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Photodynamic therapy (PDT) is a medicinal tool that uses a photosensitiser and a light source to treat several conditions, including cancer. PDT uses reactive oxygen species (ROS) such as cytotoxic singlet oxygen (1 O2 ) to induce cell death in cancer cells. Chemotherapy has historically utilized the cytotoxic effects of many metals, especially transition-metal complexes. However, chemotherapy is a systemic treatment so all cells in a patient's body are exposed to the same cytotoxic effects. Transition metal complexes have also shown high cytotoxicity as PDT agents. PDT is a potential localized method for treating several cancer types by using inorganic complexes as photosensitizing agents. This review covers several in vitro and in vivo studies, as well as clinical trials that reported on the anti-cancer properties of inorganic pharmaceuticals used in PDT against different types of cancer.

Background and Purpose: Copper is a crucial structural component for many significant enzymes, as well as a key catalytic co-factor in redox processes. The flexible Cu(I/II) redox behavior facilitates the formation of copper complexes that are more potent and less toxic. The anticancer activity of several agents can be enhanced by forming copper complexes. The purpose of this study is to evaluate the anti-proliferative effects of two copper (II) complexes, copper-tolfenamic acid (Cu-TA) and copper thiosemicarbazone (Cu-acetylethTSC or CuTSC) against medulloblastoma (MB). MB is a cancer of the cerebellum which is associated with frequent relapse and drug resistance with the current treatments. It necessitates the development of alternative strategies. The anti-cancer activity of Cu-TA was evaluated in laboratory testing in some cancer models, but it has not been studied in MB. CuTSC against colorectal cancer, leukemia and breast cancer has been studied but it has not in MB. Methods: TA and TSC were complexed with Cu and Cu-TA and CuTSC complexes were characterized through colorimetric/mass spectrometric analyses. Cancer cells and cardiomyocytes were cultured using standard protocols and cell viability was measured using Cell Titer-Glo kit (Promega). Protein expression was determined by Western blot analysis. Experiments/Results: CuTA and CuTSC complexes showed proper characterization and stability during the testing period. Cardiomyocytes (H9C2) and human cancer cell lines representing breast, Ewing sarcoma and MB were screened for anti-proliferative activity of these two Cu complexes. While, cell viability was inhibited in all cancer cell lines, MB cell lines (DAOY and D283) showed higher efficacy while H9C2 cell viability was not affected. To understand the underlying mechanism of action, the effect of Cu-TA was assessed on the expression of c-PARP, Specificity protein 1 (Sp1) and an antiapoptotic protein, survivin. Western blot results revealed a clear decrease in the expression of both Sp1 and survivin and upregulation of c-PARP. Discussion/Conclusion: Both Cu-TA and CuTSC treatments result in a dose-time dependent anti-proliferative activity against cancer cells but not affecting non-malignant cardiomyocyte cells. Cu-TA can inhibit Sp1 and survivin and increase PARP cleavage suggesting the effect on Sp1-regulated oncogenes and an induction of apoptotic pathways. The studies to establish crossing of Blood Brain Barrier and further understand the underling mechanisms of these two Cu complexes in single and combination treatment alongside chemotherapeutic agents are currently under investigation. Citation Format: Hope Korshie Fiadjoe, Christoffer Lambring, Umesh T. Sankpal, Duaa Alajroush, Alvin A. Holder, Riyaz Basha. Anti-proliferative effect of two copper complexes against medulloblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6255.

Background/Aims: Targeting survivin, an anti-apoptotic protein and mitotic regulator, is considered as an effective therapeutic option for pancreatic cancer (PaCa). Tolfenamic acid (TA) showed anti-cancer activity in pre-clinical studies. A recent discovery demonstrated a copper(II) complex of TA (Cu-TA) can result in higher activity. In this study, the ability of Cu-TA to inhibit survivin and its transcription factors, Specificity protein (Sp) 1 and 3 in PaCa cell lines and tumor growth in mouse xenograft model were evaluated. Methods: Cell growth inhibition was measured in MIA PaCa-2 and Panc1 cells for 2 days using CellTiter-Glo kit. Sp1, Sp3 and survivin expression (by Western blot and qPCR), apoptotic cells and cell cycle phase distribution (by flow cytometry) were evaluated. A pilot study was performed using athymic nude mice [treated with vehicle/Cu-TA (25 or 50 mg/kg) 3 times/week for 4 weeks. Results: The IC50 value for Cu-TA was about half than TA.Both agents repressed the protein expression of Sp1/Sp3/survivin, Cu-TA was more effective than TA. Especially effect on survivin inhibition was 5.2 (MIA PaCa-2) or 6.4 (Panc1) fold higher and mRNA expression of only survivin was decreased. Apoptotic cells increased with Cu-TA treatment in both cell lines, while Panc1 showed both effect on apoptosis and cell cycle (G2/M) arrest. Cu-TA decreased the tumor growth in mouse xenografts (25 mg/kg: 48%; 50 mg/kg: 68%). Additionally, there was no change observed in mice body weights, indicating no overt toxicity was occurring. Conclusion: These results show that Cu-TA can serve as an effective survivin inhibitor for inhibiting PaCa cell growth.

Twenty-three compounds in two series of ferrocene-based anilides, with the general formula C5H5-Fe-C5H4-C6H4-NH-CO-C6H4-R (where R = H, F, Cl, CH3 and OCH3), have been successfully synthesized. The compounds were characterized by elemental analysis and FTIR, 1H NMR and 13C NMR spectroscopy. Two compounds (M07 and P09) were characterized by X-ray crystallography. Solid state studies indicate that ferrocene derivatives with the conformation of meta amide substituents engage in intermolecular H-bonding, which stabilizes the meta derivatives over their para analogues. The H-bonding takes place when the conformation of the ferrocene changes by rotation around the C-N bond, favoring interactions between two molecules in adjacent layers in the solid state. The potential importance of this H-bonding to the biological effects of these molecules was investigated using both experimental and computational studies. All the compounds were found to inhibit butyrylcholinesterase. The most active compound shows 50% inhibition at a concentration of 9 ± 0.2 μM, similar to the known drug galantamine (with an IC50 of 8 μM). Compounds with the ferrocene moiety meta to the amide linkage were consistently found to be slightly more active than the other structural isomers, suggesting that the H-bonding may only slightly increase the overall affinity for the protein. Computational studies confirmed the limited effects of the H-bonding in the presence and absence of water in the active site of butyrylcholinesterase, supporting the importance of hydrophobicity for inhibitors of this enzyme.

