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The development of copper(II) thiosemicarbazone complexes as potential anticancer agents, possessing dual functionality as inhibitors of R2 ribonucleotide reductase (RNR) and tubulin polymerization by binding at the colchicine site, presents a promising avenue for enhancing therapeutic effectiveness. Herein, we describe the syntheses and physicochemical characterization of four isomeric proligands H 2 L 3 . Evidently, the position of the morpholine moiety and the copper(II) complex formation have marked effects on the H 2 L 6 , with the methylmorpholine substituent at pertinent positions of the pyridine ring, along with their corresponding Cu(II) complexes 3 - 6 . Evidently, the position of the morpholine moiety and the copper(II) complex formation have marked effects on the in vitro antiproliferative activity in human uterine sarcoma MES-SA cells and the multidrug-resistant derivative MES-SA/Dx5 cells. Activity correlated strongly with quenching of the tyrosyl radical (Y • ) of mouse R2 RNR protein, inhibition of RNR activity in the cancer cells, and inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity, supported by experimental results and molecular modeling calculations, are presented.

A series of latonduine and indoloquinoline derivatives HL 1 - HL 8 and their copper(II) complexes ( 1-8 ) were synthesized and comprehensively characterized. The structures of five compounds ( HL 6 , [CuCl(L 1 )(DMF)]·DMF , [CuCl(L 2 )(CH 3 OH)] , [CuCl(L 3 )]·0.5H 2 O , and [CuCl 2 (H 2 L 5 )]Cl·2DMF ) were elucidated by single crystal X-ray diffraction. The copper(II) complexes revealed low micro- to sub-micromolar IC 50 values with promising selectivity toward human colon adenocarcinoma multidrug-resistant Colo320 cancer cells as compared to the doxorubicin-sensitive Colo205 cell line. The lead compounds HL 4 and 4 as well as HL 8 and 8 induced apoptosis efficiently in Colo320 cells. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. HL 8 showed selective inhibition for the PIM-1 enzyme, while 8 revealed strong inhibition of five other enzymes, i.e., SGK-1, PKA, CaMK-1, GSK3β, and MSK1, from a panel of 50 kinases. Furthermore, molecular modeling of the ligands and complexes showed a good fit to the binding pockets of these targets.

Three new thiosemicarbazones (TSCs) HL 1 - HL 3 as triapine analogues bearing a redox-active phenolic moiety at the terminal nitrogen atom were prepared. Reactions of HL 1 O in anoxic methanol afforded three copper(II) complexes, namely, HL 3 with CuCl 2 ·2H 2 O in anoxic methanol afforded three copper(II) complexes, namely, Cu(HL 1 )Cl 2 ( 1 ), [ Cu(L 2 )Cl] ( 2' ), and Cu(HL 3 )Cl 2 ( 3 ), in good yields. Solution speciation studies revealed that the metal-free ligands are stable as HL 1 - HL 3 at pH 7.4, while being air-sensitive in the basic pH range. In dimethyl sulfoxide they exist as a mixture of E and Z isomers. A mechanism of the E/Z isomerization with an inversion at the nitrogen atom of the Schiff base imine bond is proposed. The monocationic complexes [Cu(L 1 - 3 )] + are the most abundant species in aqueous solutions at pH 7.4. Electrochemical and spectroelectrochemical studies of 1 , 2' , and 3 confirmed their redox activity in both the cathodic and the anodic region of potentials. The one-electron reduction was identified as metal-centered by electron paramagnetic resonance spectroelectrochemistry. An electrochemical oxidation pointed out the ligand-centered oxidation, while chemical oxidations of HL 1 and HL 2 as well as 1 and 2' afforded several two-electron and four-electron oxidation products, which were isolated and comprehensively characterized. Complexes 1 and 2' showed an antiproliferative activity in Colo205 and Colo320 cancer cell lines with half-maximal inhibitory concentration values in the low micromolar concentration range, while 3 with the most closely related ligand to triapine displayed the best selectivity for cancer cells versus normal fibroblast cells (MRC-5). HL 1 and 1 in the presence of 1,4-dithiothreitol are as potent inhibitors of mR2 ribonucleotide reductase as triapine.

