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A series of manganese complexes bearing 6-nitropiperonal thiosemicarbazone ligands have been synthesized and characterized. The ligands differ by the alkyl substituent on the amine nitrogen. These complexes, formulated as Mn(CO)3(TSC)Br, where TSC represents the thiosemicarbazone ligand, show very rapid release of carbon monoxide upon exposure to light, establishing them as photoCORMs (light activated carbon monoxide-releasing molecules). The photo-reactivity profile of the complexes have been studied in detail using the myoglobin assay as a detection system for carbon monoxide. Three different wavelengths of light were used: 365 nm (UV), 405 nm (purple) and 435 nm (blue). It was observed that the half-life for the CO release was dependent on the wavelength of light. These half-lives were on the order of 10 to 100 seconds which is very fast for this type of complex. Typically, the half-lives increased with a decrease in the energy of the incident radiation. For the compound bearing the phenyl-substituted amine group, t½ (in seconds) was 44.54, 59.59 and 65.90 for the UV, purple and blue light respectively. The amount of CO released was also wavelength dependent, with higher energy wavelength generally releasing more CO. UV light caused 2 equivalents of CO to be released while roughly 1.5 and 1.0 equivalents were released for the purple and blue light respectively. The biological profile of the complexes were also studied using antibacterial and anticancer assays. Against both Gram-negative and Gram-positive bacteria, the complexes showed good growth inhibitory effects with minimum inhibitory concentration (MIC) values no higher than 50 μM and as low as 3.13 μM. More importantly, these estimated MIC values were noticeably reduced when the bacteria, incubated with the complexes, were irradiated. All four compounds displayed intrinsic cytotoxicity against HEK293T (kidney) and A549 (lung carcinoma) cell lines, as indicated by relatively efficient cell killing for CORMs without irradiation. Irradiation of treated cultures with short wavelength visible spectrum light augmented these cytotoxic effects.

A series of four thiosemicarbazones from 6-nitropiperonal along with the corresponding copper complexes were synthesized. The biophysical characteristics of the complexes were investigated by the binding to DNA and human serum albumin. The binding to DNA is moderate; the binding constants run from (0.49–7.50) × 10 4 M − 1 . In relation to HSA, the complexes interact strongly with binding constants on the order of 10 5 M − 1 . The complexes also display antioxidant behavior as determined by the ability to scavenge diphenylpicrylhydrazyl (dpph) and nitric oxide radicals. The antimicrobial profiles of the compounds, tested against a panel of microbes including five of the ESKAPE pathogens ( Staphylococcus aureus , MRSA , Escherichia coli , Klebsiella pneumoniae , MDR , Acinetobacter baumannii , Pseudomonas aeruginosa ) and two yeasts ( Candida albicans and Cryptococcus neoformans var. grubii ), are also described. The compounds contain a core moiety that is similar to oxolinic acid, a quinolone antibiotic that targets DNA gyrase and topoisomerase (IV). The binding interaction between the complexes and these important antibacterial targets were studied by computational methods, chiefly docking studies. The calculated dissociation constants for the interaction with DNA gyrase B (from Staphylococcus aureus ) range from 4.32 to 24.65 μM; the binding was much stronger to topoisomerase IV, with dissociation constants ranging from 0.37 to 1.27 μM.

Ruthenium organometallic compounds represent an attractive avenue in developing alternatives to platinum-based chemotherapeutic agents. While evidence has been presented indicating ruthenium-based compounds interact with isolated DNA in vitro, it is unclear what effect these compounds exert in cells. Moreover, the antibiotic efficacy of polynuclear ruthenium organometallic compounds remains uncertain. In the present study, we report that exposure to polynuclear ruthenium organometallic compounds induces recruitment of damaged DNA sensing protein Xeroderma pigmentosum Group C into chromatin-immobilized foci. Additionally, we observed one of the tested polynuclear ruthenium organometallic compounds displayed increased cytotoxicity against human cells deficient in nucleotide excision repair (NER). Taken together, these results suggest that polynuclear ruthenium organometallic compounds induce DNA damage in cells, and that cellular resistance to these compounds may be influenced by the NER DNA repair phenotype of the cells.