Trace elements such as copper and cobalt have been associated with virus-host interactions. However, studies to show the effect of conjugation of copper(II) or cobalt(III) metal centers to thiosemicarbazone ligand(s) derived from either food additives or mosquito repellent such as 2-acetylethiazole or citral, respectively, on Zika virus (ZIKV) or dengue virus (serotype 2; DENV2) infections have not been explored. In this study, we show that four compounds comprising of thiosemicarbazone ligand derived from 2-acetylethiazole viz., (E)-N-ethyl-2-[1-(thiazol-2-yl)ethylidene]hydrazinecarbothioamide (acetylethTSC) (compound 1), a copper(II) complex with acetylethTSC as a ligand (compound 2), a thiosemicarbazone ligand-derived from citral (compound 3) and a cobalt(III) complex with a citral-thiosemicarbazone ligand (compound 4) increased DENV2 and ZIKV replication in both mosquito C6/36 cells and human keratinocytes (HaCaT cells). Treatment of both cell lines with compounds 2 or 4 showed increased dengue viral titers at all three tested doses. Enhanced dengue viral plaque formation was also noted at the tested dose of 100 μM, suggesting higher production of infectious viral particles. Treatment with the compounds 2 or 4 enhanced ZIKV and DENV2 RNA levels in HeLa cell line and primary cultures of mouse bone marrow derived dendritic cells. Also, pre- or post treatments with conjugated compounds 2 or 4 showed higher loads of ZIKV or DENV2 envelope (E) protein in HaCaT cells. No changes in loads of E-protein were found in ZIKV-infected C6/36 cells, when compounds were treated after infection. In addition, we tested bis(1,10-phenanthroline)copper(II) chloride ([Cu(phen)2]Cl2, (compound 5) and tris(1,10-phenanthroline)cobalt(III) chloride ([Co(phen)3]Cl3, (compound 6) that also showed enhanced DENV2 loads. Also, we found that copper(II) chloride dehydrate (CuCl2·2H2O) or cobalt(II) chloride hexahydrate (CoCl2·6H2O) alone had no effects as “free” cations. Taken together, these findings suggest that use of Cu(II) or Co(III) conjugation to organic compounds, in insect repellents and/or food additives could enhance DENV2/ZIKV loads in human cells and perhaps induce pathogenesis in infected individuals or individuals pre-exposed to such conjugated complexes. Importance Mosquito-borne diseases are of great concern to the mankind. Use of chemicals/repellents against mosquito bites and transmission of microbes has been the topic of interest for many years. Here, we show that thiosemicarbazone ligand(s) derived from 2-acetylethiazole or citral or 1,10-phenanthroline upon conjugation with copper(II) or cobalt(III) metal centers enhances dengue virus (serotype 2; DENV2) and/or Zika virus (ZIKV) infections in mosquito, mouse and human cells. Enhanced ZIKV/DENV2 capsid mRNA or envelope protein loads were evident in mosquito cells and human keratinocytes, when treated with compounds before/after infections. Also, treatment with copper(II) or cobalt(III) conjugated compounds increased viral titers and number of plaque formations. These studies suggest that conjugation of compounds in repellents/essential oils/natural products/food additives with copper(II) or cobalt(III) metal centers may not be safe, especially in tropical and subtropical places, where several dengue infection cases and deaths are reported annually or in places with increased ZIKV caused microcephaly.

New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor studies were carried out on the U937, HCT-116, PC3, MCF-7, A549, К562, NCI-H929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 (IC50 = 0.59 ± 0.27 µM) was observed to be 11 times more active than PPA (IC50 = 6.5 ± 0.30 µM) towards the NCI-H929 cell line, with a therapeutic index of 18. Compound 6 was determined to be over half and 16 times more active than etoposide towards the NCI-H929 (IC50 = 0.9 ± 0.05 µM) and A549 (IC50 = 100 ± 7.0 µM) cell lines, respectively.

Three coordination polymers were synthesized from pyrazine-2,3,5,6-tetracarboxylic acid (H 4 pztc) in combination with calcium, zinc and manganese ions under hydrothermal conditions and their structures were determined by single crystal X-ray diffraction, powdered X-ray diffraction, Fourier transformed infrared spectroscopy, thermogravimetric and elemental analyses. Structure 1 , {(Ca(H 2 pztc)(H 2 O) 3 ) n , crystallizes as 1-D chains, with the partially deprotonated ligand in –O,N,O– coordination mode and with the Ca atoms in an uncommon nine coordinate environment. Structure 2 , {Zn1(pztc)(H 2 O) 2 Zn2(H 2 O) 4 } n , is an infinite, 2-D coordination network that contains two nonequivalent Zn atoms, each with octahedral geometry, and the fully deprotonated pztc 4− in bis -bridging chelating coordination mode. The stacked 2-D layers are stabilized by extensive inter-layer water-carboxylate hydrogen-bonding with an inter-layer distance of 4.9 A. Structure 3, {(Mn 2 (pztc)(H 2 O) 2 )} n , is a covalently bonded 3-D network containing two nonequivalent Mn atoms, each with octahedral geometry, and the fully deprotonated pztc 4− units. Structure 3 exhibits paramagnetic behavior at room temperature, and weak antiferromagnetic properties at very low temperature, which is consistent with their nearest Mn…Mn separation distance of 4.9 A.

Background: Nanotechnology has provided significant benefits to photodynamic therapy (PDT), which has revolutionized treatments of several diseases. The success of this versatile technique is governed by the sequential in situ generation of reactive oxygen species, after a suitable photosensitizer has been irradiated by a defined wavelength of light. While PDT provides a minimally-invasive and convenient method for the treatment of several afflictions, the efficiency of this therapeutic strategy still has potential for improvements. Several bodies of works within this realm have highlighted the use of inorganic compounds, which is pivotal for the development of photosensitizers (PSs), nanoparticles (NPs) and irradiation sources. Methods: The past decade of online patented reports based on PDT were reviewed. Results: The patented reports analyzed showcased the integration of nanomaterials and inorganic compounds into PDT. The patents were grouped according to the following categories, viz., “Nanoparticles in Photodynamic Therapy”, “Photosensitizers Incorporating Various Metal Centers”, and “Modifications to Light Delivery”. Conclusion: PDT is a suitable treatment option for several diseases however there are several challenges and limitations. The incorporation of NPs in the field of PDT is an extremely promising avenue which can be utilized to improve the execution of PDT. Furthermore, the use of inorganic compounds was noted to be frequented in the development of PSs and NP conjugates. The patents presented addressed the associated problems with PDT but there still remains an opportunity for continued research efforts so that more clinical applications are possible.

Anti-cancer activity of tolfenamic acid (TA) in preclinical models for pancreatic cancer (PaCa) is well established. Since the dosage for anti-cancer actions of TA is rather high, we recently demonstrated that IC(50) values of Copper-TA are 30–80% less than TA in 12 cancer cell lines. This study elucidates the underlying mechanisms of Copper-TA in PaCa cells. Control and Copper-TA (IC(50)) treated PaCa cells were processed by next-generation sequencing (NGS) to determine differentially expressed genes using HTG EdgeSeq Oncology Biomarker panel. Ingenuity Pathway Analysis (IPA®) was used to identify functional significance of altered genes. The conformational studies for assessing the expression of key regulators and genes were conducted by Western blot and qPCR. IPA® identified several networks, regulators, as well as molecular and cellular functions associated with cancer. The top 5 molecular and cellular functions affected by Cu-TA treatment were cell death and survival, cellular development, cell growth and proliferation, cell cycle and cellular movement. The expression of top upstream regulators was confirmed by Western blot analysis while qPCR results of selected genes demonstrated that Copper-TA is efficacious at lower doses than TA. Results suggest that Copper-TA alters genes/key regulators associated with cancer and potentially serve as an effective anti-cancer agent.

