II) and copper(I) phosphane complexes of the general formulae [Cu(HLacX)2(LacX)2] and [Cu(PPh3)2(HLacX)]PF6 (X = Pz (pyrazole) or PzMe (3,5-dimethylpyrazole)), respectively. In the syntheses of the Cu(I) complexes, the triphenylphosphine coligand (PPh3) was used to stabilize copper in the +1 oxidation state, avoiding oxidation to Cu(II). All compounds were characterized by CHN analysis, 1H-NMR, 13C-NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). The ligands HLacPz (1) and HLacPzMe (2) and the copper complex [Cu(PPh3)2(HLacPz)]PF6 (3) were also characterized by X-ray crystallography. The reactivity of these new compounds was investigated and the new compounds 4-phenyl-4-(1H-pyrazol-1-yl)butan-2-one (7) and 4-(3,5-dimethyl-1H-pyrazol-1-yl)-4-phenylbutan-2-one (8) were obtained in basic conditions via the retro-Claisen reaction of related 3-monosubstituted acetylacetone, providing efficient access to synthetically useful ketone compounds. Compound 8 was also characterized by X-ray crystallography.
RESUMEN
The 3d transition metal (Mn(II), Fe(II), Co(II), Ni(II), Cu(II) and Zn(II)) complexes, supported by anions of sterically demanding ß-diketones, 1,3-dimesitylpropane-1,3-dione (HLMes) and 1,3-bis(3,5-bis(trifluoromethyl)phenyl)-3-hydroxyprop-2-en-1-one (HLCF3), were synthesized and evaluated for their antitumor activity. To assess the biological effects of substituents on phenyl moieties, we also synthesized and investigated the analogous metal(II) complexes of the anion of the less bulky 1,3-diphenylpropane-1,3-dione (HLPh) ligand. The compounds [Cu(LCF3)2], [Cu(LMes)2] and ([Zn(LMes)2]) were characterized by X-ray crystallography. The [Cu(LCF3)2] crystallizes with an apical molecule of solvent (THF) and features a rare square pyramidal geometry at the Cu(II) center. The copper(II) and zinc(II) complexes of diketonate ligands, derived from the deprotonated 1,3-dimesitylpropane-1,3-dione (HLMes), adopt a square planar or a tetrahedral geometry at the metal, respectively. We evaluated the antitumor properties of the newly synthesized (Mn(II), Fe(II), Co(II), Ni(II), Cu(II) and Zn(II)) complexes against a series of human tumor cell lines derived from different solid tumors. Except for iron derivatives, cellular studies revealed noteworthy antitumor properties, even towards cancer cells endowed with poor sensitivity to the reference drug cisplatin.
Asunto(s)
Complejos de Coordinación , Cobre , Humanos , Cobre/química , Metales/química , Zinc/química , Hierro/química , Compuestos Ferrosos , Ligandos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Cristalografía por Rayos X , Estructura MolecularRESUMEN
Design, synthesis, and in vitro antitumor properties of Cu(I) and Ag(I) phosphane complexes supported by the anions of sterically hindered ß-diketone ligands, 1,3-dimesitylpropane-1,3-dione (HLMes) and 1,3-bis(3,5-bis(trifluoromethyl)phenyl)-3-hydroxyprop-2-en-1-one (HLCF3) featuring trifluoromethyl or methyl groups on the phenyl moieties have been reported. In order to compare the biological effects of substituents on the phenyl moieties, the analogous copper(I) and silver(I) complexes of the anion of the parent 1,3-diphenylpropane-1,3-dione (HLPh) ligand were also synthesized and included in the study. In the syntheses of the Cu(I) and Ag(I) complexes, the phosphane coligands triphenylphosphine (PPh3) and 1,3,5-triaza-7-phosphaadamantane (PTA) were used to stabilize silver and copper in the +1 oxidation state, preventing the metal ion reduction to Ag(0) or oxidation to Cu(II), respectively. X-ray crystal structures of HLCF3 and the metal adducts [Cu(LCF3)(PPh3)2] and [Ag(LPh)(PPh3)2] are also presented. The antitumor properties of both classes of metal complexes were evaluated against a series of human tumor cell lines derived from different solid tumors, by means of both 2D and 3D cell viability studies. They display noteworthy antitumor properties and are more potent than cisplatin in inhibiting cancer cell growth.