A series of thiosemicarbazone-coumarin hybrids ( HL 1 -HL 3 and H 2 L 4 ) has been synthesised in 12 steps and used for the preparation of mono- and dinuclear copper(II) complexes, namely Cu(HL 1 )Cl 2 ( 1 ), Cu(HL 2 )Cl 2 ( 2 ), Cu(HL 3 )Cl 2 ( 3 ) and Cu 2 (H 2 L 4 )Cl 4 ( 4 ), isolated in hydrated or solvated forms. Both the organic hybrids and their copper(II) and dicopper(II) complexes were comprehensively characterised by analytical and spectroscopic techniques, i.e., elemental analysis, ESI mass spectrometry, 1D and 2D NMR, IR and UV-vis spectroscopies, cyclic voltammetry (CV) and spectroelectrochemistry (SEC). Re-crystallisation of 1 from methanol afforded single crystals of copper(II) complex with monoanionic ligand Cu(L 1 )Cl , which could be studied by single crystal X-ray diffraction (SC-XRD). The prepared copper(II) complexes and their metal-free ligands revealed antiproliferative activity against highly resistant cancer cell lines, including triple negative breast cancer cells MDA-MB-231, sensitive COLO-205 and multidrug resistant COLO-320 colorectal adenocarcinoma cell lines, as well as in healthy human lung fibroblasts MRC-5 and compared to those for triapine and doxorubicin. In addition, their ability to reduce the tyrosyl radical in mouse R2 protein of ribonucleotide reductase has been ascertained by EPR spectroscopy and the results were compared with those for triapine.

Thiosemicarbazones continue to attract the interest of researchers as potential anticancer drugs. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, or triapine, is the most well-known representative of this class of compounds that has entered multiple phase I and II clinical trials. Two new triapine derivatives HL 1 and HL 2 were prepared by condensation reactions of 2-pyridinamidrazone and S-methylisothiosemicarbazidium chloride with 3- N -( tert -butyloxycarbonyl) amino-pyridine-2-carboxaldehyde, followed by a Boc-deprotection procedure. Subsequent reaction of HL 1 and HL 2 with CuCl 2 ·2H 2 O in 1:1 molar ratio in methanol produced the complexes [Cu II (HL 1 )Cl 2 ]·H 2 O ( 1·H 2 O ) and [Cu II (HL 2 )Cl 2 ] ( 2 ). The reaction of HL 2 with Fe(NO 3 ) 3 ∙9H 2 O in 2:1 molar ratio in the presence of triethylamine afforded the complex [Fe III (L 2 ) 2 ]NO 3 ∙0.75H 2 O ( 3∙0.75H 2 O ), in which the isothiosemicarbazone acts as a tridentate monoanionic ligand. The crystal structures of HL 1 , HL 2 and metal complexes 1 and 2 were determined by single crystal X-ray diffraction. The UV-Vis and EPR spectroelectrochemical measurements revealed that complexes 1 and 2 underwent irreversible reduction of Cu(II) with subsequent ligand release, while 3 showed an almost reversible electrochemical reduction in dimethyl sulfoxide (DMSO). Aqueous solution behaviour of HL 1 and 1, as well as of HL 2 and its complex 2 , was monitored as well. Complexes 1 - 3 were tested against ovarian carcinoma cells, as well as noncancerous embryonic kidney cells, in comparison to respective free ligands, triapine and cisplatin. While the free ligands HL 1 and HL 2 were devoid of antiproliferative activity, their respective metal complexes showed remarkable antiproliferative activity in a micromolar concentration range. The activity was not related to the inhibition of ribonucleotide reductase (RNR) R2 protein, but rather to cancer cell homeostasis disturbance-leading to the disruption of cancer cell signalling.

A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([H 2 L R ]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HL R )Cl]Cl ( 1 - 4 ) were synthesised with the aim to study (i) their antiproliferative activity in cancer cells and, (ii) for the first time for thiosemicarbazones, the interaction with membrane transport proteins, specifically organic cation transporters OCT1-3. The compounds were comprehensively characterised by analytical, spectroscopic and X-ray diffraction methods. The highest cytotoxic effect was observed in the neuroblastoma cell line SH-5YSY after 24 h exposure and follows the rank order: 3 > 2 > 4 > cisplatin > 1 >>[H 2 L R ]Cl. The copper(II) complexes showed marked interaction with OCT1-3, comparable to that of well-known OCT inhibitors (decynium 22, prazosin and corticosterone) in the cell-based radiotracer uptake assays. The work paves the way for the development of more potent and selective anticancer drugs and/or OCT inhibitors., Competing Interests: The authors declare no conflict of interest.

Four Schiff bases derived from 7-hydrazin-yl-5,8-dihydroindolo[2,3-d][2]benzazepin-(6H)-one and its bromo-substituted analogue (HL1-HL4) and four copper(ii) complexes 1-4 have been synthesised and fully characterised by standard spectroscopic methods (1H and 13C NMR, UV-vis), ESI mass spectrometry, single crystal X-ray diffraction and spectroelectrochemistry. In addition, two previously reported complexes with paullone ligands 5 and 6 were prepared and studied for comparison reasons. The CuII ion in 1-4 is five-coordinate and adopts a square-pyramidal or slightly distorted square-pyramidal coordination geometry. The ligands HL1-4 act as tridentate, the other two coordination places are occupied by two chlorido co-ligands. The organic ligands in 2 and 3 are bound tighter to copper(ii) when compared to related paullone ligands in 5 and 6. The new compounds show very strong cytotoxic activity against human colon adenocarcinoma doxorubicin-sensitive Colo 205 and multidrug resistant Colo 320 cancer cell lines with IC50 values in the low micromolar to nanomolar concentration range.