In this study, 9-anthraldehyde-N(4)-methylthiosemicarbazone (MeATSC) 1 and [Co(phen)(2)(O(2)CO)]Cl·6H(2)O 2 (where phen = 1,10-phenanthroline) were synthesized. [Co(phen)(2)(O(2)CO)]Cl·6H(2)O 2 was used to produce anhydrous [Co(phen)(2)(H(2)O)(2)](NO(3))(3) 3. Subsequently, anhydrous [Co(phen)(2)(H(2)O)(2)](NO(3))(3) 3 was reacted with MeATSC 1 to produce [Co(phen)(2)(MeATSC)](NO(3))(3)·1.5H(2)O·C(2)H(5)OH 4. The ligand, MeATSC 1 and all complexes were characterized by elemental analysis, FT IR, UV–visible, and multinuclear NMR ((1)H, (13)C, and (59)Co) spectroscopy, along with HRMS, and conductivity measurements, where appropriate. Interactions of MeATSC 1 and complex 4 with calf thymus DNA (ctDNA) were investigated by carrying out UV–visible spectrophotometric studies. UV–visible spectrophotometric studies revealed weak interactions between ctDNA and the analytes, MeATSC 1 and complex 4 (K(b) = 8.1 × 10(5) and 1.6 × 10(4) M(−1), respectively). Topoisomerase inhibition assays and cleavage studies proved that complex 4 was an efficient catalytic inhibitor of human topoisomerases I and IIα. Based upon the results obtained from the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay on 4T1-luc metastatic mammary breast cancer cells (IC(50) = 34.4 ± 5.2 μM when compared to IC(50) = 13.75 ± 1.08 μM for the control, cisplatin), further investigations into the molecular events initiated by exposure to complex 4 were investigated. Studies have shown that complex 4 activated both the apoptotic and autophagic signaling pathways in addition to causing dissipation of the mitochondrial membrane potential (ΔΨ(m)). Furthermore, activation of cysteine-aspartic proteases3 (caspase 3) in a time- and concentration-dependent manner coupled with the ΔΨ(m), studies implicated the intrinsic apoptotic pathway as the major regulator of cell death mechanism.

[Co(tpy)(phen)Cl](PF6)2•0.25CH3CN (where tpy = 2,2′;6′,2″-terpyridine and phen = 1,10-phenanthroline) was prepared from a one pot mixture involving stoichiometric quantities of tpy and phen. The structure of [Co(tpy)(phen)Cl](PF6)2•0.25CH3CN was confirmed by elemental analysis, high resolution mass spectroscopy (HRMS), various spectroscopic analyses, and X-ray crystallography. Density functional theory calculations were also carried out. The crystal structure of [Co(tpy)(phen)Cl](PF6)2•0.25CH3CN, which was grown from acetonitrile, revealed a monoclinic crystal system with a C2/c space group. The cyclic voltammogram which was acquired in acetonitrile revealed reversible CoIII/II, CoII/I, and CoI/0 mixed with ligand-based redox couples at E½ = +0.35, –0.81, and –1.37 V (vs Ag/AgCl), respectively. In the presence of p-cyanoanillinium tetrafluoroborate with acetonitrile as the solvent, [Co(tpy)(phen)Cl](PF6)2•0.25CH3CN displayed electrocatalytic hydrogen evolution activity at a 830 mV overpotential, as evidenced by a catalytic wave which was observed in the voltammogram, and by the detection of hydrogen in the headspace of the reaction vessel of a controlled potential electrolysis experiment. Photocatalytic hydrogen evolution studies with [Co(tpy)(phen)Cl](PF6)2•0.25CH3CN produced a turnover frequency (TOF) of 3300 mmol H2 mol−1 CAT min−1 when compared to [Co(dmgH)2(py)Cl] (where dmgH = dimethylglyoximato), which had a TOF of 4500 mmol H2.mol−1 CAT min−1 under the same conditions. [Co(tpy)(phen)Cl](PF6)2•0.25CH3CN produced a turnover number (TON) of 79 when compared to 141 for [Co(dmgH)2Cl(py)] in DMF in ca 3 h.

A ruthenium(II) complex of 6-(4,7-dimethoxy-2-benzothiazolyl)-N-(2,5-dimethoxyphenyl)-2-pyridinecarbothioamide (pbcta), of the formula [Ru(pbcta)Cl2(dmf)] (1, where DMF = dimethyl formamide) was prepared from RuCl3•xH2O and pbcta in DMF at reflux under argon atmosphere. The identity of 1 was confirmed from its elemental analysis, ESI MS, and a series of spectroscopic measurements. Voltammetric measurements on 1 in DMF and DFT studies on the structure optimized in the gas phase revealed predominantly ligand based electron transfer processes under argon. In the presence of a proton source, proton coupled electron transfer to the ligand occurs. Under a carbon dioxide atmosphere, voltammetric studies revealed that 1 is inactive for CO2 reduction, and the redox responses observed in the presence of the proton source and/or CO2 are ligand based leading to reactions with the coordinated pbcta. Transfer hydrogenation (TH) of aryl ketones was efficiently carried out in 2-propanol using 1 at reflux. TH of the aryl ketone substrates proceeded in air with almost quantitative conversions at 0.2–1.0 mol% catalyst.

In this article, we report the removal of a reactive dye, viz. sunset yellow, from the aqueous solution using micellar media of two cationic surfactants, viz. cetyltrimethylammonium bromide and ethyl hexadecyldimethyl ammonium bromide (. The values of rejection coefficient (R%) and permeate flux (J) have been calculated using membranes with different pore sizes, viz. 10,000 (10k) molecular weight cutoff (MWCO) and 30,000 (30k) MWCO at 1.5 bar transmembrane pressure. The membrane of 30k MWCO was found to be more suitable in order to retain the dye molecules incorporated in the micelles.

A novel complex, [Cu(acetylethTSC)Cl]Cl•0.25C2H5OH 1 (where acetylethTSC = (E)-N-ethyl-2-[1-(thiazol-2-yl)ethylidene]hydrazinecarbothioamide), was shown to have anti-proliferative activity against various colon and aggressive breast cancer cell lines. In vitro studies showed that complex 1 acted as a poison inhibitor of human topoisomerase IIα, which may account for the observed anti-cancer effects.