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.

We have synthesized a trio of gallium complexes bearing 9-anthraldehyde thiosemicarbazones. The complexes were assessed for their anticancer activity and their biophysical reactivity was also investigated. The three complexes displayed good cytotoxic profiles against two human colon cancer cell lines, HCT-116 and Caco-2. The IC50 ranged from 4.7 – 44.1 μM with the complex having an unsubstituted amino group on the thiosemicarbazone being the most active. This particular complex also showed a high therapeutic index. All three complexes bind strongly to DNA via intercalation with binding constants ranging from 7.46 × 104 M-1 to 3.25 × 105 M-1. The strength of the binding cannot be directly related to the level of anticancer activity. The complexes also bind strongly to human serum albumin with binding constants on the order of 104 – 105 M-1 as well. The complexes act as chemical nucleases as evidenced by their ability to cleave pBR322 plasmid DNA. The binding constants along with the cleavage results may suggest that the extent of DNA interaction is not directly correlated with anticancer activity. The results of docking studies with DNA, ribonucleotide reductase and human serum albumin, however showed that the complex with the best biological activity had the largest binding constant to DNA.

We have used a novel microwave-assisted method to synthesize a pair of half-sandwich ruthenium–arene–thiosemicarbazone complexes of the type [(η6-C6H6Ru(TSC)Cl]PF6. The thiosemicarbazone (TSC) ligands are 2-(anthracen-9-ylmethylene)hydrazinecarbothioamide and 2-(anthracen-9-ylmethylene)-N-ethylhydrazinecarbothioamide derived from 9-anthraldehyde. The complexes are moderately strong binders of DNA, with binding constants of 104 m−1. They are also strong binders of human serum albumin, having binding constants of the order of 105 m−1. The complexes show some in vitro anticancer activity against human colon cancer cells, Caco-2 and HCT-116, with positive therapeutic indices. They did not show any activity as antibacterial agents against the organisms that were studied. Copyright © 2013 John Wiley & Sons, Ltd.

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.

The synthesis and characterization of a number of organometallic ruthenium(II) complexes containing a series of bidentate thiosemicarbazone ligands derived from piperonal is reported. The structure of compounds have been confirmed by spectroscopic analysis (IR and NMR) as well as X-ray crystallographic analysis of [(η 6 - p -cymene)Ru(pPhTSC)Cl]Cl ( 4 ) (pPhTSC is piperonal-N(4)-phenylthiosemicarbazone). The interaction of the complexes ([(η 6 - p -cymene)Ru(pEtTSC)Cl]Cl) ( 3 ) (pEtTSC is piperonal-N(4)-ethylthiosemicarbazone) and 4 with calf thymus DNA, human serum albumin (HSA) and pBR322 plasmid DNA were studied by spectroscopic, gel electrophoresis and hydrodynamic methods. The apparent binding constant for the interaction with DNA was determined to be 3.97 × 10 3 M − 1 and 4.07 × 10 3 M − 1 at 293 K for 3 and 4 respectively. The complexes bind strongly to HSA with binding constants of 2.94 × 10 4 M − 1 and 12.2 × 10 4 M − 1 at 296 K for 3 and 4 respectively. The in vitro anticancer activity of 3 and 4 has been evaluated against two human colon cancer cell line (HCT-116 and Caco-2) with IC 50 values in the range of 26–150 μM. Both 3 and 4 show good activity as a catalytic inhibitor of human topoisomerase II at concentrations as low as 20 μM. The proficiency of 3 and 4 to act as antibacterial agents was also evaluated against six pathogenic bacterial strains with the best activity seen against Gram-positive strains.