Six morpholine-(iso)thiosemicarbazone hybrids HL 1 -HL 6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L 1-6 )Cl] (1-6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2-5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC 50 values at 2-5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.

X- and Q-band electron paramagnetic resonance (EPR) spectroscopy was used to characterize polycrystalline Cu(II) complexes that contained sodium 5-sulfonate salicylaldehyde thiosemicarbazones possessing a hydrogen, methyl, ethyl, or phenyl substituent at the terminal nitrogen. The ability of thiosemicarbazone proligands to generate superoxide radical anions and hydroxyl radicals upon their exposure to UVA irradiation in aerated aqueous solutions was evidenced by the EPR spin trapping technique. The UVA irradiation of proligands in neutral or alkaline solutions and dimethylsulfoxide (DMSO) caused a significant decrease in the absorption bands of aldimine and phenolic chromophores. Mixing of proligand solutions with the equimolar amount of copper(II) ions resulted in the formation of 1:1 Cu(II)-to-ligand complex, with the EPR and UV-Vis spectra fully compatible with those obtained for the dissolved Cu(II) thiosemicarbazone complexes. The formation of the complexes fully inhibited the photoinduced generation of reactive oxygen species, and only subtle changes were found in the electronic absorption spectra of the complexes in aqueous and DMSO solutions upon UVA steady-state irradiation. The dark redox activity of copper(II) complexes and proligand/Cu(II) aqueous solutions towards hydrogen peroxide which resulted in the generation of hydroxyl radicals, was confirmed by spin trapping experiments., Competing Interests: The authors declare no conflict of interest.

A series of water-soluble sodium salts of 3-formyl-4-hydroxybenzenesulfonic acid thiosemicarbazones (or sodium 5-sulfonate-salicylaldehyde thiosemicarbazones) containing different substituents at the terminal nitrogen atom (H, Me, Et, Ph) and their copper(ii) complexes have been prepared and characterised by elemental analysis, spectroscopic techniques (IR, UV-vis, 1 H NMR), ESI mass spectrometry, X-ray crystallography and cyclic voltammetry. The proligands and their copper(ii) complexes exhibit moderate water solubility and good stability in aqueous environment, determined by investigating their proton dissociation and complex formation equilibria. The copper(ii) complexes showed moderate anticancer activity in established human cancer cell lines, while the proligands were devoid of cytotoxicity. The anticancer activity of the copper(ii) complexes correlates with their ability to induce ROS accumulation in cells, consistent with their redox potentials within the biological window, triggering the activation of antioxidation defense mechanisms in response to the ROS insult. These studies pave the way for the investigation of ROS-inducing copper(ii) complexes as prospective antiproliferative agents in cancer chemotherapy.

In this study, 2-formylpyridine thiosemicarbazones and three different heterocyclic pharmacophores were combined to prepare thiosemicarbazone–piperazine mPip-FTSC (HL1) and mPip-dm-FTSC (HL2), thiosemicarbazone–morpholine Morph-FTSC (HL3) and Morph-dm-FTSC (HL4), thiosemicarbazone–methylpyrrole-2-carboxylate hybrids mPyrr-FTSC (HL5) and mPyrr-dm-FTSC (HL6) as well as their copper(II) complexes [CuCl(mPipH-FTSC-H)]Cl (1 + H)Cl, [CuCl(mPipH-dm-FTSC-H)]Cl (2 + H)Cl, [CuCl(Morph-FTSC-H)] (3), [CuCl(Morph-dm-FTSC-H)] (4), [CuCl(mPyrr-FTSC-H)(H2O)] (5) and [CuCl(mPyrr-dm-FTSC-H)(H2O)] (6). The substances were characterized by elemental analysis, one- and two-dimensional NMR spectroscopy (HL1–HL6), ESI mass spectrometry, IR and UV–vis spectroscopy and single crystal X-ray diffraction (1–5). All compounds were prepared in an effort to generate potential antitumor agents with an improved therapeutic index. In addition, the effect of structural alterations with organic hybrids on aqueous solubility and copper(II) coordination ability was investigated. Complexation of ligands HL2 and HL4 with copper(II) was studied in aqueous solution by pH-potentiometry, UV–vis spectrophotometry and EPR spectroscopy. Proton dissociation processes of HL2 and HL4 were also characterized in detail and microscopic constants for the Z/E isomers were determined. While the hybrids HL5, HL6 and their copper(II) complexes 5 and 6 proved to be insoluble in aqueous solution, precluding antiproliferative activity studies, the thiosemicarbazone–piperazine and thiosemicarbazone–morpholine hybrids HL1–HL4, as well as copper(II) complexes 1–4 were soluble in water enabling cytotoxicity assays. Interestingly, the metal-free hybrids showed very low or even a lack of cytotoxicity (IC50 values > 300 μM) in two human cancer cell lines HeLa (cervical carcinoma) and A549 (alveolar basal adenocarcinoma), whereas their copper(II) complexes were cytotoxic showing IC50 values from 25.5 to 65.1 μM and 42.8 to 208.0 μM, respectively in the same human cancer cell lines after 48 h of incubation. However, the most sensitive for HL4 and complexes 1–4 proved to be the human cancer cell line LS174 (colon carcinoma) as indicated by the calculated IC50 values varying from 13.1 to 17.5 μM.

