Ru(II)-Arene Complexes of Curcumin and Bisdesmethoxycurcumin Metabolites.

Curcuminoids and their complexes continue to attract attention in medicinal chemistry, but little attention has been given to their metabolic derivatives. Here, the first examples of (arene)Ru(II) complexes with curcuminoid metabolites, tetrahydrocurcumin (THcurcH), and tetrahydrobisdesmethoxycurcumin (THbdcurcH) were prepared and characterized. The neutral complexes [Ru(arene)(THcurc)Cl] and [Ru(arene)(THbdcurc)Cl] (arene = cymene, benzene, or hexamethylbenzene) were characterized by NMR spectroscopy and ESI mass spectrometry, and the crystal structures of the three complexes were determined by X-ray diffraction analysis. Compared to curcuminoids, these metabolites lose their conjugated double bond system responsible for their planarity, showing unique closed conformation structures. Both closed and open conformations have been analyzed and rationalized by using density functional theory (DFT). The cytotoxicity of the complexes was evaluated in vitro against human ovarian carcinoma cells (A2780 and A2780cisR), human breast adenocarcinoma cells (MCF-7 and MCF-7CR), as well as against non-tumorigenic human embryonic kidney cells (HEK293) and human breast (MCF-10A) cells and compared to the free ligands, cisplatin, and RAPTA-C. There is a correlation between cellular uptake and the cytotoxicity of the compounds, suggesting that cellular uptake and binding to nuclear DNA may be the major pathway for cytotoxicity. However, the levels of complex binding to DNA do not strictly correlate with the cytotoxic potency, indicating that other mechanisms are also involved. In addition, treatment of MCF-7 cells with [Ru(cym)(THcurc)Cl] showed a significant decrease in p62 protein levels, which is generally assumed as a noncisplatin-like mechanism of action involving autophagy. Hence, a cisplatin- and a noncisplatin-like concerted mechanism of action, involving both apoptosis and autophagy, is possible.

Copper and Zinc Metal-Organic Frameworks with Bipyrazole Linkers Display Strong Antibacterial Activity against Both Gram+ and Gram- Bacterial Strains.

Here, we report a new synthetic protocol based on microwave-assisted synthesis (MAS) for the preparation of higher yields of zinc and copper in MOFs based on different bis(pyrazolyl)-tagged ligands ([M(BPZ)]n where M = Zn(II), Cu(II), H2BPZ = 4,4'-bipyrazole, [M(BPZ-NH2)]n where M = Zn(II), Cu(II); H2BPZ-NH2 = 3-amino-4,4'-bipyrazole, and [Mx(Me4BPZPh)] where M = Zn(II), x = 1; Cu(II), x = 2; H2Me4BPZPh = bis-4'-(3',5'-dimethyl)-pyrazolylbenzene) and, for the first time, a detailed study of their antibacterial activity, tested against Gram-negative (E. coli) and Gram-positive (S. aureus) bacteria, as representative agents of infections. The results show that all MOFs exert a broad-spectrum activity and strong efficiency in bacterial growth inhibition, with a mechanism of action based on the surface contact of MOF particles with bacterial cells through the so-called "chelation effect" and reactive oxygen species (ROS) generation, without a significant release of Zn(II) and Cu(II) ions. In addition, morphological changes were elucidated by using a scanning electron microscope (SEM) and bacterial cell damage was further confirmed by a confocal laser scanning microscopy (CLSM) test.

Zinc(II) Complex with Pyrazolone-Based Hydrazones is Strongly Effective against Trypanosoma brucei Which Causes African Sleeping Sickness.