We have used a novel microwave-assisted method developed in our laboratories to synthesize a series of ruthenium-thiosemicarbazone complexes. The new thiosemicarbazone ligands are derived from benzo[d][1,3]dioxole-5-carbaldehyde (piperonal) and the complexes are formulated as [(diimine)(2)Ru(TSC)](PF(6))(2) (where the TSC is the bidentate thiosemicarbazone ligand). The diimine in the complexes is either 2,2'-bipyridine or 1,10-phenanthroline. The complexes have been characterized by spectroscopic means (NMR, IR and UV-Vis) as well as by elemental analysis. We have studied the biophysical characteristics of the complexes by investigating their anti-oxidant ability as well as their ability to disrupt the function of the human topoisomerase II enzyme. The complexes are moderately strong binders of DNA with binding constants of 10(4) M(-1). They are also strong binders of human serum albumin having binding constants on the order of 10(4) M(-1). The complexes show good in vitro anticancer activity against human colon cancer cells, Caco-2 and HCT-116 and indeed show some cytotoxic selectivity for cancer cells. The IC(50) values range from 7 - 159 μM (after 72 h drug incubation). They also have antibacterial activity against Gram-positive strains of pathogenic bacteria with IC(50) values as low as 10 μM; little activity was seen against Gram-negative strains. It has been established that all the compounds are catalytic inhibitors of human topoisomerase II.

The reaction of [(η6-p-cymene)Ru(ATSC)Cl]PF6 (ATSC =9-anthraldehyde thiosemicarbazone) with human serum albumin was investigated at different temperatures using fluorescence and infrared spectrophotometry. The binding constant, K, for the reaction was determined using a number of different methods. Using a modified Stern-Volmer equation, K was determined to be 9.09×104,12.1×104, and 13.1×104 M−1 at 293 K, 298 K, and 308 K, respectively. A thermodynamic analysis showed that the reaction is spontaneous with ΔG being negative. The enthalpy of reaction ΔH=16.5 kJ mol−1 and the entropy of reaction ΔS=152 Jmol−1K−1. The values of ΔH and ΔS suggest that hydrophobic forces are dominant in the mode of interaction and that the process is mostly entropy driven.

A series of half-sandwich arene-ruthenium complexes of the type [(eta(6)-p-cymene) Ru(thiosemicarbazone)Cl](+) have been synthesized and their biological activity investigated. The first structurally characterized arene-ruthenium half-sandwich complex with a thiosemicarbazone ligand is reported.

The kinetics of the stepwise reduction of the title complex [Fe2(CN)10]4− by sulfite have been studied in the presence of air as a function of pH, sulfite concentration, temperature and ionic strength using stopped-flow and conventional spectrophotometric techniques. The kobs versus pH profile shows a marked increase in rate with increase of pH over the range 3.7 ⩽ pH ⩽ 6.1 due to the increase in concentration of the more reactive sulfite species SO 3 2 - . The reaction proceeds in several stages, the first of which involves a one electron transfer process with the formation of the radical anion SO 3 - This then adds on in a rapid stage to form a species [ Fe 2 III ( CN ) 10 ( SO 3 ) ] 5 - . The second and third stages also involve one electron transfer. In the third, or possibly a fourth stage cleavage occurs, the final product being [FeII(CN)5(SO3)]5−. The reaction rate is sensitive to the nature of the cation present with a reactivity sequence Li + Na + K + NH 4 + .

Deprotonation of gramine with nBuLi and subsequent reaction with PCl3 yielded [(LiCl)6{(Me2NCH2C8H5N)3P}2] (2). Compound 2 was characterized by NMR (1H, 13C, 31P) spectroscopy, elemental analysis, and X-ray crystallography. The molecular structure of 2 reveals a novel hexameric lithium chloride aggregate ligated on each of two hexagonal faces by three dimethylamino groups from the intended product, tris{(3-dimethylamino-methyl)indolyl}phosphine. Crystal data for 2 · 3CH2Cl2: C36H45Cl9Li3N6P, monoclinic, P21/n, a = 12.732(4) A, b = 22.251(6) A, c = 16.815(5) A, β = 108.233(5)°, V = 4525(2) A3, Z = 4, Dcalc = 1.369 g/cm3.

