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The success of a classic inorganic coordination compound, Cisplatin, cis-[Pt(NH 3 ) 2 Cl 2 ], as the first anticancer metallodrug started a field of research dedicated to discovering coordination compounds with antitumor activity, encompassing various metals. Among these, copper complexes have emerged as interesting candidates to develop drugs to treat cancer. In this work, mixed ligand complexes of Cu(II) with diimines (phenanthroline or 4-methylphenanthroline) and 3-(4-hydroxyphenyl)propanoate, phenylcarboxylate or phenylacetate were synthesized. They were characterized in the solid state, including a new crystal structure of [Cu 2 (3-(4-hydroxyphenyl)propanoate) 3 (phenanthroline) 2 ]Cl·H 2 O. The obtained complexes presented a variety of stoichiometries. In solution, complexes were partially dissociated in the corresponding Cu-diimine complex. The complexes bound to the DNA by partial intercalation and groove binding, as assessed by Circular Dichroism, relative viscosity change and UV-Vis titration. The cytotoxicity of the complexes was determined in vitro on MDA-MB-231, MCF-7 (human metastatic breast adenocarcinomas, the first triple negative), MCF-10A (breast nontumoral), A549 (human lung epithelial carcinoma), and MRC-5 (human nontumoral lung epithelial cells), finding an activity higher than that of Cisplatin, although with less selectivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Copper can be opportunely complexed to modulate oncogenic pathways, being a promising strategy for cancer treatment. Herein, three new copper(II) complexes containing long-chain aliphatic hydrazides and 1,10-phenanthroline (1,10-phen), namely, [Cu(octh)(1,10-phen)(H 2 O)](NO 3 ) 2 1, [Cu(dech)(1,10-phen)(H 2 O)](NO 3 ) 2 2 and [Cu(dodh)(1,10-phen)(H 2 O)](NO 3 ) 2 .H 2 O 3 (where octh = octanoic hydrazide, dech = decanoic hydrazide, dodh = dodecanoic hydrazide) were successfully prepared and characterized by several physical-chemical methods. Furthermore, X-ray structural analysis of complex 2 indicated that the geometry around the copper(II) ion is distorted square-pyramidal, in which hydrazide and 1,10-phenanthroline act as bidentate ligands. A water molecule in the apical position completes the coordination sphere of the metal ion. All new copper(II) complexes were cytotoxic to breast cancer cell lines (MCF7, MDA-MB-453, MDA-MB-231, and MDA-MB-157) and selective when compared to the non tumor lineage MCF-10A. In particular, complex 2 showed half-maximal inhibitory concentration (IC 50 ) values ranging between 2.7 and 13.4 μM in MDA-MB231 cells after 24 and 48 h of treatment, respectively. Furthermore, this complex proved to be more selective for tumor cell lines when compared to doxorubicin and docetaxel. Complex 2 inhibited the clonogenicity of MDA-MB231 cells, increasing adenosine diphosphate (ADP) hydrolysis and upregulating ecto-nucleoside triphosphate diphosphohydrolase 1 (ENTPD1) transcriptional levels. In this sense, we suggest that the inhibitory effect on cell proliferation may be related to the modulation of adenosine monophosphate (AMP) levels. Thus, a novel copper(II) complex with increased cytotoxic effects and selectivity against breast cancer cells was obtained, contributing to medicinal chemistry efforts toward the development of new chemotherapeutic agents., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Upon exploration of the chemistry of the combination of ruthenium/arene with anthraquinone alizarin (L), three new complexes with the general formulas [Ru(L)Cl(η 6 - p -cymene)] ( C1 ), [Ru(L)(η 6 - p -cymene)(PPh 3 )]PF 6 ( C2 ), and [Ru(L)(η 6 - p -cymene)(PEt 3 )]PF 6 ( C3 ) were synthesized and characterized using spectroscopic techniques (mass, IR, and 1D and 2D NMR), molar conductivity, elemental analysis, and X-ray diffraction. Complex C1 exhibited fluorescence, such as free alizarin, while in C2 and C3 , the emission was probably quenched by monophosphines and the crystallographic data showed that hydrophobic interactions are predominant in intermolecular contacts. The cytotoxicity of the complexes was evaluated in the MDA-MB-231 (triple-negative breast cancer), MCF-7 (breast cancer), and A549 (lung) tumor cell lines and MCF-10A (breast) and MRC-5 (lung) nontumor cell lines. Complexes C1 and C2 were more selective to the breast tumor cell lines, and C2 was the most cytotoxic (IC 50 = 6.5 μM for MDA-MB-231). In addition, compound C1 performs a covalent interaction with DNA, while C2 and C3 present only weak interactions; however, internalization studies by flow cytometry and confocal microscopy showed that complex C1 does not accumulate in viable MDA-MB-231 cells and is detected in the cytoplasm only after cell permeabilization. Investigations of the mechanism of action of the complexes indicate that C2 promotes cell cycle arrest in the Sub-G 1 phase in MDA-MB-231, inhibits its colony formation, and has a possible antimetastatic action, impeding cell migration in the wound-healing experiment (13% of wound healing in 24 h). The in vivo toxicological experiments with zebrafish indicate that C1 and C3 exhibit the most zebrafish embryo developmental toxicity (inhibition of spontaneous movements and heartbeats), while C2 , the most promising anticancer drug in the in vitro preclinical tests, revealed the lowest toxicity in in vivo preclinical screening.