Two pyrazolone-based hydrazones H2L' [in general, H2L'; in detail, H2L1 = 5-methyl-2-phenyl-4-(2-phenyl-1-(2-(4-(trifluoromethyl)phenyl)hydrazineyl)ethyl)-2,4-dihydro-3H-pyrazol-3-one, H2L2 = (Z)-5-methyl-2-phenyl-4-(2-phenyl-1-(2-(pyridin-2-yl)hydrazineyl)ethylidene)-2,4-dihydro-3H-pyrazol-3-one] were reacted with Zn(II) and Cu(II) acceptors affording the complexes [Zn(HL1)2(MeOH)2], [Cu(HL1)2], and [M(HL2)2] (M = Cu or Zn). X-ray and DFT studies showed the free proligands to exist in the N-H,N-H tautomeric form and that in [Zn(HL1)2(MeOH)2], zinc is six-coordinated by the N,O-chelated (HL1) ligand and other two oxygen atoms of coordinated methanol molecules, while [Cu(HL1)2] adopts a square planar geometry with the two (HL1) ligands in anti-conformation. Finally, the [M(HL2)2] complexes are octahedral with the two (HL2) ligands acting as κ-O,N,N-donors in planar conformation. Both the proligands and metal complexes were tested against the parasite Trypanosoma brucei and Balb3T3 cells. The Zn(II) complexes were found to be very powerful, more than the starting proligands, while maintaining a good safety level. In detail, H2L1 and its Zn(II) complex have high selective index (55 and >100, respectively) against T. brucei compared to the mammalian Balb/3T3 reference cells. These results encouraged the researchers to investigate the mechanism of action of these compounds that have no structural relations with the already known drugs used against T. brucei. Interestingly, the analysis of NTP and dNTP pools in T. brucei treated by H2L1 and its Zn(II) complex showed that the drugs had a strong impact on the CTP pools, making it likely that CTP synthetase is the targeted enzyme.

Enhancing the Amyloid-ß Anti-Aggregation Properties of Curcumin via Arene-Ruthenium(II) Derivatization.

Alzheimer's disease (AD) is a fatal neurodegenerative disorder associated with severe dementia, progressive cognitive decline, and irreversible memory loss. Although its etiopathogenesis is still unclear, the aggregation of amyloid-ß (Aß) peptides into supramolecular structures and their accumulation in the central nervous system play a critical role in the onset and progression of the disease. On such a premise, the inhibition of the early stages of Aß aggregation is a potential prevention strategy for the treatment of AD. Since several natural occurring compounds, as well as metal-based molecules, showed promising inhibitory activities toward Aß aggregation, we herein characterized the interaction of an organoruthenium derivative of curcumin with Aß(1-40) and Aß(1-42) peptides, and we evaluated its ability to inhibit the oligomerization/fibrillogenesis processes by combining in silico and in vitro methods. In general, besides being less toxic to neuronal cells, the derivative preserved the amyloid binding ability of the parent compound in terms of equilibrium dissociation constants but (most notably) was more effective both in retarding the formation and limiting the size of amyloid aggregates by virtue of a higher hindering effect on the amyloid-amyloid elongation surface. Additionally, the complex protected neuronal cells from amyloid toxicity.

Ligand Design for N, O- or N, N-Pyrazolone-Based Hydrazones Ruthenium(II)-Arene Complexes and Investigation of Their Anticancer Activity.

Three pyrazolone-based hydrazone ligands HL' (HL' in general; in detail, HL1 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl)(phenyl)methylene)-1-(2,4-nitrophenyl)hydrazine, HL2 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl) (phenyl)methylene)-1-(4-nitrophenyl)hydrazine, and HL3 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl)(phenyl)methylene)-1-(pyridin-2-yl)hydrazine) have been prepared starting from 4-benzoyl-3-methyl-1-phenyl-1 H-pyrazol-5(4 H)-one and fully characterized in the solid state and solution, where the existing tautomeric forms were identified by taking advantage of natural abundance 1H-15N coupling in {1H-15N}-HSQC and {1H-15N}-HMBC NMR spectroscopy. Then, six half-sandwich arene-ruthenium(II) derivatives (arene = hexamethylbenzene and p-cymene) of composition [(arene)Ru(L')Cl] have been synthesized and fully characterized by IR, 1H, and 13C NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis, and density functional theory calculations. The crystal structures of three complexes, together with the E configurational isomer (with respect to the C═N double bond) of the free proligand HL2 and the zwitterionic proligand HL3 were determined by X-ray analysis. The anionic ligands L1 and L2 were found bonded to ruthenium in the N,O-form, while L3 coordinates the metal in the N,N-form affording five-membered chelating rings. The cytotoxicity of the complexes was evaluated against human breast adenocarcinoma cells (MCF-7 and MCF-7CR), as well as against nontumorigenic human breast (MCF-10A) cells and compared to the free ligand and cisplatin.