A new paullone-TEMPO conjugate and its copper(II) complex inhibit RNR activity and show high antiproliferative activity in human cancer cell lines.

Dicopper(II) and dizinc(II) complexes [Cu2((MeOOC)L(COO))(CH3COO)2] (1) and [Zn2((MeOOC)L(COO))(CH3COO)2] (2) were synthesized by reaction of Cu(CH3COO)2·H2O and Zn(CH3COO)2·2H2O with a new nonsymmetric dinucleating ligand (EtOOC)HL(COOEt) prepared by condensation of 6-hydrazinyl-11H-indolo[3,2-c]quinoline with diethyl-2,2'-((3-formyl-2-hydroxy-5-methylbenzyl)azanediyl)diacetate. The design and synthesis of this elaborate ligand was performed with the aim of increasing the aqueous solubility of indolo[3,2-c]quinolines, known as biologically active compounds, and investigating the antiproliferative activity in human cancer cell lines and the cellular distribution by exploring the intrinsic fluorescence of the indoloquinoline scaffold. The compounds have been comprehensively characterized by elemental analysis, spectroscopic methods (IR, UV-vis, (1)H and (13)C NMR spectroscopy), ESI mass spectrometry, magnetic susceptibility measurements, and UV-vis complex formation studies (for 1) as well as by X-ray crystallography (1 and 2). The antiproliferative activity of (EtOOC)HL(COOEt), 1, and 2 was determined by the MTT assay in three human cancer cell lines, namely, A549 (nonsmall cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon adenocarcinoma), yielding IC50 values in the micromolar concentration range and showing dependence on the cell line. The effect of metal coordination on cytotoxicity of (EtOOC)HL(COOEt) is also discussed. The subcellular distribution of (EtOOC)HL(COOEt) and 2 was investigated by fluorescence microscopy, revealing similar localization for both compounds in cytoplasmic structures.

Two proline-thiosemicarbazone bioconjugates with excellent aqueous solubility, namely, 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone [L-Pro-FTSC or (S)-H2L] and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone [D-Pro-FTSC or (R)-H2L], have been synthesized and characterized by elemental analysis, one- and two-dimensional (1)H and (13)C NMR spectroscopy, and electrospray ionization mass spectrometry. The complexation behavior of L-Pro-FTSC with copper(II) in an aqueous solution and in a 30% (w/w) dimethyl sulfoxide/water mixture has been studied via pH potentiometry, UV-vis spectrophotometry, electron paramagnetic resonance, (1)H NMR spectroscopy, and spectrofluorimetry. By the reaction of copper(II) acetate with (S)-H2L and (R)-H2L in water, the complexes [Cu(S,R)-L] and [Cu(R,S)-L] have been synthesized and comprehensively characterized. An X-ray diffraction study of [Cu(S,R)-L] showed the formation of a square-pyramidal complex, with the bioconjugate acting as a pentadentate ligand. Both copper(II) complexes displayed antiproliferative activity in CH1 ovarian carcinoma cells and inhibited Topoisomerase IIα activity in a DNA plasmid relaxation assay.

Two enantiomerically pure thiosemicarbazone-proline conjugates with enhanced aqueous solubility, namely, 2-hydroxy-3-methyl-(S)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [L-Pro-STSC or (S)-H(2)L] and 2-hydroxy-3-methyl-(R)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [D-Pro-STSC or (R)-H(2)L] have been synthesized and characterized by elemental analysis, spectroscopic methods (UV-vis and (1)H and (13)C NMR), and electrospray ionization mass spectrometry. The metal complexation behavior of L-Pro-STSC, stoichiometry, and thermodynamic stability of iron(II), iron(III), copper(II), and zinc(II) complexes in 30% (w/w) dimethyl sulfoxide/H(2)O solvent mixture have been studied by pH-potentiometric, UV-vis-spectrophotometric, circular dichroism, electron paramagnetic resonance, (1)H NMR spectroscopic, and spectrofluorimetric measurements. By the reaction of CuCl(2)·2H(2)O with (S)-H(2)L and (R)-H(2)L, respectively, the complexes [Cu[(S)-H(2)L]Cl]Cl and [Cu[(R)-H(2)L]Cl]Cl have been prepared and comprehensively characterized. An X-ray diffraction study of [Cu[(R)-H(2)L]Cl]Cl showed the formation of a square-planar copper(II) complex, which builds up stacks with interplanar separation of 3.3 Å. The antiproliferative activity of two chiral ligands and their corresponding copper(II) complexes has been tested in two human cancer cell lines, namely, SW480 (colon carcinoma) and CH1 (ovarian carcinoma). The thiosemicarbazone-proline conjugates L- and D-Pro-STSC show only moderate cytotoxic potency with IC(50) values of 62 and 75 μM, respectively, in CH1 cells and >100 μM in SW480 cells. However, the corresponding copper(II) complexes are 13 and 5 times more potent in CH1 cells, based on a comparison of IC(50) values, and in SW480 cells the increase in the antiproliferative activity is even higher. In both tested cell lines, L-Pro-STSC as well as its copper(II) complex show slightly stronger antiproliferative activity than the compounds with a D-Pro moiety, yielding IC(50) values of 4.6 and 5.5 μM for [Cu(L-Pro-STSC)Cl]Cl in CH1 and SW480 cells, respectively.