RESUMEN
Bis(pyrazol-1-yl)acetic acid (HC(pz)2COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pzMe2)2COOH) were converted into the methyl ester derivatives 1 (LOMe) and 2 (L2OMe), respectively, and were used for the preparation of silver(I) complexes 3-5. The Ag(I) complexes were prepared by the reaction of AgNO3 and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine (PPh3) with LOMe and L2OMe in methanol solution. All Ag(I) complexes showed a significant in vitro antitumor activity, proving to be more effective than the reference drug cisplatin in the in-house human cancer cell line panel containing examples of different solid tumors. Compounds were particularly effective against the highly aggressive and intrinsically resistant human small-cell lung carcinoma (SCLC) cells, either in 2D and 3D cancer cell models. Mechanistic studies revealed their ability to accumulate into cancer cells and to selectively target Thioredoxin (TrxR), thus leading to redox homeostasis unbalance and ultimately inducing cancer cell death through apoptosis.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Humanos , Plata , Ligandos , Acetatos , Tiorredoxinas , Antineoplásicos/farmacología , Complejos de Coordinación/farmacologíaRESUMEN
Bis(pyrazol-1-yl)acetic acid (HC(pz)2COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pzMe2)2COOH) were converted into the methyl ester derivatives 1 (LOMe) and 2 (L2OMe), respectively, and were used for the preparation of Cu(I) and Cu(II) complexes 3-10. The copper(II) complexes were prepared by the reaction of CuCl2·2H2O or CuBr2 with ligands 1 and 2 in methanol solution. The copper(I) complexes were prepared by the reaction of Cu[(CH3CN)4]PF6 and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine with LOMe and L2OMe in acetonitrile solution. Synchrotron radiation-based complementary techniques (XPS, NEXAFS, and XAS) were used to investigate the electronic and molecular structures of the complexes and the local structure around copper ions in selected Cu(I) and Cu(II) coordination compounds. All Cu(I) and Cu(II) complexes showed a significant in vitro antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human cancer cell lines, and were able to overcome cisplatin resistance. Noticeably, Cu complexes appeared much more effective than cisplatin in 3D spheroid cultures. Mechanistic studies revealed that the antitumor potential did not correlate with cellular accumulation but was consistent with intracellular targeting of PDI, ER stress, and paraptotic cell death induction.
Asunto(s)
Complejos de Coordinación , Cobre , Acetatos , Cisplatino , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Cobre/química , Cristalografía por Rayos X , Ésteres/farmacología , Humanos , LigandosRESUMEN
Bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetates were conjugated with the 2-hydroxyethylester and 2-aminoethylamide derivatives of the antineoplastic drug lonidamine to prepare Cu(I) and Cu(II) complexes that might act through synergistic mechanisms of action due to the presence of lonidamine and copper in the same chemical entity. Synchrotron radiation-based complementary techniques [X-ray photorlectron spectroscopy and near-edge X-ray absorption fine structure (NEXAFS)] were used to characterize the electronic and molecular structures of the complexes and the local structure around the copper ion (XAFS) in selected complexes. All complexes showed significant antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human tumor cell lines, and were able to overcome oxaliplatin and multidrug resistance. Noticeably, these Cu complexes appeared much more effective than cisplatin against 3D spheroids of pancreatic PSN-1 cancer cells; among these, PPh3-containing Cu(I) complex 15 appeared to be the most promising derivative. Mechanistic studies revealed that 15 induced cancer cell death by means of an apoptosis-alternative cell death.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Cobre/química , Cobre/farmacología , Cristalografía por Rayos X , Humanos , Indazoles , Ligandos , Estructura MolecularRESUMEN