[Co(dmgBF2)2(H2O)2] 1 (where dmgBF2 = difluoroboryldimethylglyoximato) was used to synthesize [Co(dmgBF2)2(H2O)(py)]·0.5(CH3)2CO 2 (where py = pyridine) in acetone. The formulation of complex 2 was confirmed by elemental analysis, high resolution MS, and various spectroscopic techniques. The complex [Co(dmgBF2)2(solv)(py)] (where solv = solvent) was readily formed in situ upon the addition of pyridine to complex 1. A spectrophotometric titration involving complex 1 and pyridine proved the formation of such a species, with formation constants, log K = 5.5, 5.1, 5.0, 4.4, and 3.1 in 2-butanone, dichloromethane, acetone, 1,2-difluorobenzene/acetone (4 : 1, v/v), and acetonitrile, respectively, at 20 °C. In strongly coordinating solvents, such as acetonitrile, the lower magnitude of K along with cyclic voltammetry, NMR, and UV-visible spectroscopic measurements indicated extensive dissociation of the axial pyridine. In strongly coordinating solvents, [Co(dmgBF2)2(solv)(py)] can only be distinguished from [Co(dmgBF2)2(solv)2] upon addition of an excess of pyridine, however, in weakly coordinating solvents the distinctions were apparent without the need for excess pyridine. The coordination of pyridine to the cobalt(II) centre diminished the peak current at the Epc value of the CoI/0 redox couple, which was indicative of the relative position of the reaction equilibrium. Herein we report the first experimental and theoretical 59Co NMR spectroscopic data for the formation of Co(I) species of reduced cobaloximes in the presence and absence of py (and its derivatives) in CD3CN. From spectroelectrochemical studies, it was found that pyridine coordination to a cobalt(I) metal centre is more favourable than coordination to a cobalt(II) metal centre as evident by the larger formation constant, log K = 4.6 versus 3.1, respectively, in acetonitrile at 20 °C. The electrosynthesis of hydrogen by complexes 1 and 2 in various solvents demonstrated the dramatic effects of the axial ligand and the solvent on the turnover number of the respective catalyst.

Derivatives of phaeosphaeride A (PPA) were synthesised and characterised; then anti-cancer studies were carried out on the A549 cancer cell line. It was found that the acetyl derivative (compound 3) displayed comparable in vitro cytotoxicity to that of PPA (EC50=49±7 μM and EC50=46±5 μM, respectively), while chloroacetyl derivative 6 (EC50=33±7 μM) was found to have better efficacy towards the A549 cancer cell line.

This is a preface of the influence of Professor Karen Brewer on my life as she taught me how to carry out good and sensible chemistry with osmium(II), ruthenium(II), and rhodium(III) complexes. Photodynamic therapeutic studies with pUC18 and pBluescript DNA plasmids and Vero cells were the order of the day! This research catalyzed my career and research in the U.S.A.

Two mixed-ligand cobalt(III) complexes containing 2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen), and N-(3,5-bis(trifluoromethyl)phenyl)pyridine-2-carbothioamide (PCA-(CF3)2) as ligands were synthesized, and characterized by a variety of spectroscopic techniques and elemental analyses. Crystals of the PCA-(CF3)2 molecule are of the monoclinic, C2/c crystal system and space group as determined via X-ray crystallography. The voltammetric properties of six cobalt(III) complexes, [Co(bpy)2Cl2]Cl 1, [Co(phen)2Cl2]Cl 2, [Co(bpy)2(PCA-(CF3)2)](PF6)2·H2O 3, [Co(phen)2(PCA-(CF3)2)](PF6)2·1.25H2O 4, [Co(bpy)3](PF6)3 5, and [Co(phen)3](PF6)3 6, were compared to assess the potential influence of the PCA-(CF3)2 ligand on the effectiveness of cobalt in the catalytic hydrogen evolution reaction (HER) under electrochemical and photochemical conditions. The PCA-(CF3)2 moiety caused an anodic shift in the reduction potential of CoII/I redox couple of complexes 3 and 4, in comparison to the other complexes. Complexes 3 and 4 demonstrated catalytic HER in the presence of p-cyanoanilinium tetrafluoroborate in CH3CN, with overpotentials for the HER of 730 and 630 mV for complexes 3 and 4, respectively. The reduction potentials suggest that the HER was most likely facilitated by a homolytic pathway. Complexes 3 and 4 also demonstrated photocatalytic HER in the presence of [Ru(bpy)3](PF6)2 as a photosensitizer and triethanolamine as a sacrificial reductant in DMF. Complexes 3 and 4 attained rates of 2700 mmol H2.mol−1 CAT min−1 and 2600 mmol H2 mol−1 CAT min−1, respectively, compared to a standard complex [Co(dmgH)2(py)Cl] which had a rate of 4500 mmol H2 mol−1 CAT min−1, under similar conditions. Turnover numbers (TON) of 140 were observed for [Co(dmgH)2(py)Cl] and complex 4, compared to 91 for complex 3, over a 3 h period.

The reduction of sodium bromate (NaBrO3) by [Co(dmgBF2)2(OH2)2] (where dmgBF2 = difluoroboryldimethylglyoximato) was investigated in hydrochloric and nitric acids. Analytical studies were carried out via gravimetric analysis and UV–visible spectrophotometry. Gravimetric analysis proved that sodium bromate was reduced to from quantitative amounts of sodium bromide in the presence of hydrochloric acid. Biochar was used to sequester the complex from the reaction mixture and to neutralize the acidic media. The UV–visible data confirmed the sequestration of the complex from the reaction mixture after exposure to the biochar. The collected pH data proved a direct relationship between pH and the amount of biochar used in the form of a titration curve. Kinetic studies were also carried out to ascertain the mechanism of the oxidation of [Co(dmgBF2)2(OH2)2] by NaBrO3. The oxidation of [Co(dmgBF2)2(OH2)2] by NaBrO3 was carried out by stopped-flow spectrophotometry at 450 nm by varying temperature and over the range of 1.00 mM ≤ [HCl] ≤ 11.00 mM, at a constant ionic strength of 0.60 M (NaCl). From the data, a mechanism for the reaction was proposed. From the mechanism the following rate expression was derived, k obs = k 2 K a \; + \;k \; 1 H + BrO 3 - T [ H + ] \; + \; K a , where k1 was calculated to be 4.2 × 104 M−1 s−1 at 25 °C, and the activation parameters (ΔH‡ and ΔS‡) were calculated as 57 ± 1 kJ mol−1 and 34 ± 4 J mol−1 K−1, respectively.

The H2salen ligand 1 was used as a precursor ligand to produce a series of new complexes, [Ti(salen)(OPh-m-CH3)2] 2 (where salen = N,N’-ethylenebis(salicylideneiminate) dianion and −OPh-m-CH3 = 3-methylphenolato), [Ti(salen)(OPh-p-NO2)2] 3 (where −OPh-p-NO2 = 4-nitrophenolato), [Ti(salen)(3,5-bis(trifluoromethyl)phenolate)2] 4, Ti(salen)(OPh)2] 5a (where −OPh = phenolato), [Ti(salen)(OPh-o-F)2] 6a (where −OPh-o-F = 2-fluorophenolato), [Ti(salen)(OPh-p-CH3)2] 7a (where −OPh-p-CH3 = 4-methylphenolato), [Ti(salen)(OPh-o-CH3)2] 8 (where −OPh-o-CH3 = 2-methylphenolato), [Ti(salen)(OPh-m-F)2] 9 (where −OPh-m-F = 3-fluorophenolato), and [Ti(salen)(OPh-p-F)2] 10 (where −OPh-p-F = 4-fluorophenolato). The ligand and the complexes were characterized by elemental analysis, FTIR, 1H, 19F, and 49Ti NMR spectroscopies, and X-ray crystallography. All the complexes, as synthesized, were consistent as mononuclear titanium(IV) complexes, but complexes 5b, 6b, and 7b after being characterized by X-ray crystallography were found to be binuclear in nature. 49Ti NMR spectroscopic studies proved that this is the very first report of 49Ti NMR spectra of titanium(IV) complexes with Schiff bases as ligands in deuterated chloroform.