Cytotoxic Half-Sandwich Rh(III) and Ir(III) ß-Diketonates.

A series of half-sandwich pentamethylcyclopentadienyl rhodium(III) and iridium(III) complexes [Cp*M(DBM/HDB/AVB)Cl] and [Cp*M(DBM/HDB/AVB)(PTA)][SO3CF3], where Cp* = pentamethylcyclopentadienyl, the proligands DBMH = dibenzoylmethane, HDBH = o-hydroxydibenzoylmethane, AVBH = avobenzone, and PTA = 1,3,5-triaza-7-phosphaadamantane, is reported. All the complexes were characterized by IR, 1H and 13C NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis, and DFT calculations. Five of the complexes have also been characterized in the solid-state by X-ray crystallography. The cytotoxicity of the complexes has been evaluated against human ovarian A2780 and A2780cisR cell lines and, with the only exception of complexes 1 and 2 that display a negligible cytotoxicity, exhibit moderate cytotoxicity toward both cancer cell lines. However, the complexes do not show cancer cell selectivity with respect to human embryonic kidney HEK293 cells.

The water soluble ruthenium(II) organometallic compound [Ru(p-cymene)(bis(3,5 dimethylpyrazol-1-yl)methane)Cl]Cl suppresses triple negative breast cancer growth by inhibiting tumor infiltration of regulatory T cells.

Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favorable toxicity and clearance properties. Here, we show that the ruthenium(II) complex [Ru(p-cymene)(bis(3,5-dimethylpyrazol-1-yl)methane)Cl]Cl (UNICAM-1) exhibits potent in vivo antitumor effects. When administered as four-dose course, by repeating a single dose (52.4mgkg-1) every three days, UNICAM-1 significantly reduces the growth of A17 triple negative breast cancer cells transplanted into FVB syngeneic mice. Pharmacokinetic studies indicate that UNICAM-1 is rapidly eliminated from kidney, liver and bloodstream thanks to its high hydrosolubility, exerting excellent therapeutic activity with minimal side effects. Immunohistological analysis revealed that the efficacy of UNICAM-1, mainly relies on its capacity to reverse tumor-associated immune suppression by significantly reducing the number of tumor-infiltrating regulatory T cells. Therefore, UNICAM-1 appears very promising for the treatment of TNBC.

Linkage Isomerism in Silver Acylpyrazolonato Complexes and Correlation with Their Antibacterial Activity.