Template condensation of 3,5-di-tert-butyl-2-hydroxybenzaldehyde S-methylisothiosemicarbazone with pentane-2,4-dione and triethyl orthoformate at elevated temperatures resulted in metal complexes of the type M(II)L, where M = Ni and Cu and H(2)L = a novel tetradentate ligand. These complexes are relevant to the active site of the copper enzymes galactose oxidase and glyoxal oxidase. Demetalation of Ni(II)L with gaseous hydrogen chloride in chloroform afforded the metal-free ligand H(2)L. Then by the reaction of H(2)L with Zn(CH(3)COO)(2)·2H(2)O in a 1:1 molar ratio in 1:2 chloroform/methanol, the complex Zn(II)L(CH(3)OH) was prepared. The three metal complexes and the prepared ligand were characterized by spectroscopic methods (IR, UV-vis, and NMR spectroscopy), X-ray crystallography, and DFT calculations. Electrochemically generated one-electron oxidized metal complexes [NiL](+), [CuL](+), and [ZnL(CH(3)OH)](+) and the metal-free ligand cation radical [H(2)L](+•) were studied by EPR/UV-vis-NIR and DFT calculations. These studies demonstrated the interaction between the metal ion and the phenoxyl radical.

The reaction of copper(II) chloride or copper(II) acetate with 6-N-(2-N',N'-dimethylaminoethylamino)-7,12-dihydroindolo-[3,2-d][1]benzazepine (HL(1)), 9-bromo-6-N-(2-N',N'-dimethylaminoethylamino)-7,12-dihydroindolo[3,2-d][1]benzazepine (HL(2)), N-(9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-yliden-N'-(1-pyridin-2-yl-methylidene)azine (HL(3)), or N-(9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-yliden-N'-(1-pyridin-2-yl-ethylidene)azine (HL(4)) in methanol affords the novel copper(II) complexes [Cu(HL(1))Cl(2)] (1), [Cu(HL(2))Cl(2)] (2), [Cu(HL(3))Cl(2)] (3), [Cu(HL(4))Cl(2)] (4), and [Cu(L(4))(CH(3)COO)(CH(3)OH)] (5). The new ligands (HL(2) and HL(3)) and the complexes 1-5 were characterized by (1)H and (13)C NMR, IR and electronic absorption spectroscopy, ESI mass spectrometry, and X-ray crystallography. Two ligands, HL(1) and HL(2), and complexes 1-4 were tested for cytotoxicity in three human cancer cell lines, namely, CH1 (ovarian carcinoma), A549 (non-small cell lung cancer), and SW480 (colon carcinoma). Additionally, complexes 1, 2, and 4 were assayed in an isogenic pair of ovarian cancer cell lines, one being sensitive to cisplatin (A2780) and the other having acquired cisplatin resistance (A2780cisR). All of the compounds evaluated are cytotoxic, with complexes 3 and 4 exhibiting IC(50) values in the nanomolar range.

Quite recently we discovered that copper(II) complexes with isomeric morpholine-thiosemicarbazone hybrid ligands show good cytotoxicity in cancer cells and that the molecular target responsible for this activity might be tubulin. In order to obtain better lead drug candidates, we opted to exploit the power of coordination chemistry to (i) assemble structures with globular shape to better fit the colchicine pocket and (ii) vary the metal ion. We report the synthesis and full characterization of bis-ligand cobalt(III) and iron(III) complexes with 6-morpholinomethyl-2-formylpyridine 4N-(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL1), 6-morpholinomethyl-2-acetylpyridine 4N-(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL2), and 6-morpholinomethyl-2-formylpyridine 4N-phenyl-3-thiosemicarbazone (HL3), and mono-ligand nickel(II), zinc(II) and palladium(II) complexes with HL1, namely [CoIII(HL1)(L1)](NO3)2 (1), [CoIII(HL2)(L2)](NO3)2 (2), [CoIII(HL3)(L3)](NO3)2 (3), [FeIII(L2)2]NO3 (4), [FeIII(HL3)(L3)](NO3)2 (5), [NiII(L1)]Cl (6), [Zn(L1)Cl] (7) and [PdII(HL1)Cl]Cl (8). We discuss the effect of the metal identity and metal complex stoichiometry on in vitro cytotoxicity and antitubulin activity. The high antiproliferative activity of complex 4 correlated well with inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity were supported by experimental results and molecular docking calculations. [ABSTRACT FROM AUTHOR]