Searching for new copper compounds which may be useful as antitumor drugs, a series of new [Cu(L-dipeptide)(batho)] (batho:4,7-diphenyl-1,10-phenanthroline, L-dipeptide: Gly-Val, Gly-Phe, Ala-Gly, Ala-Ala, Ala-Phe, Phe-Ala, Phe-Val and Phe-Phe) complexes were synthesized and characterized. To interpret the experimental IR spectra, [Cu(ala-gly)(batho)] was modelled in the gas phase using DFT at the B3LYP/LANL2DZ level of theory and the calculated vibrational frequencies were analyzed. Solid-state characterization is in agreement with pentacoordinate complexes of the general formula [Cu(L-dipeptide)(batho)]·x solvent, similar to other [Cu(L-dipeptide)(diimine)] complexes. In solution, the major species are heteroleptic, as in the solid state. The mode of binding to the DNA was evaluated by different techniques, to understand the role of the diimine and the dipeptide. To this end, studies were also performed with complexes [CuCl 2 (diimine)], [Cu(L-dipeptide)(diimine)] and free diimines, with phenanthroline, neocuproine and 3,4,7,8-tetramethyl-phenanthroline. The cytotoxicity of the complexes was determined on human cancer cell lines MDA-MB-231, MCF-7 (breast, the first triple negative), and A549 (lung epithelial) and non-tumor cell lines MRC-5 (lung) and MCF-10A (breast). [Cu(L-dipeptide)(batho)] complexes are highly cytotoxic as compared to cisplatin and [Cu(L-dipeptide)(phenanthroline)] complexes, being potential candidates to study their in vivo activity in the treatments of aggressive tumors for which there is no curative pharmacological treatment.

In this work we present the synthesis and characterization of six new ruthenium compounds with general formulae [Ru(L)(dppb)(bipy)]PF 6 and [Ru(L)(dppe) 2 ]PF 6 where L = salicylic acid (Sal), 4-aminosalicylic acid (AmSal) or 2,4-dihydroxybenzoic acid (DiSal), dppb = 1,4-bis(diphenylphosphino)butane, dppe = 1,2-bis(diphenylphosphino)ethane and bipy = 2,2'-bipyridine. The complexes were characterized by elemental analysis, molar conductivity, cyclic voltammetry, NMR, UV-vis and IR spectroscopies, and two by X-ray crystallography. The 31 P{ 1 H} NMR spectra of the complexes with the general formula [Ru(L)(dppe) 2 ]PF 6 showed that the phosphorus signals are solvent-dependent. Aprotic solvents, which form strong hydrogen bonds with the complexes, inhibit the free rotation of the salicylic acid-based, modifying the diphosphine cone angles, leading to distortion of the phosphorus signals in the NMR spectra. The cytotoxicity of the complexes was evaluated in MCF-7, MDA-MB-231, SKBR3 human breast tumor cells, and MCF-10 non-tumor cell lines. The complexes with the structural formula [Ru(L)(dppe) 2 ]PF 6 were the most cytotoxic, and the complex [Ru(AmSal)(dppe) 2 ]PF 6 with L = 4-aminosalicylic acid ligand was the most selective for the MDA-MB-231 cell line. This complex interacts with the transferrin and induces apoptosis through the intrinsic pathway, as demonstrated by increased levels of proteins involved in apoptotic cell death., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