Novel silver(I) acylpyrazolonato coordination polymers of formula [Ag(Q(R))]n (1-3) have been synthesized by interaction of silver nitrate with HQ(R) in methanol in the presence of an equivalent quantity of KOH (in general HQ(R) = 1-phenyl-3-methyl-4-RC(═O)-5-pyrazolone, in detail HQ(fb), R = -CF2CF2CF3; HQ(cy), R = -cyclo-C6H11; HQ(be), R = -C(H)═C(CH3)2). [Ag(Q(R))]n react with 2-ethylimidazole (2EtimH), 1-methylimidazole (Meim), and triphenylphosphine (PPh3), affording the mononuclear Ag(Q(fb))(EtimH) (4), Ag(Q(cy))(Meim)2 (5), Ag(Q(be))(Meim) (6), and Ag(Q(R))(PPh3)2 (7-9). All complexes have been analytically and spectroscopically characterized, and for some of them the X-ray crystal structure has been resolved. In particular, the single crystal molecular structure determination of Ag(Q(fb))(EtimH) and Ag(Q(be))(PPh3)2 has confirmed the different coordination modes of the HQ(fb) and HQ(be) acylpyrazolone ligands, the former being bound to the silver(I) ion in a monodentate fashion while the latter in the O2-chelating mode. Density functional theory computations suggest new insights about metal-ligand interactions and the observed linkage isomerism. While phosphine-containing complexes Ag(Q(R))(PPh3)2 (7-9) seem not to be able to efficiently inhibit the growth of Escherichia coli and Staphylococcus aureus, the polynuclear complexes [Ag(Q(R))]n (1-3) and the mononuclear Ag(Q(fb))(EtimH) (4), Ag(Q(cy))(Meim)2 (5), and Ag(Q(be))(Meim) (6) show a high and almost steady in time antibacterial activity, comparable to that of AgNO3. This activity is likely related to the degree of saturation of the silver center and to the presence of different ancillary ligands in the diverse typologies of complexes.

Synthesis, Structure, and Anticancer Activity of Arene-Ruthenium(II) Complexes with Acylpyrazolones Bearing Aliphatic Groups in the Acyl Moiety.

A series of neutral ruthenium(II) arene complexes [(arene)Ru(QR)Cl] (arene = p-cymene (cym) or hexamethylbenzene (hmb)) containing 4-acyl-5-pyrazolonate QR ligands with different electronic and steric substituents (R = 4-cyclohexyl, 4-stearoyl, or 4-adamantyl) and related ionic complexes [(arene)Ru(QR)(PTA)][PF6] (PTA = 1,3,5-triaza-7-phosphaadamantane) were synthesized and characterized by spectroscopy (IR, UV-vis, ESI-MS, and 1H and 13C NMR), elemental analysis, X-ray crystallography, and density functional theory studies. The cytotoxicity of the proligands and metal complexes was evaluated in vitro against human ovarian carcinoma cells (A2780 and A2780cisR), as well as against nontumorous human embryonic kidney (HEK293) cells. In general the cationic PTA-containing complexes are more cytotoxic than their neutral precursors with a chloride ligand in place of the PTA. Moreover, the complexes do not show cross-resistance and are essentially equally cytotoxic to both the A2780 and A2780cisR cell lines, although they only show limited selectivity toward the cancer cell lines.

Novel composite plastics containing silver(I) acylpyrazolonato additives display potent antimicrobial activity by contact.

New silver(I) acylpyrazolonato derivatives displaying a mononuclear, polynuclear, or ionic nature, as a function of the ancillary azole ligands used in the synthesis, have been fully characterized by thermal analysis, solution NMR spectroscopy, solid-state IR and NMR spectroscopies, and X-ray diffraction techniques. These derivatives have been embedded in polyethylene (PE) matrix, and the antimicrobial activity of the composite materials has been tested against three bacterial strains (E. coli, P. aeruginosa, and S. aureus): Most of the composites show antimicrobial action comparable to PE embedded with AgNO3 . Tests by contact and release tests for specific migration of silver from PE composites clearly indicate that, at least in the case of the PE, for composites containing polynuclear silver(I) additives, the antimicrobial action is exerted by contact, without release of silver ions. Moreover, PE composites can be re-used several times, displaying the same antimicrobial activity. Membrane permeabilization studies and induced reactive oxygen species (ROS) generation tests confirm the disorganization of bacterial cell membranes. The cytotoxic effect, evaluated in CD34(+) cells by MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazoliumbromide) and CFU (colony forming units) assays, indicates that the PE composites do not induce cytotoxicity in human cells. Studies of ecotoxicity, based on the test of Daphnia magna, confirm tolerability of the PE composites by higher organisms and exclude the release of Ag(+) ions in sufficient amounts to affect water environment.

New RuII (arene) complexes with halogen-substituted bis- and tris(pyrazol-1-yl)borate ligands.