The syntheses of Ru3(CO)9(PTA)3 and Ir4(CO)7(PTA)5 were accomplished through the thermal reactions of Ru3(CO)12 or Ir4(CO)12 with the water-soluble phosphine, PTA(1,3,5-triaza-7-phosphaadamantane). The ruthenium derivative was shown by X-ray crystallography to consist of a triangular Ru3 core with three nearly equal Ru–Ru bonds, with each ruthenium atom bearing an equatorially positioned PTA ligand. In Ir4(CO)7(PTA)5 the iridium atoms define a tetrahedron which is bridged on three edges by CO ligands. One basal iridium atom contains two PTA ligands, while the other two basal and the apical iridium atoms each possess one PTA ligand in their coordination spheres. Although, Ru3(CO)9(PTA)3 is only sparingly soluble in pure water, it is very soluble in aqueous solution of pH 24 h).

[VO(Sal-L-tryp)(H2O)] 1 (where sal-L-tryp = N-salicylidene-L-tryptophanate) was used as a precursor to produce the novel complexes, [VO(Sal-L-tryp)(MeATSC)].1.5C2H5OH 2 (where MeATSC = 9-Anthraldehyde-N(4)-methylthiosemicarbazone), [VO(Sal-L-tryp)(N-Ethhymethohcarbthio)].H2O 3 (where N-Ethhymethohcarbthio = (E)-N-ethyl-2-(4-hydroxy-3-methoxybenzylidene)hydrazinecarbothioamide), and [VO(Sal-L-tryp)(acetylethTSC)].C2H5OH 4 (where acetylethTSC = (E)-N-ethyl-2-(1-(thiazol-2-yl)ethylidene)hydrazinecarbothioamide), by reaction with the respective thiosemicarbazone. The chemical and structural properties of these ligands and complexes were characterised by elemental analysis, ESI MS, FT-IR, UV-visible, ESR, 1H and 13C NMR spectroscopy, and X-ray crystallography. DMSO and DMSO-d6 solutions of compounds 1-4 were oxidised in air to produce vanadium(V) species which were verified by ESI MS and 51V NMR spectroscopy. Anti-cancer properties of compounds 2-4 were examined with three colon cancer cell lines, HTC-116, Caco-2, and HT-29, and also with non-cancerous colonic myofibroblasts, CCD18-Co. Compounds 2-3 exhibited less inhibitory effects in the CCD-18Co cells, indicating a possible cytotoxic selectivity towards colon cancer cells. In general, those compounds which exhibited anti-proliferative activity on cancer cells, but did not affect non-cancerous cells, may have a potential in chemotherapy.

A novel thiosemicarbazone from 2-acetonaphthone (represented as acnTSC) has been synthesized and its basic coordination chemistry with zinc(II), cobalt(II), and copper(II) explored. The complexes were characterized by elemental analysis and various spectroscopic techniques and are best formulated as [M(acnTSC)2Cl2] with the metal likely in an octahedral environment. The anticancer activity of the complexes was determined against a panel of human colon cancer cells (HCT-116 and Caco-2). The compounds bind to DNA via an intercalative mode with binding constants of 9.7×104 M-1, 1.8×105 M-1, and 9.5×104 M-1 for the zinc, cobalt, and copper complexes, respectively.

The oxidation of thiosulfate by the iron(III) dimeric complex [Fe2(CN)10]4– in acidic aqueous solution at an ionic strength of 1.0 mol dm–3(Na2SO4) has been investigated by stopped-flow and conventional spectrophotometry. The overall reaction is quite complicated, occurring in two distinct processes. The first comprises two steps, involving an intermediate, and results in a relatively fast one-electron reduction to [Fe2(CN)10]5–, the rate of which was monitored by the stopped-flow technique; this is followed by a much slower second reaction leading to fission of the cyanide bridges and the formation of the pentacyano(thiosulfato)ferrate-(II) and -(III) complexes. Separate mechanisms are given for each step based on the observed kinetic data.