New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor activity studies were carried out on the HCT-116, PC3, MCF-7, A549, К562, NCI-Н929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All of the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 was potent against six cancer cell lines, HCT-116, PC-3, K562, NCI-H929, Jurkat, and RPMI8226, showing a 47, 13.5, 16, 4, 1.5, and 7-fold increase in anticancer activity comparative to those of etoposide, respectively. Compound 1 possessed selectivity toward the NCI-H929 cell line (IC50 = 1.35 &plusmn, 0.69 &mu, M), while product 7 was selective against three cancer cell lines, HCT-116, MCF-7, and NCI-H929, each having IC50 values of 1.65 &mu, M, 1.80 &mu, M and 2.00 &mu, M, respectively.

The non-steroidal anti-inflammatory drug, Tolfenamic acid (TA) acts as an anti-cancer agent in several adult and pediatric cancer models. Copper (Cu) is an important element with multiple biological functions and has gained interest in medical applications. Recently, [Cu(TA)2(bpy)] (Cu-TA) has been synthesized in order to enhance therapeutic activity. In this study, we synthesized Cu-TA using an established method, characterized it by UV visible spectroscopy and Fourier-transform infrared spectroscopy (FTIR), and tested its anti-cancer activity using twelve cell lines representing various cancers, such as Ewing sarcoma, glioblastoma, medulloblastoma, neuroblastoma, pancreatic and prostate. The anti-proliferative activity of Cu-TA was determined at 48 h post-treatment and compared with the parental compound, TA. The IC50 values were calculated using GraphPad Prism software. The biological stability of Cu-TA was evaluated using twelve-month-old powder and six-month-old stock solution. Cardiomyocytes (H9C2) were used to test the cytotoxicity in non-malignant cells. Cu-TA showed higher anti-proliferative activity, and the IC50 values were 30 to 80% lower when compared with TA. H9C2 cells were non-responsive to Cu-TA, suggesting that it is selective towards malignant cells. Comparison of the twelve-month-old powder and six-month-old stock solution using the Panc1 cell line showed similar IC50 values (

The synthesis, X-ray crystallographic, electrochemical, and spectroscopic studies of bis-(1,10-phenanthroline)(2,2′-bipyridine)cobalt(III) hexafluorophosphate with acetone solvent of crystallization ([Co(phen)2(bpy)](PF6)3·1.6(CH3)2CO) is reported. The compound crystallized in a monoclinic space group P2(1)/n with a = 13.215(3) A, b = 17.823(4) A, c = 19.823(4) A, β = 96.80(3)° and V = 4636.1(16) A3 with Z = 4. The cobalt(III) metal center has a slightly distorted octahedral geometry. 1,10-Phenanthroline and 2,2′-bipyridine ligands were generally planar, and did not exhibit π–π overlap. The packing of the cations was stabilized by hydrogen bonding with hexafluorophosphate anions. The electrochemical studies revealed the CoIII/II, CoII/I and CoI/0 redox couples at E 1/2 = +0.32, −0.91 and −1.61 V (vs AgCl/Ag) respectively in acetonitrile. 59Co NMR spectroscopic studies revealed that the [Co(phen)2(bpy)](PF6)3·0.5(C2H5)2O species has a chemical shift of 6900 ppm in DMSO-d 6. The mononuclear complex, [Co(phen)2(bpy)](PF6)3·1.6(CH3)2CO) was synthesized and characterized, but more revealing 59Co NMR spectroscopic studies on the complex revealed interesting species in DMSO-d 6.

This is a review of the literature concerning the interesting properties of p-, d-, and f-block elements when coordinated with 2,6-pyridinedicarboxylic acid (dipicolinic acid, H2 dipic) and its derivatives as ligands, with a focus on their use as inorganic pharmaceuticals. Some of the complexes reported were used as insulin-like, bioimaging contrasting agents, antimicrobial agents, and anticancer agents.

Metal–organic frameworks {[Ln4(pztc)3(H2O)11]·10(H2O)}n (Ln = Gd(1), Tb(2); pztc = pyrazine-2,3,5,6-tetracarboxylate) containing variable coordination spheres and with a complex and unusual three dimensional structure, were synthesized by the reaction of H4pztc with the respective Ln(III) salt in water under hydrothermal conditions. The compounds were characterized by single crystal X-ray crystallography, elemental and thermal analysis, and FTIR spectroscopy. The asymmetric units in these compounds have four symmetry-independent Ln(III) ions and these are octa- and nona-coordinate centers, with irregular coordination polyhedra from [Ln(pztc)2(H2O)6], [Ln(pztc)2(H2O)4], [Ln(pztc)3(H2O)3], [Ln(pztc)3(H2O)], and [Ln(pztc)4] cluster units. The fully deprotonated ligand, pztc, coordinates to the Ln3+ ions through seven or through ten of its atoms (i.e., the maximum coordination number for this ligand). The three-dimensional open framework contains irregular channels along the [001] crystallographic direction. The channels are approximately 12 A wide at their largest dimension and contain strongly hydrogen bonded water molecules of crystallization which further stabilize the structure. The solvent accessible volume is 20% of the total volume. The structures exhibit magnetic behavior that is characteristic of the respective isolated paramagnetic lanthanide ions.

The kinetics and mechanism of the oxidation of [Co(dmgBF2)2(OH2)2] (where dmgBF2 = difluoroboryldimethylglyoximato) by sodium hypochlorite (NaOCl) were investigated by stopped-flow spectrophotometry at 450 nm over the temperature range of 10 °C ≤ θ ≤ 25 °C, pH range of 5.0 ≤ pH ≤ 7.8, and at an ionic strength of 0.60 M (NaCl). The pKa1 value for [Co(dmgBF2)2(H2O)2] was calculated as 5.27 ± 0.14 at I = 0.60 (NaCl). The redox process was dependent on pH and oxidant concentration in a complex manner, that is, kobs = ((k2[H+] + k1Ka)/([H+] + Ka))[OCl-]T, where at 25.3 °C, k1 was calculated as 3.54 × 104 M-1 s-1, and k2 as 2.51 × 104 M-1 cm-1. At a constant pH value, while varying the concentration of sodium hypochlorite two rate constants were calculated, viz., k'1 = 7.56 s-1 (which corresponded to a reaction pathway independent of the NaOCl concentration) and k'2 = 2.26 × 104 M-1 s-1, which was dependent on the concentration of NaOCl. From the variation in pH, [Formula: see text], and [Formula: see text] were calculated as 58 ± 16 kJ mol-1, 46 ± 1 kJ mol-1, 34 ± 55 J mol-1 K-1, and -6 ± 4 Jmol-1 K-1, respectively. The self-exchange rate constant, k11, for sodium hypochlorite (as ClO-) was calculated to be 1.2 × 103 M-1 s-1, where an outer-sphere electron transfer mechanism was assumed. A green product, [Co(dmgBF2)2(OH2)(OH)]·1.75NaOCl, which can react with DMSO, was isolated from the reaction at pH 8.04 with a yield of 13%.