[RuCl(arene)(µ-Cl)]2 dimers were treated in a 1:2 molar ratio with sodium or thallium salts of bis- and tris(pyrazolyl)borate ligands [Na(Bp(Br3))], [Tl(Tp(Br3))], and [Tl(Tp(iPr, 4Br))]. Mononuclear neutral complexes [RuCl(arene)(κ(2)-Bp(Br3))] (1: arene=p-cymene (cym); 2: arene=hexamethylbenzene (hmb); 3: arene=benzene (bz)), [RuCl(arene)(κ(2)-Tp(Br3))] (4: arene=cym; 6: arene=bz), and [RuCl(arene)(κ(2)-Tp(iPr, 4Br))] (7: arene=cym, 8: arene=hmb, 9: arene=bz) have been always obtained with the exception of the ionic [Ru2 (hmb)2-(µ-Cl)3][Tp(Br3)] (5'), which formed independently of the ratio of reactants and reaction conditions employed. The ionic [Ru-(CH3OH)(cym)(κ(2)-Bp(Br3))][X] (10: X=PF6, 12: X=O3SCF3) and the neutral [Ru(O2CCF3)(cym)(κ(2)-Bp(Br3))] (11) have been obtained by a metathesis reaction with corresponding silver salts. All complexes 1-12 have been characterized by analytical and spectroscopic data (IR, ESI-MS, (1)H and (13)C NMR spectroscopy). The structures of the thallium and calcium derivatives of ligand Tp(Br3), [Tl(Tp(Br3))] and [Ca(dmso)6][Tp(Br3)]2 ⋅2 DMSO, of the complexes 1, 4, 5', 6, 11, and of the decomposition product [RuCl(cym)(Hpz(iPr, 4Br))2][Cl] (7') have been confirmed by using single-crystal X-ray diffraction. Electrochemical studies showed that 1-9 and 11 undergo a single-electron Ru(II) →Ru(III) oxidation at a potential, measured by cyclic voltammetry, which allows comparison of the electron-donor characters of the bis- and tris(pyrazol-1-yl)borate and arene ligands, and to estimate, for the first time, the values of the Lever EL ligand parameter for Bp(Br3), Tp(Br3), and Tp(iPr, 4Br). Theoretical calculations at the DFT level indicated that both oxidation and reduction of the Ru complexes under study are mostly metal-centered with some involvement of the chloride ligand in the former case, and also demonstrated that the experimental isolation of the µ(3)-binuclear complex 5' (instead of the mononuclear 5) is accounted for by the low thermodynamic stability of the latter species due to steric reasons.

Synthesis, structure, and antiproliferative activity of ruthenium(II) arene complexes with N,O-chelating pyrazolone-based ß-ketoamine ligands.

Novel ruthenium half-sandwich complexes containing (N,O)-bound pyrazolone-based ß-ketoamine ligands have been prepared, and the solid-state structures of one ligand and five complexes have been determined by single-crystal X-ray diffraction. Some of the complexes display moderate cytotoxicity toward the human ovarian cancer cell lines A2780 and A2780cisR, the latter line having acquired resistance to cisplatin.

Synthesis, characterization, and antitumor activity of water-soluble (arene)ruthenium(II) derivatives of 1,3-dimethyl-4-acylpyrazolon-5-ato ligands. First example of Ru(arene)(ligand) antitumor species involving simultaneous Ru-N7(guanine) bonding and ligand intercalation to DNA.