A series of four indolo[2,3-e]benzazocines HL1–HL4 and two indolo[2,3-f]benzazonines HL5 and HL6, as well as their respective copper(II) complexes 1–6, were synthesized and characterized by 1H and 13C NMR spectroscopy, ESI mass spectrometry, single crystal X-ray diffraction (SC-XRD) and combustion analysis (C, H, N). SC-XRD studies of precursors Vd, VIa·0.5MeOH, of ligands HL4 and HL6·DCM, and complexes 2·2DMF, 5·2DMF, 5′·iPrOH·MeOH provided insights into the energetically favored conformations of eight- and nine-membered heterocycles in the four-ring systems. In addition, proton dissociation constants (pKa) of HL1, HL2 and HL5, complexes 1, 2 and 5, overall stability constants (log β) of 1, 2 and 5 in 30% (v/v) DMSO/H2O at 298 K, as well as thermodynamic solubility of HL1–HL6 and 1–6 in aqueous solution at pH 7.4 were determined by UV–vis spectroscopy. All compounds were tested for antiproliferative activity against Colo320, Colo205 and MCF-7 cell lines and showed IC50 values in the low micromolar to sub-micromolar concentration range, while some of them (HL1, HL5 and HL6, 1, 2 and 6) showed remarkable selectivity towards malignant cell lines. Ethidium bromide displacement studies provided evidence that DNA is not the primary target for these drugs. Rather, inhibition of tubulin assembly is likely the underlying mechanism responsible for their antiproliferative activity. Tubulin disassembly experiments showed that HL1 and 1 are effective microtubule destabilizing agents binding to the colchicine site. This was also confirmed by molecular modelling investigations. To the best of our knowledge, complex 1 is the first reported transition metal complex to effectively bind to the tubulin-colchicine pocket. [ABSTRACT FROM AUTHOR]

In the title hydrated mol­ecular salt, [Cu(C7H20N4)(H2O)2](C8H4O4)·H2O, the metal ion is coordinated by the two primary and two secondary N atoms of the amine ligand and the mutually trans O atoms of the water mol­ecules in a tetra­gonally distorted octa­hedral geometry. The average equatorial Cu--N bond lengths (2.013 and 2.026 Å for Cu--Nprim and Cu--Nsec, respectively) are substanti­ally shorter than the average axial Cu--O bond length (2.518 Å). The tetra­amine ligand adopts its energetically favored conformation with its five- and six-membered chelate rings in gauche and chair conformations, respectively. In the crystal, the N--H donor groups of the tetra­amine, the acceptor carboxyl­ate groups of the isophthalate dianion and both the coordinated water mol­ecules and the water mol­ecule of crystallization are involved in numerous N--H...O and O--H...O hydrogen bonds, resulting in the formation of electroneutral layers oriented parallel to the ac plane. [ABSTRACT FROM AUTHOR]

The asymmetric unit of the title com­pound, catena-poly[[[(perchlorato-κO)copper(II)]-μ-3-(3-carb­oxy­prop­yl)-1,5,8,12-tetra­aza-3-azonia­cyclo­tetra­decane-κ4N¹,N5,N8,N12] bis­(per­chlorate)], {[Cu(C13H30N5O2)(ClO4)](ClO4)2}n, (I), consists of a macrocyclic cation, one coordinated per­chlorate anion and two per­chlorate ions as counter-anions. The metal ion is coordinated in a tetra­gonally distorted octa­hedral geometry by the four secondary N atoms of the macrocyclic ligand, the mutually trans O atoms of the per­chlorate anion and the carbonyl O atom of the protonated carb­oxy­lic acid group of a neighbouring cation. The average equatorial Cu—N bond lengths [2.01 (6) Å] are significantly shorter than the axial Cu—O bond lengths [2.379 (8) Å for carboxyl­ate and average 2.62 (7) Å for disordered per­chlorate]. The coordinated macrocyclic ligand in (I) adopts the most energetically favourable trans-III conformation with an equatorial orientation of the substituent at the protonated distal 3-position N atom in a six-membered chelate ring. The coordination of the carb­oxy­lic acid group of the cation to a neighbouring com­plex unit results in the formation of infinite chains running along the b-axis direction, which are cross­linked by N—H∙∙∙O hydrogen bonds between the secondary amine groups of the macrocycle and O atoms of the per­chlorate counter-anions to form sheets lying parallel to the (001) plane. Additionally, the extended structure of (I) is consolidated by numerous intra- and interchain C—H∙∙∙O contacts. [ABSTRACT FROM AUTHOR]