A cobalt(III) oxo cubane water oxidation catalyst, a structural mimic of the natural oxygen-evolving center, was immobilized on indium tin oxide (ITO) to promote recycling. The structure and composition of the complex were characterized by Fourier transform-infrared (FT-IR) spectroscopy, surface FT-IR, scanning electron microscopy, and energy dispersive X-ray spectroscopy. Cyclic voltammetry was used to assess catalyst functionality, stability, and recyclability. The results showed that this catalyst can be successfully immobilized on ITO, and that the complex functions in the same manner as the free catalyst in solution. This separation of synthesis and immobilization has great potential for optimizing heterogeneous catalysts.

A Br-substituted dioxidovanadate dipicolinate complex was prepared and structurally characterized by X-ray crystallography. The counter ion in the solid state is the ammonium cation in a monoclinic crystal cell with, P 2(1)/ c . The X-ray structure is similar to the structure generated from the analogous nitro substituted dipicolinate ligand. When exploring reactions of this and other dipicolinate-containing compounds with L -ascorbic acid, both vanadium(IV) and vanadium(III) species were formed under acidic conditions; then identified by conventional (X-band) and high-frequency and -field electron paramagnetic resonance (EPR) spectroscopy. A reaction with half an equivalent of L -ascorbic acid led to the formation of vanadium(IV) species, and addition of substituents (X = H, Cl, Br, OH, and NH 2 ) in the para position of dipicolinic acid did not have a major effect on the vanadium(IV) species formed. In a reaction with excess L -ascorbic acid and vanadium(V)dipic-X complexes (where X = H, Cl, Br, OH, and NH 2 ), vanadium(III) species were observed, thus proving that vanadium(III) species can be formed under acidic conditions resembling those in biological systems.

Anti-cancer activity of tolfenamic acid (TA) has been studied using several preclinical cancer models including pancreatic cancer (PaCa). Since the dosage used for the anti-cancer actions of TA is rather high, we investigated Copper-TA (Cu-TA) for anti-proliferative activity using 12 cancer cells (representing 6 cancers) and demonstrated that Cu-TA is more effective than TA (IC50 values are 30-80% less than TA). Recently, we reported that Cu-TA inhibits tumor growth in mouse xenograft (pancreatic tumor) model. The objective of this investigation is to elucidate the underlying mechanisms of Cu-TA using PaCa cell lines. MIA PaCa-2 cells were treated with vehicle (dimethyl sulfoxide) or 29 µM (IC50) of Cu-TA and processed by next-generation sequencing (NGS) to determine the differentially expressed genes using Oncology Biomarker (HTG EdgeSeq) panel. The functional significance of the altered gene expression was determined via Ingenuity Pathway Analysis which identified several networks, regulators, as well as molecular and cellular functions that were affected by Cu-TA treatment. A total of 18 networks were found to be involved with Cu-TA treatment and these networks had a significant overlap. Confirmation experiments assessing the alterations in the expression of selected candidate markers were conducted by qPCR and Western blot analysis using both MIA PaCa-2 and PANC 1 cell lines. The top upstream regulators included tumor protein p53, human epidermal receptor growth factor 2, Sp1 and signal transducer and activator of transcription 3. These regulators were confirmed by Western blot analysis. The top five molecular/cellular functions affected by Cu-TA treatment were cell death/survival, cellular development, cell growth/proliferation, cell cycle and cellular movement. qPCR results of selected genes, Centromere protein F, DNA damage inducible transcript 3 and S-phase kinase-associated protein 2 (differentially expressed genes in sequencing) demonstrated that Cu-TA is efficacious at lower doses than TA. In summary, the NGS and Ingenuity Pathway Analysis identified critical genes or pathways altered by Cu-TA. This investigation demonstrated that the networks and regulators associated with cancer cell survival or apoptosis that are modulated in PaCa cells suggests that Cu-TA is altering genes associated with cancer, thereby demonstrating its potential as an effective anti-cancer agent. Citation Format: Myrna Hurtado, Laszlo Prokai, Umesh T. Sankpal, Blair Levesque, Rajasekhar Maram, Jaya Chhabra, Deondra T. Brown, Raj K. Gurung, Alvin A. Holder, Jamboor Vishwanatha, Riyaz Basha. Functional pathway analysis in pancreatic cancer cells treated with a novel anti-cancer agent, copper-tolfenamic acid [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4811.

Introduction. Medulloblastoma is the most common malignant brain tumor in children. New treatment strategies are urgently needed as the current options often result in significant long term neurocognitive and growth defects among survivors. We have previously demonstrated the anti-cancer activity of small-molecule non-steroidal anti-inflammatory drug tolfenamic acid (TA) in medulloblastoma cells and tumor model. The anti-cancer activity of TA can be correlated to its ability to downregulate the anti-apoptotic protein Survivin, cause cell cycle arrest, and induce apoptosis. A recent publication has shown that the activity of TA can be enhanced by forming a complex with copper (II). In this study we tested the function of the copper complex as an anti-cancer agent against pediatric medulloblastoma. Methods. Pediatric medulloblastoma cell lines DAOY and D283 were used in this study. We have previously demonstrated the synthesis, stability, and anti-cancer activity of Copper-Tolfenamic acid (Cu-TA) complex using various cancer cell lines. The efficacy of Cu-TA against medulloblastoma cells was determined by studying the effect of increasing dose on cell viability, using the CellTiter-Glo Luminescent Cell Viability Assay. Further experiments, using optimized doses of Cu-TA, were carried out to determine its effect on cell cycle and its ability to induce apoptosis. Based on our previous results with TA, we also investigated the effect of Cu-TA on survivin protein levels. Results. Inhibition of cell viability was observed with increasing doses of Cu-TA as well as with increasing time. The IC50 values were 2-fold lower compared to that of TA and were used in further experiments. Cell cycle analysis using propidium iodide staining and flow cytometry revealed that treatment with Cu-TA results in accumulation of cells in G0/G1 phase, as early as 12h after treatment. Cu-TA induced apoptosis was studied by flow cytometric analysis of AnnexinV stained cells and by western blot analysis of cleaved-PARP. At 48h post-treatment, significant increase in apoptosis was detected by flow cytometry, that also correlated with increased levels of c-PARP. Cu-TA treatment also resulted in a significant decrease in survivin levels compared to TA at 24 and 48h post-treatment. Conclusion. Our earlier studies with TA have demonstrated its potential as an anti-cancer agent with relatively safe toxicity profile, both in vitro and in pre-clinical mouse model studies. TA also has the capability to enhance the response of standard treatments when used in combination. Here, we demonstrate the ability to increase the efficacy of TA when complexed with copper (II). Cu-TA, with its increased anti-cancer activity and potential to sensitize cells to chemotherapy and radiation, provides a novel therapeutic option for the treatment of medulloblastoma. Citation Format: Julie Hong, Melissa Schullek, John K. Smith, Joseph Reitman, Amil Dudhia, Nihant Tallapaka, Rassil Basha, Deondra T. Brown, Jaya Chhabra, Alvin Holder, Umesh T. Sankpal. Effect of novel copper-tolfenamic acid complex on medulloblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2972.