We report on the synthesis of novel water-soluble [(arene)Ru(II)(Q)Cl] and [(arene)Ru(II)(Q)(X)]BF4 compounds (arene = p-cymene, benzene, hexamethylbenzene; HQ = 1,3-dimethyl-4-R-(C═O)-5-pyrazolone, HQ(Me), R = methyl, HQ(Ph), R = phenyl, HQ(Naph), R = naphthyl; X = H2O, 9-ethylguanine), and their in vitro antitumor activity toward the cell lines MCF7 (HTB-22, human breast adenocarcinoma), HCT116 (CCL-247, human colorectal carcinoma), A2780 (human ovarian carcinoma), A549 (CCL-185, human lung carcinoma), and U87 MG (HTB-1, human glioblastoma). The X-ray crystal structures of two complexes were determined. One of them, {chlorido-(p-cymene)-[(1,3-dimethyl-4-(1-naphthoyl)-pyrazolon-5-ato]ruthenium(II)}, was also studied with density functional theory methods and was selected for docking on a DNA octamer showing intercalation between DNA bases by the naphthyl moiety and for Ru-N7(guanine) bonding.

NRF2 activation in BON­1 neuroendocrine cancer cells reduces the cytotoxic effects of a novel Ruthenium(II)­curcumin compound: A pilot study.

Gastroenteropancreatic neuroendocrine neoplasms (GEP­NEN) are a group of rare tumors whose specific pathogenetic mechanisms of resistance to therapies have not been completely revealed yet. Chemotherapy is the main therapeutic approach in patients with GEP­NEN, however, novel combination regimens and targeted therapy are continuously explored. In the present study, the anticancer effect of a novel Ruthenium (Ru)(II)­Bisdemethoxycurcumin (Ru­bdcurc) compound was evaluated in BON­1 cell line, one of the few cell lines derived from GEP­NEN, largely used in experimental research of this type of tumors. The experimental data revealed that the Ru­bdcurc compound induced cell death in a dose­dependent manner, in vitro. Biochemical studies demonstrated that, in response to the lower dose of treatment, BON­1 cells activated the nuclear factor erythroid 2­related factor 2 (NRF2) pathway with induction of some of its targets including catalase and p62 as well as of the antiapoptotic marker Bcl2, all acting as chemoresistance mechanisms. NRF2 induction associated also with increased expression of endogenous p53 which is reported to be dysfunctional in BON­1 cells and to inhibit apoptosis. Genetic or pharmacologic targeting of NRF2 inhibited the activation of the NRF2 pathway, as well as of endogenous dysfunctional p53, in response to the lower dose of Ru­bdcurc, increasing the cell death. To assess the interplay between NRF2 and dysfunctional p53, genetic targeting of p53 showed reduced activation of the NRF2 pathway in response to the lower dose of Ru­bdcurc, increasing the cell death. These findings identified for the first time a possible dysfunctional p53/NRF2 interplay in BON­1 cell line that can be a novel key determinant in cell resistance to cytotoxic agents to be evaluated also in GEP­NEN.

Halogen-Decorated Metal-Organic Frameworks for Efficient and Selective CO2 Capture, Separation, and Chemical Fixation with Epoxides under Mild Conditions.