A new dimeric copper(II) bromide complex, [Cu(LOHex)Br(µ-Br)]2 (1), was prepared by a reaction of CuBr2 with the hexyl bis(pyrazol-1-yl)acetate ligand (LOHex) in acetonitrile solution and fully characterized in the solid state and in solution. The crystal structure of 1 was also determined: the complex is interlinked by two bridging bromide ligands and possesses terminal bromide ligands on each copper atom. The two pyrazolyl ligands in 1 coordinate with the nitrogen atoms to complete the Cu coordination sphere, resulting in a five-coordinated geometry-away from idealized trigonal bipyramidal and square pyramidal geometries-which can better be described as distorted square pyramidal, as measured by the τ and χ structural parameters. The pendant hexyloxy chain is disordered over two arrangements, with final site occupancies refined to 0.705 and 0.295. The newly synthesized complex was evaluated as a catalyst in copper-catalyzed C-H oxidation for allylic functionalization through a Kharasch-Sosnovsky reaction without any external reducing agent. Using 0.5 mol% of this catalyst, and tert-butyl peroxybenzoate (Luperox) as an oxidant, allylic benzoates were obtained with up to 90% yield. The general reaction time was only slightly decreased to 24 h but a very significant decrease in the alkene:Luperox ratio to 3:1 was achieved. These factors show relevant improvements with respect to classical Kharasch-Sosnovsky reactions in terms of rate and amount of reagents. The present study highlights the potential of copper(II) complexes containing functionalized bis(pyrazol-1-yl)acetate ligands as efficient catalysts for allylic oxidations.
RESUMEN
The search for anticancer metal-based drugs alternative to platinum derivatives could not exclude zinc derivatives due to the importance of this metal for the correct functioning of the human body. Zinc, the second most abundant trace element in the human body, is one of the most important micro-elements essential for human physiology. Its ubiquity in thousands of proteins and enzymes is related to its chemical features, in particular its lack of redox activity and its ability to support different coordination geometries and to promote fast ligands exchange. Analogously to other trace elements, the impairment of its homeostasis can lead to various diseases and in some cases can be also related to cancer development. However, in addition to its physiological role, zinc can have beneficial therapeutic and preventive effects on infectious diseases and, compared to other metal-based drugs, Zn(II) complexes generally exert lower toxicity and offer few side effects. Zinc derivatives have been proposed as antitumor agents and, among the great number of zinc coordination complexes which have been described so far, this review focuses on the design, synthesis and biological studies of zinc complexes comprising N-donor ligands and that have been reported within the last five years.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Zinc/química , Zinc/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ligandos , Estructura Molecular , Nitrógeno/química , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Bases de Schiff/química , Bases de Schiff/farmacología , Zinc/metabolismoRESUMEN
In this study, two new hexyl bis(pyrazol-1-yl)acetate ligands and related copper(ii) complexes were prepared and fully characterized in the solid state and in solution. Their electronic and molecular structures were investigated by X-ray photoelectron spectroscopy and near edge X-ray absorption; their ligand molecular structural stability upon coordination to copper was also investigated. The Cu(ii) complexes were studied as new catalysts in copper-catalyzed C-H oxidation for allylic functionalization (the Kharasch-Sosnovsky reaction) avoiding the use of any external reducing agents. Using 5 mol% of these catalysts and tert-butylperoxybenzoate as the oxidant, allylic benzoates were obtained in up to 90% yield: the general reaction time was decreased to 6 h and a 5 to 1 ratio of the alkene and tert-butylperoxybenzoate was used to overcome the two most important limitations on their use in chemistry.