We have synthesized and evaluated the biological properties of a compound of the type [η(6)-p-cymene)Ru(EtATSC)Cl]Cl (1) where EtATSC = 2-anthracen-9-ylmethylene-N-ethylhydrazinecarbothioamide, a thiosemicarbazone. The complex has been characterized by elemental analysis, spectroscopically (NMR, UV-Vis, and IR) and structurally by XRD. The in vitro anticancer activity of 1 has been evaluated against two human colon cancer cell lines. The IC(50) value for activity against HCT-116 was 224 ± 7 μM and 205 ± 5 μM against the Caco-2 cell line. The proficiency of 1 as an antibacterial agent was also evaluated against six bacterial strains. The minimum inhibitory concentration for Bacillus cereus was determined to be 5 μM and for Enterococcus faecalis it was 20 μM. At the maximum concentration tested the complex showed no activity against the Gram-negative strains. The complex binds strongly to human serum albumin with a binding constant of 1.37 ± 0.02 M(-1) at 308 K on a single binding site. It is also a strong binder to DNA with an apparent binding constant of 2.82 × 10(5) M(-1) at 308 K. 1 shows very good activity as a catalytic inhibitor of human topoisomerase II at concentrations as low as 20 μM.

A novel microwave-assisted synthetic method has been used to synthesise a series of mixed ligand ruthenium(II) compounds containing diimine as well as bidentate thiosemicarbazone ligands. The compounds contain the diimine 1,10-phenanthroline (phen) or 2,2'-bipyridine (bpy) and the thiosemicarbazone is derived from 9-anthraldehyde. Based on elemental analyses and spectroscopic data, the compounds are best formulated as [(phen)(2)Ru(thiosemicarbazone)](PF(6))(2) and [(phen)(2)Ru(thiosemicarbazone)](PF(6))(2) where thiosemicarbazone = 9-anthraldehydethiosemicarbazone, 9-anthraldehyde-N(4)-methylthiosemicarbazone, and 9-anthraldehyde-N(4)-ethylthiosemicarbazone. Fluorescence competition studies with ethidium bromide, along with viscometric measurements suggests that the complexes bind calf thymus DNA (CTDNA) relatively strongly via an intercalative mode possibly involving the aromatic rings of the diimine ligands. The complexes show good cytotoxic profiles against MCF-7 and MDA-MB-231 (breast adenocarcinoma) as well as HCT 116 and HT-29 (colorectal carcinoma) cell lines.

L-Cysteine reduces [Fe2(CN)10]4– to [Fe2(CN)10]6– in a two stage process, a rapid reduction to [Fe2(CN)10]5– followed by a slower second order reaction involving HSCH2CH(NH3+)CO2– and a conjugate base.

The oxidation of L-ascorbic acid by the iron(III) dimeric complex [Fe2(CN)10]4– in acidic aqueous solution at an ionic strength of 1.0 mol dm–3(NaClO4) has been studied by stopped-flow spectrophotometry. The overall reaction, which entails reduction of both iron(III) centres followed by aquation resulting in the formation of 2 mol of [Fe(CN)5(OH2)]3–, takes place in three stages. The first is a one-electron reduction to form the mixed-valence iron(III, II) dimer followed by a second one-electron reduction of the other iron(III) centre to form the iron(II) dimer. The third stage which occurs with a very small absorbance change was not studied. The mechanisms for both stages of the reaction are similar and involve formation of an ion triplet [Fe2(CN)10]n–·M+·Ap– where n= 4 or 5 and Ap– is the reacting ascorbate species with p= 1 or 2. The rate law was found to be of the form (i) where [A]T is the total concentration of added ascorbate, k1 and k2 the acid dissociation constants Rate =k′K1[H+]+k″K1K2//K1K2+K1[H+]+[H+]2[A]T[complex](i), of ascorbic acid and k′ and k″ the pseudo-second-order rate constants. They were found to be 6.44 × 103, 2.48 × 109 and 1.25 × 103, 2.98 × 108 dm3 mol–1 s–1 at 19 °C for HA– and A2– for the first and second stages respectively. The reaction is affected by alkali-metal cations, increasing rate with increasing size of the metal ions: Li+ < Na+ < K+.