In the present work, three novel halogen-appended cadmium(II) metal-organic frameworks [Cd2(L1)2(4,4'-Bipy)2]n·4n(DMF) (1), [Cd2(L2)2(4,4'-Bipy)2]n·3n(DMF) (2), and [Cd(L3)(4,4'-Bipy)]n·2n(DMF) (3) [where L1 = 5-{(4-bromobenzyl)amino}isophthalate; L2 = 5-{(4-chlorobenzyl)amino}isophthalate; L3 = 5-{(4-fluorobenzyl)amino}isophthalate; 4,4'-Bipy = 4,4'-bipyridine; and DMF = N,N'-dimethylformamide] have been synthesized under solvothermal conditions and characterized by various analytical techniques. The single-crystal X-ray diffraction analysis demonstrated that all the MOFs feature a similar type of three-dimensional structure having a binuclear [Cd2(COO)4(N)4] secondary building block unit. Moreover, MOFs 1 and 2 contain one-dimensional channels along the b-axis, whereas MOF 3 possesses a 1D channel along the a-axis. In these MOFs, the pores are decorated with multifunctional groups, i.e., halogen and amine. The gas adsorption analysis of these MOFs demonstrate that they display high uptake of CO2 (up to 5.34 mmol/g) over N2 and CH4. The isosteric heat of adsorption (Qst) value for CO2 at zero loadings is in the range of 18-26 kJ mol-1. In order to understand the mechanism behind the better adsorption of CO2 by our MOFs, we have also performed configurational bias Monte Carlo simulation studies, which confirm that the interaction between our MOFs and CO2 is stronger compared to those with N2 and CH4. Various noncovalent interactions, e.g., halogen (X)···O, Cd···O, and O···O, between CO2 and the halogen atom, the Cd(II) metal center, and the carboxylate group from the MOFs are observed, respectively, which may be a reason for the higher carbon dioxide adsorption. Ideal adsorbed solution theory (IAST) calculations of MOF 1 demonstrate that the obtained selectivity values for CO2/CH4 (50:50) and CO2/N2 (15:85) are ca. 28 and 193 at 273 K, respectively. However, upon increasing the temperature to 298 K, the selectivity value (S = 34) decreases significantly for the CO2/N2 mixture. We have also calculated the breakthrough analysis curves for all the MOFs using mixtures of CO2/CH4 (50:50) and CO2/N2 (50:50 and 15:85) at different entering gas velocities and observed larger retention times for CO2 in comparison with other gases, which also signifies the stronger interaction between our MOFs and CO2. Moreover, due to the presence of Lewis acidic metal centers, these MOFs act as heterogeneous catalysts for the CO2 fixation reactions with different epoxides in the presence of tetrabutyl ammonium bromide (TBAB), for conversion into industrially valuable cyclic carbonates. These MOFs exhibit a high conversion (96-99%) of epichlorohydrin (ECH) to the corresponding cyclic carbonate 4-(chloromethyl)-1,3-dioxolan-2-one after 12 h of reaction time at 1 bar of CO2 pressure, at 65 °C. The MOFs can be reused up to four cycles without compromising their structural integrity as well as without losing their activity significantly.

NRF2 and Bip Interconnection Mediates Resistance to the Organometallic Ruthenium-Cymene Bisdemethoxycurcumin Complex Cytotoxicity in Colon Cancer Cells.

Organometallic ruthenium (Ru)(II)-cymene complexes display promising pharmacological properties and might represent alternative therapeutic agents in medical applications. Polyphenols, such as curcumin and curcuminoids, display beneficial properties in medicine, including chemoprevention. Here we analyzed the anticancer effect of a cationic Ruthenium (Ru)(II)-cymene Bisdemethoxycurcumin (Ru-bdcurc) complex. The experimental data show that Ru-bdcurc induced cell death of colon cancer cells in vitro. In response to treatment, cancer cells activated the endoplasmic reticulum (ER)-resident chaperone GRP78/BiP and NRF2, the master regulators of the unfolded protein response (UPR) and the antioxidant response, respectively. Pharmacologic targeting of either NRF2 or BiP potentiated the cytotoxic effect of Ru-bdcurc. We also found that NRF2 and UPR pathways were interconnected as the inhibition of NRF2 reduced BiP protein levels. Mechanistically, the increased Ru-bdcurc-induced cell death, following NRF2 or BiP inhibition, correlated with the upregulation of the UPR apoptotic marker CHOP and with increased H2AX phosphorylation, a marker of DNA damage. The findings reveal that BiP and NRF2 interconnection was a key regulator of colon cancer cells resistance to Ru-bdcurc cytotoxic effect. Targeting that interconnection overcame the protective mechanism and enhanced the antitumor effect of the Ru-bdcurc compound.

Multitarget-Directed Gallium(III) Tris(acyl-pyrazolonate) Complexes Induce Ferroptosis in Cancer Cells via Dysregulation of Cell Redox Homeostasis and Inhibition of the Mevalonate Pathway.