Four Schiff bases derived from 7-hydrazin-yl-5,8-dihydroindolo[2,3-d][2]benzazepin-(6H)-one and its bromo-substituted analogue (HL1–HL4) and four copper(ii) complexes 1–4 have been synthesised and fully characterised by standard spectroscopic methods (1H and 13C NMR, UV-vis), ESI mass spectrometry, single crystal X-ray diffraction and spectroelectrochemistry. In addition, two previously reported complexes with paullone ligands 5 and 6 were prepared and studied for comparison reasons. The CuII ion in 1–4 is five-coordinate and adopts a square-pyramidal or slightly distorted square-pyramidal coordination geometry. The ligands HL1–4 act as tridentate, the other two coordination places are occupied by two chlorido co-ligands. The organic ligands in 2 and 3 are bound tighter to copper(ii) when compared to related paullone ligands in 5 and 6. The new compounds show very strong cytotoxic activity against human colon adenocarcinoma doxorubicin-sensitive Colo 205 and multidrug resistant Colo 320 cancer cell lines with IC50 values in the low micromolar to nanomolar concentration range. [ABSTRACT FROM AUTHOR]

The asymmetric units of the title compounds, trans-di­aqua­(3-benzyl-1,3,5,8,12-penta­aza­cyclo­tetra­decane-κ4N¹,N5,N8,N12)copper(II) isophthalate monohydrate, [Cu(C16H29N5)(H2O)2](C8H4O4)·H2O, (I), and trans-di­aqua­[3-(pyridin-3-ylmeth­yl)-1,3,5,8,12-penta­aza­cyclo­tetra­decane-κ4N¹,N5,N8,N12]copper(II) iso­phthalate 0.9-hydrate, [Cu(C15H28N6)(H2O)2](C8H4O4)·0.9H2O, (II) consist of one di­aqua macrocyclic cation, one di­carboxyl­ate anion and uncoordinated water mol­ecule(s). In each compound, the metal ion is coordinated by the four secondary N atoms of the macrocyclic ligand and the mutually trans O atoms of the water mol­ecules in a tetra­gonally distorted octa­hedral geometry. The average equatorial Cu—N bond lengths are significantly shorter than the average axial Cu—O bond lengths [2.020 (9) versus 2.495 (12) Å and 2.015 (4) versus 2.507 (7) Å for (I) and (II), respectively]. The coordinated macrocyclic ligand in the cations of both compounds adopts the most energetically favorable trans-III conformation. In the crystals, the complex cations and counter-anions are connected via hydrogen-bonding inter­actions between the N—H groups of the macrocycles and the O—H groups of coordinated water mol­ecules as the proton donors and the O atoms of the carboxyl­ate as the proton acceptors. Additionally, as a result of O—H···O hydrogen bonding with the coordinated and water mol­ecules of crystallization, the isophthalate dianions form layers lying parallel to the (01) and (100) planes in (I) and (II), respectively. [ABSTRACT FROM AUTHOR]

The asymmetric unit of the title compound, trans-di­aqua­(3,10-dimethyl-1,3,5,8,10,12-hexa­aza­cyclo­tetra­decane-κ4N¹,N5,N8,N12)copper(II) 4,4′-methyl­ene­bis(3-hy­droxy­naphthalene-2-carboxyl­ate), [Cu(C10H26N6)(H2O)2](C23H14O6) {[Cu(L)(H2O)2](pam), where L = 3,10-dimethyl-1,3,5,8,10,12-hexa­aza­cyclo­tetra­decane and pam = dianion of pamoic acid} consists of two independent halves of the [Cu(L)(H2O)2]2+ cation and one di­carboxyl­ate anion. The CuII atoms, lying on inversion centres, are coordinated by the four secondary N atoms of the macrocyclic ligands and the mutually trans O atoms of the water mol­ecules in a tetra­gonally elongated octa­hedral geometry. The average equatorial Cu--N bond length is significantly shorter than the average axial Cu--O bond length [2.007 (10) and 2.486 (18) Å, respectively]. The macrocyclic ligand in the complex cations adopts the most energetically stable trans-III conformation. The complex cations and anions are connected via hydrogen-bonding inter­actions between the N--H groups of the macrocycles and the O--H groups of coordinated water mol­ecules as the proton donors and the O atoms of the carboxyl­ate as the proton acceptors into layers lying parallel to the (111) plane. [ABSTRACT FROM AUTHOR]