RESUMEN
In this study, four new N-(alkyl/aryl)imidazolium-borates were prepared, and their deprotonation reactions were investigated. Addition of BH3â¢THF to N-benzylimidazoles and N-mesitylimidazoles leads to imidazolium-trihydridoborate adducts. Ammonium tetraphenylborate reacts with benzyl- or mesityl-imidazoles with the loss of one of the phenyl groups yielding the corresponding imidazolium-triphenylborates. Their authenticity was confirmed by CHN analysis, 1H-NMR, 13C-NMR, 11B-NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). 3-Benzyl-imidazolium-1-yl)trihydridoborate, (HImBn)BH3, and (3-mesityl-imidazolium-1-yl)trihydridoborate, (HImMes)BH3, were also characterized by X-ray crystallography. The reactivity of these new compounds as carbene precursors in an effort to obtain borate-NHC complexes was investigated and a new carbene-borate adduct (which dimerizes) was obtained via a microwave-assisted procedure.
RESUMEN
In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L2H), and bis(pyrazol-1-yl) acetates conjugated with an N-methyl-d-aspartate (NMDA) receptor antagonist (LNMDA or L2NMDA) and phosphane ligands (triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane) were synthesized. The selection of an NMDA antagonist for the coupling with LH and L2H was suggested by the observation that NMDA receptors are expressed and play a role in different types of cancer models. All the new complexes showed a significant antitumor activity on a panel of human tumor cell lines of different histology, with cisplatin-sensitive, cisplatin-resistant, or multi-drug-resistant phenotype. Their half maximal inhibitory concentration (IC50) values were in the low- and sub-micromolar range and, in general, significantly lower than that of cisplatin. Interestingly, the fact that all the complexes proved to be significantly more active than cisplatin even in three-dimensional (3D) spheroids of H157 and BxPC3 cancer cells increased the relevance of the in vitro results. Finally, morphological analysis revealed that the most representative complex 8 induced a massive swelling of the endoplasmic reticulum (ER) membrane, which is a clear sign of ER stress.
Asunto(s)
Acetatos/química , Antineoplásicos/química , Antineoplásicos/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Cobre/química , Pirazoles/química , Receptores de N-Metil-D-Aspartato/agonistas , Antineoplásicos/síntesis química , Línea Celular Tumoral , Células Cultivadas , Complejos de Coordinación/síntesis química , Humanos , Ligandos , Estructura MolecularRESUMEN
Copper(II) complexes of bis(pyrazol-1-yl)- and bis(triazol-1-yl)-acetate heteroscorpionate ligands have been synthesized. The copper(II) complexes [HC(COOH)(pzMe2)2]Cu[HC(COO)(pzMe2)2]·ClO4, [HC(COOH)(pz)2]2Cu(ClO4)2 (pzMe2 = 3,5-dimethylpyrazole; pz = pyrazole) were prepared by the reaction of Cu(ClO4)2·6H2O with bis(3,5-dimethylpyrazol-1-yl)acetic acid (HC(COOH)(pzMe2)2) and bis(pyrazol-1-yl)acetic acid (HC(COOH)(pz)2) ligands in ethanol solution. The copper(II) complex [HC(COOH)(tz)2]2Cu(ClO4)2·CH3OH (tz = 1,2,4-triazole) was prepared by the reaction of Cu(ClO4)2·6H2O with bis(1,2,4-triazol-1-yl)acetic acid (HC(COOH)(tz)2) ligand in methanol solution. The synthesized Cu(II) complexes, as well as the corresponding uncoordinated ligands, were evaluated for their cytotoxic activity in monolayer and 3D spheroid cancer cell cultures with different Pt(II)-sensitivity. The results showed that [HC(COOH)(pzMe2)2]Cu[HC(COO)(pzMe2)2]·ClO4 was active against cancer cell lines derived from solid tumors at low IC50 and this effect was retained in the spheroid model. Structure and ultra-structure changes of treated cancer cells analyzed by Transmission Electron Microscopy (TEM) highlighted the induction of a cytoplasmic vacuolization, thus suggesting paraptotic-like cancer cell death triggering.