A series of Ga(Qn)3 coordination compounds have been synthesized, where HQn is 1-phenyl-3-methyl-4-RC(═O)-pyrazolo-5-one. The complexes have been characterized through analytical data, NMR and IR spectroscopy, ESI mass spectrometry, elemental analysis, X-ray crystallography, and density functional theory (DFT) studies. Cytotoxic activity against a panel of human cancer cell lines was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, with interesting results in terms of both cell line selectivity and toxicity values compared with cisplatin. The mechanism of action was explored by spectrophotometric, fluorometric, chromatographic, immunometric, and cytofluorimetric assays, SPR biosensor binding studies, and cell-based experiments. Cell treatment with gallium(III) complexes promoted several cell death triggering signals (accumulation of p27, PCNA, PARP fragments, activation of the caspase cascade, and inhibition of the mevalonate pathway) and induced changes in cell redox homeostasis (decreased levels of GSH/GPX4 and NADP(H), increased reactive oxygen species (ROS) and 4-hydroxynonenal (HNE), mitochondrial damage, and increased activity of CPR and CcO), identifying ferroptosis as the mechanism responsible for cancer cell death.

Electrochemical aptasensing strategy based on a multivariate polymertitanium-metal-organic framework for zearalenone analysis.

An electrochemical aptasensing strategy was developed with a novel bioplatform based on a multivariate titanium metal-organic framework, i.e. MTV polyMOF(Ti), to detect zearalenone (ZEN). MTV polyMOF(Ti) was prepared by using mixed linkers of polyether polymer (pbdc-xa or L8, pbdc = poly(1,4-benzenedicarboxylate) and 1,4-benzenedicarboxylic acid (H2bdc or L0) as well as tetrabutyl titanate as nodes (MTV polyMOF(Ti)-L8,0). Compared with Ti-MOFs synthesized by using the single ligand of L8 or L0, MTV polyMOF(Ti)-L8,0 shows more porous structure assembled with multilayered nanosheets. In light of the improved electrochemical activity and strong bioaffinity to the aptamer, the aptasensor based on MTV polyMOF(Ti)-L8,0 shows excellent performance for detecting ZEN with the ultralow detection limit at fg mL-1 level in the linear range of 10 fg mL-1 to 10 ng mL-1, along with good selectivity, reproducibility, stability, regenerability, and applicability.

Potent and selective anticancer activity of half-sandwich ruthenium and osmium complexes with modified curcuminoid ligands.

We have recently reported a series of half-sandwich ruthenium(II) complexes with curcuminoid ligands showing excellent cytotoxic activities (particularly ionic derivatives containing PTA (PTA = 1,3,5-triaza-7-phosphaadamantane). In the present study, new members of this family of compounds have been prepared with the objective to investigate the effect of a long hydrophobic chain obtained by replacing the OH-groups, present in curcumin and bisdemethoxycurcumin, with the palmitic acid ester. We report the synthesis of ruthenium(II) and osmium(II) p-cymene derivatives containing palmitic acid curcumin ester ligands ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-methoxy-4,1-phenylene)dipalmitate (p-curcH) and ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(4,1-phenylene)dipalmitate (p-bdcurcH). Complexes [M(II)(cym)(p-curc)/(p-bdcurc)(Cl)] 1-4 (M = Ru or Os) are neutral, whereas [M(II)(cym)(p-curc)/(p-bdcurc)(PTA)][SO3CF3] 5-8 are salts obtained when the chloride ligand is replaced by the PTA ligand. Stability studies performed on 1-8 in DMSO-PBS under physiological conditions (pH = 7.4) indicate that the complexes remain intact. The complexes exhibit potent and selective cytotoxic activity against an ovarian carcinoma cell line and its cisplatin-resistant form (A2780 and A2780cis), and non-cancerous human embryonic kidney (HEK293T) cells. To define the structure-activity relationships (SAR), the compounds have been compared with other Ru(II) and Os(II) complexes with curcuminoid ligands previously reported. SAR data reveal that the bisdemethoxycurcumin complexes are generally more active and selective than analogous curcumin-containing complexes.

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.