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and young children. NB often metastasizes to lymph nodes and bone marrow. When compared to low or intermediate risk tumors, high risk neuroblastoma (HRNB) is more aggressive with low (40-50%) 5 year survival rates. Furthermore, current intensive treatment methods induce higher toxicity and side effects. In search of identifying less-toxic agents to induce anti-cancer activity in NB cells, our group reported the anti-cancer activity of a non-steroidal anti-inflammatory drug, Clotam (TA) using HRNB cell lines potentially inhibiting the transcription factor, Specificity protein 1 (Sp1) and an inhibitor of apoptosis protein, survivin. Recently, our laboratories tested a copper complex of TA (Cu-TA) using 12 cell lines and found that Cu-TA’s IC50 values were 30-80% lower when compared to TA. In this study, we investigated the cytotoxicity of SH-SY 5Y, LA1-55n and SMS-KCNR cells in the presence of vehicle (Dimethyl sulfoxide) or TA or Cu-TA using CellTiter-Glo kit and determined the IC50 values using SigmaPlot software. The effect of TA or Cu-TA on apoptosis and cell cycle phase distribution was evaluated by flow cytometry using Annexin-V and Propidium Iodide kits respectively. The characterization and stability of the Cu-TA was also determined. SH SY5Y and SMS-KCNR cells were treated with IC50 values of TA or Cu-TA and the expression of Sp1 and survivin was measured by qPCR and Western blot analysis. The results showed that while both TA and Cu-TA inhibited NB cell growth, Cu-TA’s IC50 values were 60-70% less than TA. The inhibition of NB cells with Cu-TA was accompanied by induced apoptotic cell population and cell cycle arrest at G2M phase. Western blot and qPCR results confirmed that Cu-TA inhibited the expression of both Sp1 and survivin with predominant effect on SMS-KCNR cells. These results demonstrate that Cu-TA is more effective than TA for inhibiting Sp1 and survivin in NB cells, which was consistent with the anti-proliferative activity against NB cells. Since TA and Cu-TA are less toxic than standard chemotherapeutic agents, employing these agents for the treatment of pediatric malignancies could be useful. Eventually, combination of Cu-TA and chemotherapeutic agents will be tested. If Cu-TA sensitizes NB cells to chemotherapy, it will help to address the issues associated with the side effects of chemotherapy. Citation Format: Yazmin Hernandez, Sarah Sarah Grebennikov, Emily Zakhary, Ashni Dudhia, Rajasekhar Maram, Diego Casanova, Umesh T. Sankpal, W. Paul Bowman, Deondra T. Brown, Jaya Chhabra, Alvin A. Holder, Riyaz M. Basha. Antiproliferative effect of copper complex of clotam in neuroblastoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2881.

DNA sensing always has an open meadow of curiosity for biotechnologists and other researchers. Recently, in this field, we have introduced an emerging class of molecules containing azo and guanidine functionalities. In this study, we have synthesized three new compounds ( UA1 , UA6 and UA7 ) for potential application in DNA sensing in alcoholic medium. The synthesized materials were characterized by elemental analysis, FTIR, UV-visible, 1 H NMR and 13 C NMR spectroscopies. Their DNA sensing potential were investigated by UV-visible spectroscopy. The insight of interaction with DNA was further investigated by electrochemical (cyclic voltammetry) and hydrodynamic (viscosity) studies. The results showed that compounds have moderate DNA binding properties, with the binding constants range being 7.2 × 10 3 , 2.4 × 10 3 and 0.2 × 10 3 M −1 , for UA1 , UA6 and UA7 , respectively. Upon binding with DNA, there was a change in colour (a blue shift in the λ max value) which was observable with a naked eye. These results indicated the potential of synthesized compounds as DNA sensors with detection limit 1.8, 5.8 and 4.0 ng µl −1 for UA1 , UA6 and UA7 , respectively.

This article details the development of a thin film piezoresistive screen printed pressure sensor on a flexible substrate using a composite ink based on functionalised graphene nanoplatelets (GNPs). The sensor operates through direct interfacial contact between two distinct films of the composite ink deposited over conductive substrates, without requiring any intermediate gap through spacers. The sensors showed consistent results and sensitivity forces ranging between 10 N to 2000 N. The piezoresistive range of the sensor can be tuned with the number of layers deposited per side.

Vanadium, which arouses interest of many research centers worldwide, is a biologically essential redox-active metal with an ability to evoke diametrically opposite effects. Due to its dual character and multidirectional action, vanadium receives a great deal of attention of pharmacologists and researchers from different scientific disciplines.

A series of copper complexes were synthesized from benzo[d][1,3]dioxole-5-carbaldehyde (piperonal) thiosemicarbazones (RHpTSC where R = H, CH3, C2H5 or C6H5 (Ph)). The complexes show interesting variations in geometry depending on the thiosemicarbazone; a dinuclear complex [Cu(HpTSC)Cl]2, a mononuclear complex [Cu(RHpTSC)2Cl2] (R = CH3 or C2H5) and another mononuclear complex [Cu(PhHpTSC)(PhpTSC)Cl] was generated. The complexes bind in a moderately strong fashion to DNA with binding constants on the order of 10 4 M − 1 . They are also strong binders of human serum albumin with binding constants near 10 4 M − 1 . The complexes show good in vitro cytotoxic profiles against two human colon cancer cell lines (HCT-116 and HT29) and two human breast cancer cell lines (MCF-7 and MDA-MB-231) with IC50 values in the low millimolar concentration range.

Design of inhibitors for amyloid-β (Aβ) peptide aggregation has been widely investigated over the years towards developing viable therapeutic agents for Alzheimer's disease (AD). The biggest challenge seems to be inhibiting Aβ aggregation at the early stages of aggregation possibly at the monomeric level, as oligomers are known to be neurotoxic. In this regard, exploiting the metal chelating property of Aβ to generate molecules that can overcome this impediment presents some promise. Recently, one such metal complex containing Pt(II) ([Pt(BPS)Cl(2)]) was reported to effectively inhibit Aβ42 aggregation and toxicity (1). This complex was able bind to Aβ42 at the N-terminal part of the peptide and triggered a conformational change resulting in effective inhibition. In the current report, we have generated a mixed-binuclear metal complex containing Pt(II) and Ru(II) that inhibited Aβ42 aggregation at an early stage of aggregation and seemed to have different modes of interaction than the previously reported Pt(II) complex, suggesting an important role of the second metal center. This 'proof-of-concept' compound will help in developing more effective molecules against Aβ aggregation by modifying the two metal centers as well as their ligands, which will open doors to new rationale for Aβ inhibition.