Asunto(s)
Complejos de Coordinación/química , Pirazoles/química , Triazoles/química , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Cobre/química , Cristalografía por Rayos X , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/farmacología , Esferoides Celulares/efectos de los fármacos , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
Gold nanoparticles (AuNPs), which are strongly hydrophilic and dimensionally suitable for drug delivery, were used in loading and release studies of two different copper(I)-based antitumor complexes, namely [Cu(PTA)4]+ [BF4]- (A; PTA = 1, 3, 5-triaza-7-phosphadamantane) and [HB(pz)3Cu(PCN)] (B; HB(pz)3 = tris(pyrazolyl)borate, PCN = tris(cyanoethyl)phosphane). In the homoleptic, water-soluble compound A, the metal is tetrahedrally arranged in a cationic moiety. Compound B is instead a mixed-ligand (scorpionate/phosphane), neutral complex insoluble in water. In this work, the loading procedures and the loading efficiency of A and B complexes on the AuNPs were investigated, with the aim to improve their bioavailability and to obtain a controlled release. The non-covalent interactions of A and B with the AuNPs surface were studied by means of dynamic light scattering (DLS), UV-Vis, FT-IR and high-resolution x-ray photoelectron spectroscopy (HR-XPS) measurements. As a result, the AuNPs-A system proved to be more stable and efficient than the AuNPs-B system. In fact, for AuNPs-A the drug loading reached 90%, whereas for AuNPs-B it reached 65%. For AuNPs-A conjugated systems, a release study in water solution was performed over 4 days, showing a slow release up to 10%.
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The potent N-methyl-d-aspartate (NMDA) receptor antagonists 1-3 have been demonstrated to show antiproliferative and cytotoxic effects in MCF-7 and SKBR3 breast cancer cell lines. To improve the knowledge about the role played by the NMDA receptor in the antitumor activity of these compounds, the enantiomers of 1 were prepared and evaluated for their affinity for the phencyclidine (PCP) site of the NMDA receptor and for their cytotoxic effect in MCF-7 and SKBR3 cell lines, both expressing the NMDA receptor. The (S)-1 enantiomer, showing negligible affinity for the PCP site, exhibited antiproliferative activity higher than that of (R)-1, which instead bound the PCP site. The downregulation of NMDA GluN1 expression resulted in a decreased (S)-1-induced cytotoxicity and apoptotic cell death, unequivocally demonstrating the involvement of the NMDA receptor in the antitumor effect of this compound. Due to its interesting biological profile, (S)-1 represents a lead compound to develop novel antitumor agents for breast cancer treatment.
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Copper(I) and copper(II) complexes of 5-nitroimidazole conjugated heteroscorpionate ligands have been synthesized. In particular, the new 2,2-bis(pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (LHMN) was synthesized by direct coupling of preformed side chain acid with 5-nitroimidazole and its coordination chemistry was investigated towards Cu(I) and Cu(II) acceptors and compared with that of the related 2,2-bis(3,5-dimethyl-1-H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (LMeMN). The copper(II) complexes {[(LMeMN)2Cu]Cl2} and {[(LHMN)2Cu]Cl2} were prepared by the reaction of CuCl2·2H2O with LHMN or LMeMN ligands in methanol solution. The water soluble copper(I) complexes {[(LMeMN)Cu(PTA)2]}(PF6) and {[(LHMN)Cu(PTA)2]}(PF6) were prepared by the reaction of Cu(CH3CN)4PF6 and 1,3,5-triaza-7-phosphaadamantane (PTA) with LHMN or LMeMN ligands in acetonitrile solution. The new Cu(I) and Cu(II) complexes as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity against 2D monolayer cultures of multiple human cancer cell lines and 3D-cultured HCT-15 colon cancer spheroids. Morphological analysis by Transmission Electron Microscopy (TEM) revealed the induction of a massive cytoplasmic vacuolization consistent with a paraptotic-like cancer cell death.