Two new tetranuclear copper(II) complexes [Cu4(μ4-O)( L1)Cl4] ( 1) and [Cu4(μ4-O)( L2)2Cl4] ( 2), where H2L1 is a macrocyclic ligand resulting from [2+2] condensation of 2,6-diformyl-4-methylphenol (DFF) and 1,3-bis(aminopropyl)tetramethyldisiloxane, and HL2 is a 1:2 condensation product of DFF with trimethylsilyl p-aminobenzoate, have been prepared. The structures of the products were established by X-ray diffraction. The complexes have been characterised by FTIR, UV/Vis spectroscopy, ESI mass-spectrometry and magnetic susceptibility measurements. The latter revealed that the tetranuclear complexes can be described as two ferromagnetically coupled dinuclear units, in which the two copper(II) ions interact antiferromagnetically. The compounds act as homogeneous catalyst precursors for a number of single-pot reactions, including (i) hydrocarboxylation, with CO, H2O and K2S2O8, of a variety of linear and cyclic( n = 5-8) alkanes into the corresponding C n+1 carboxylic acids, (ii) peroxidative oxidation of cyclohexane, and (iii) solvent-free microwave-assisted oxidation of 1-phenylethanol. [ABSTRACT FROM AUTHOR]

Schiff bases derived from aminoguanidine are extensively investigated for their structural versatility. The tridentate 2-formylpyridine guanylhydrazones act as analogues of 2-formyl or 2-acetylpyridine thiosemicarbazones, where the thioamide unit is replaced by the guanidyl group. Six derivatives of 2-formylpyridine guanylhydrazone were synthesized and their proton dissociation and complex formation processes with Cu(II), Fe(II) and Fe(III) ions were studied using pH-potentiometry, UV–visible, NMR and electron paramagnetic resonance spectroscopic methods. The ligands have substituents such as amine, morpholine, N -methyl-piperazine at different positions of the pyridine ring. The influence of the different structural elements on the solution chemical properties and cytotoxicity has been disclosed. The solid state structure of four ligands was determined by X-ray crystallography. The ligands bind to Cu(II) in a tridentate fashion via an (N,N,N) donor set, forming mono-ligand complexes. However, for ligands with heterocyclic morpholine and piperazine nitrogen atoms in coordination position a tetradentate binding was observed. Despite the additional coordinating donor atom, the stability of these Cu(II) complexes showed little or no increase. The Cu(II), Fe(II) and Fe(III) complexes of the studied 2-formylpyridine guanylhydrazones exhibited significantly lower stability compared to their corresponding 2-formyl or 2-acetylpyridine thiosemicarbazone analogues. The ligands underwent slow partial hydrolysis (and oxidation) in the presence of Cu(II) ions, leading to the formation of new ligands through the reorganization of structural components around the metal ion. Additionally, the studied Cu(II) complexes demonstrated a great propensity for reduction by glutathione. All these features contributed to the finding that these 2-formylpyridine guanylhydrazones and their Cu(II) complexes did not display measurable cytotoxic activity. Synopsis Five novel 2-formylpyridine guanylhydrazones were synthesized and characterized to study how different substituents and the C=S → C=NH replacement affect the stability and redox properties of their metal complexes. Compared to thiosemicarbazones, they form weaker Cu(II), Fe(II) and Fe(III) complexes, with reduced cytotoxicity. [Display omitted] • Solution speciation of 2-formylpyridine guanylhydrazone derivatives • Effect of replacing the thioamide moiety by a guanidyl group • Reorganization of structural components around the Cu(II) ion to form new ligands • Morpholine and N -methylpiperazine substituents as additional donor atoms • Weak complexes with endogenous metal ions such as Cu(II), Fe(II) and Fe(III) [ABSTRACT FROM AUTHOR]

An analysis of the molecular structure of the copper(II)complexeswith open-chain and macrocyclic malonamide-derived tetradentate ligandsbased on single crystal X-ray diffraction study of four copper(II)complexes [CuL1(H2O)]·4H2O,[CuL2(H2O)], [CuL3(H2O)],and [CuL4(H2O)] (H2L1= 1,4,8,11-tetraazaundecane-5,7-dione, H2L2= 13-methyl-13-nitro-1,4,8,11-tetraazacyclotetradecane-5,7-dione,H2L3= 1,4,8,11-tetraazacyclotetradecane-5,7-dione,and H2L4= 1,4,8,11-tetraazacyclotridecane-5,7-dione)as well as on published data regarding related compounds revealedthat the violations of planarity of the metal-amide fragments aredue almost exclusively to the deviation of the copper(II) ion fromthe amide plane. Both the deviation of the copper(II) ion from theamide plane and the angle between amide planes in the 6-membered malonamidering are strongly affected by substituents with minimal values observedin the complexes of unsubstituted ligands. The deviation of the copper(II)ion from the basal plane of donor atoms was shown to relate to thesum of bite angles around the copper(II) ion and roughly correlatesto Cu–Laxdistances when apical ligands are present.The crystals of the macrocyclic complexes CuL2to CuL4are built up from similar corrugated layers in which metalcomplex molecules are linked in a “head-to-tail” manner viaNH···OC hydrogen bonds. In contrast,[CuL1(H2O)]·4H2O has a lamellarcrystal structure in which the layers built up of [CuL1(H2O)] units alternate with sheets formed by water molecules. [ABSTRACT FROM AUTHOR]