Clotam (tolfenamic acid or TA) is a nonsteroidal anti-inflammatory drug used to treat migraine headaches. Research from our laboratory and other groups has demonstrated that TA also acts as an anticancer agent in several adult and pediatric cancer models. It is well established that the anticancer activity of TA is partly mediated by its ability to downregulate the specificity protein (Sp) family of transcription factors and their downstream targets, notably the inhibitor of apoptosis protein family member survivin. Both Sp1 and survivin are upregulated in cancer cells and are associated with poor prognosis, making them ideal therapeutic targets. It was recently suggested that the therapeutic potential of TA could be enhanced by forming a complex with copper(II). In this study we synthesized a copper(II) complex of TA (Cu-TA) and tested its anticancer activity using cell lines representing various cancers such as breast, prostate, pancreatic, brain, colon, neuroblastoma, medulloblastoma, and sarcoma. The compound was synthesized and its purity was assessed by UV-visible spectrophotometry. Purified compound (>98%) was dissolved in DMSO and its antiproliferative activity was determined using the CellTiter-Glo cell viability assay kit. In our initial screening various cancer cells were treated with increasing concentration of Cu-TA or TA, and cell viability was assessed at 24 and 48h post-treatment. The effect of Cu-TA on expression of Sp1 and survivin was determined by Western blot analysis of lysates prepared using cells treated with Cu-TA or TA for 48h. We also studied the effect of Cu-TA on cell cycle and apoptosis using medulloblastoma cell lines. Both Cu-TA and TA decreased cell viability in a dose-dependent manner; however, Cu-TA consistently had lower IC50 values in all the cell lines tested, suggesting its higher efficacy compared to TA. In line with the viability results, Western blot analysis of survivin expression demonstrated that Cu-TA was more effective in inhibiting its expression compared to TA. Also, treatment of medulloblastoma cells with Cu-TA resulted in cell cycle arrest in G0/G1 phase accompanied by an increased apoptosis as determined by annexin-V staining. This preliminary screening demonstrates the potential of Cu-TA as an effective anticancer agent with the ability to target survivin. Further studies to delineate the mechanism of action of Cu-TA are under way. Citation Format: Umesh T. Sankpal, Rafid Patel, Bianca Arechiga, Abigail Hunter, Jaya Chhabra, Deondra T. Brown, Raj K. Gurung, Alvin A. Holder, Riyaz M. Basha. Improved anticancer activity of clotam as a copper-complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5424.

Despite advances in research, pancreatic cancer (PC) remains one of the most lethal malignancies. The five-year survival rate is 8% and standard treatment options often cause high toxicity. Thus, there is a pressing need for identifying less toxic yet more effective agents for the treatment of this malignancy. Tolfenamic acid (TA) is a NSAID used as migraine medicine but has recently been demonstrated in pre-clinical studies to have anti-cancer properties. It is known to downregulate the transcription factor Specificity protein 1 and 3 (Sp1, Sp3). Sp1 and Sp3 regulate several genes involved with apoptosis and cell growth, including survivin, an inhibitor of apoptosis. Recently, it has been suggested that a copper(II) complex of TA (Cu-TA) can produce a higher therapeutic response; however, its efficacy has yet to be tested in gastro-intestinal cancers. Previously we presented that both TA and Cu-TA caused a dose-dependent response in inhibition of cell growth in PC cells, however, Cu-TA had an enhanced effect. Here, we used human PC cell lines (MIA PaCa-2 and Panc1) to evaluate the therapeutic efficacy of Cu-TA. Physical characterization of Cu-TA was performed using Fourier-transform infrared spectroscopy (FTIR) to analyze purity. To demonstrate the compound's stability, dose curve with Cu-TA was carried out using a stock solution that is one-year old as well as a 6-month old stock solution. Cells were also treated with the components used in the formation of Cu-TA (CuCl2 and BPY) to ensure the anti-cancer activity is due to the Cu-TA compound as a whole and cell viability was measured at 24 and 48 h. Western blot and quantitative PCR (qPCR) was done to assess Cu-TA's effect on Sp1, Sp3 and survivin protein and mRNA levels at 24 and 48 h post-treatment. To evaluate potential cardiotoxicity, cardiomyocytes (H9C2) were treated with increasing dosages of Cu-TA or TA and cell viability was measured at 24 and 48 h. Cu-TA was highly effective in suppressing Sp1, Sp3 and survivin protein expression. qPCR results showed that survivin mRNA expression was significantly lower following both Cu-TA and TA treatment; however, the mRNA expression of Sp1 and Sp3 remained unaltered. This suggests that both Cu-TA and TA could be working through a similar mechanism by effecting Sp1 and Sp3 post-translationally, possibly by proteasome-dependent degradation. FTIR results confirmed Cu-TA's purity (>99%) while the dose curves demonstrated the compound's stability. Both Cu-TA and TA did not cause any significant cytotoxicity to H9C2 cells. These results show that Cu-TA is more effective than TA and potentially useful for PC treatment. Studies to precisely understand the underlying mechanisms of Cu-TA are under investigation through molecular profiling analysis. Citation Format: Myrna L. Hurtado, Umesh T. Sankpal, Shahela Mahammad, Jaya Chhabra, Deondra K. Brown, Raj K. Gurung, Alvin Holder, Riyaz Basha. A novel copper(II) complex of tolfenamic acid exhibits anticancer activity in pancreatic cancer cells via downregulation of transcription factors Sp1 and Sp3 and an anti-apoptotic protein, survivin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5804.

The coordination chemistry of bisphosphonates with Yb(3+) was investigated to evaluate the potential of the UV-vis based detection method using the Yb(3+)-pyrocatechol complexation reaction as a sensor for bisphosphonates. The complexation chemistry of Yb(3+) with phosphate and ATP analogs was previously described (E. Gaidamauskas, K. Saejueng, A.A. Holder, S. Bharuah, B.A. Kashemirov, D.C. Crans, C.E. McKenna, J. Biol. Inorg. Chem. 13 (2008) 1291-1299), and we here studied the complexation chemistry of bisphosphonates in this system. The spectrophotometric assay yields direct evidence for formation of a 4:3 metal to ligand complex at neutral pH. Direct evidence for Yb(3+):methylenebis(phosphonate) complexes with 1:1 and 1:2 stoichiometry was also obtained by potentiometry at acidic and basic pH. Direct evidence for complex formation was obtained using (1)H NMR spectroscopy although the stoichiometry was not accessed at neutral pH. Our results suggest that the spectroscopic observation of the YbPV complex can be used to conveniently measure concentrations of bisphosphonates down to 2-3 microM.