Asunto(s)
Antineoplásicos , Neoplasias del Colon , Complejos de Coordinación , Cobre , Nitroimidazoles , Células A549 , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Cobre/química , Cobre/farmacología , Humanos , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Nitroimidazoles/química , Nitroimidazoles/farmacología , SolubilidadRESUMEN
Within the research field of antitumor metal-based agents alternative to platinum drugs, gold(I/III) coordination complexes have always been in the forefront due mainly to the familiarity of medicinal chemists with gold compounds, whose application in medicine goes back in the ancient times, and to the rich chemistry shown by this metal. In the last decade, N-heterocyclic carbene ligands (NHC), a class of ligands that largely resembles the chemical properties of phosphines, became of interest for gold(I) medicinal applications, and since then, the research on NHC-gold(I/III) coordination complexes as potential antiproliferative agents boosted dramatically. Different classes of gold(I/III)-NHC complexes often showed an outstanding in vitro antiproliferative activity, however up to now very few in vivo data have been reported to corroborate the in vitro results. This review summarizes all achievements in the field of gold (I/III) complexes comprising NHC ligands proposed as potential antiproliferative agents in the period 2004-2016, and critically analyses biological data (mainly IC50 values) in relation to the chemical structures of Au compounds. The state of art of the in vivo studies so far described is also reported.
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Antineoplásicos/farmacología , Oro/farmacología , Compuestos Heterocíclicos/farmacología , Metano/análogos & derivados , Animales , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Oro/química , Compuestos Heterocíclicos/química , Humanos , Metano/química , Metano/farmacología , Estructura Molecular , Relación Estructura-ActividadRESUMEN
[Cu(thp)4][PF6] (HydroCuP) is a phosphino copper(I) complex highly soluble and stable in physiological media that has been developed as a possible viable alternative to platinum-based drugs for anticancer therapy. HydroCuP potently inhibited the growth of human cancer cells derived from solid tumors by inducing endoplasmatic reticulum (ER) stress thus leading to cell death through paraptosis with a preferential efficacy against cancer rather than non-cancer cells. Aim of the present study was to assess the therapeutic potential of HydroCuP in vivo, in syngenic and xenograft murine models of solid tumors by triggering the Unfolded Protein Response (UPR) pathway. With respect to platinum drugs, HydroCuP induced a markedly higher reduction of tumor growth associated with minimal animal toxicity. In human colorectal cancer xenografts, chemotherapy with HydroCuP was extremely effective in both oxaliplatin-sensitive and resistant models. The favorable in vivo tolerability of HydroCuP was also correlated to an encouraging biodistribution profile. Additionally, no signs of drug-related neurotoxicity and nephrotoxicity were observed. Altogether, these results demonstrate that HydroCuP appears worth of further investigation to evaluate its therapeutic activity towards a broad spectrum of solid malignancies.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Cobre/química , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Fosfinas/química , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica , Resistencia a Antineoplásicos/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Ratones , Compuestos Organometálicos/efectos adversos , Compuestos Organometálicos/farmacocinética , Distribución Tisular , Respuesta de Proteína Desplegada/efectos de los fármacosRESUMEN
The water soluble phosphane complexes [M(L)4]PF6 (M=Cu(I), Ag(I)) and [Au(L)4]Cl (L=thp (tris(hydroxymethyl)phosphane) or PTA (1,3,5-triaza-7-phosphaadamantane)) showed notable in vitro activity against Plasmodium early sporogonic stages, the sexual forms of the malaria parasite that are responsible for infection of the mosquito vector. Effects varied according to both, the type of metal and phosphane ligands. [Ag(thp)4]PF6 was the best performing complex exhibiting a half inhibitory concentration (IC50) value in the low micromolar range (0.3-15.6µM). The silver complex [Ag(thp)4]PF6 was characterized by X-ray crystallography revealing that the structure comprises the cationic complex [Ag(thp)4]+, the PF6- anion, and a water molecule of crystallization. Our results revealed that Cu(I), Ag(I) and Au(I) phosphanes complexes elicited similar activity profiles showing potential for the development of antimalarial, transmission blocking compounds. Molecules targeting the sexual parasite stages in the human and/or mosquito host are urgently needed to complement current artemisinin based treatments and next generation antimalarials in a vision not only to cure the disease but to interrupt its transmission.