New compounds to fight cancer are needed due to cancer high incidence and lack of curative treatments for several classes of this disease. Metal-based coordination compounds offer a variety of molecules that can turn into drugs. Among them, coordination copper complexes are emerging as an attractive class of compounds for cancer treatment. A series of [Cu(L-dipeptide)(tmp)] (tmp = 3,4,7,8-tetramethyl-1,10-phenanthroline) complexes were synthesized and characterized in the solid state, including the determination of the crystalline structure of [Cu(Gly-Gly)(tmp)]·3.5 H 2 O and [Cu 2 Cl 4 (tmp) 2 ]. The complexes were studied in solution, where the major species are also ternary ones. The lipophilicity of the complexes was determined and the binding to the DNA was evaluated, suggesting that it occurs in the DNA's major groove. The cytotoxicity of the complexes was evaluated on different cancer cell lines: human metastatic breast adenocarcinoma MDA-MB-231 (triple negative, ATCC: HTB-26), MCF-7 (ATCC: HTB-22), SK-BR-3 (ATCC: HTB-30), human lung epithelial carcinoma A549 (ATCC: CCL-185), cisplatin resistant-human ovarian carcinoma A2780cis (SIGMA) and nontumoral cell lines: MRC-5 (lung; ATCC: CCL-171) and MCF-10A (breast, ATCC: CRL-10317). [Cu(L-dipeptide)(tmp)] complexes are highly cytotoxic as compared to [Cu(L-dipeptide)(phenanthroline)] and cisplatin. Therefore, [Cu(L-dipeptide)(tmp)] complexes are promising candidates to have their in vivo activity further studied toward new treatments for triple negative breast cancer and other aggressive tumors for which there is no curative pharmacological treatment to the date., (© 2022. The Author(s), under exclusive licence to Society for Biological Inorganic Chemistry (SBIC).)

This study reports the synthesis, structural characterization and cytotoxic activity of four new palladium/pyridylporphyrin complexes, with the general formula {TPyP[PdCl(P-P)] 4 }(PF 6 ) 4 , where P-P is 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)butane (dppb) or 1,1'-bis(diphenylphosphino)ferrocene (dppf). The complexes were characterized by elemental analysis, and by FT-IR, UV/Vis, 1 H and 31 P{ 1 H} NMR (1D/2D) spectroscopy. The slow evaporation of a methanolic solution of {TPyP[PdCl(dppb)] 4 }(PF 6 ) 4 (in an excess of NaBF 4 salt) resulted in single crystals suitable for X ray diffraction, allowing the determination of the tridimensional structure of this complex, which crystallized in the P 2 1 / a space group. The cytotoxicity of the complexes against MDA-MB-231 (breast cancer cells) and MCF-10A (non-tumor breast cancer cells), was determined by the colorimetric MTT method, which revealed that all four complexes show selective indexes close to 1.2, lower than that of cisplatin for the same cells (12.12). The interaction of the complexes with CT-DNA was evaluated by UV-visible and viscosity measurements and it was determined that the complexes interact moderately with CT-DNA, probably by H-bonding/π-π stacking and electrostatic interactions.

In a search for new antitumoral agents, a series of homoleptic copper(II) complexes with amino acids and dipeptides, as well as heteroleptic complexes containing both dipeptides and 1,10-phenanthroline, were studied. Furthermore, a single-crystal structure containing alanyl-leucinato ([Cu 3 (AlaLeu) 3 (H 2 O) 3 (CO 3 )]·PF 6 ·H 2 O), which is the first homotrinuclear carbonato-bridged copper(II) complex with a dipeptide moiety, is presented. To assess possible antitumor action mechanisms, we focused on the comparative analysis of pro- and antioxidant behaviors. Pro-oxidant activity, in which the reactive oxygen species (ROS) formed by the reaction of the complexes with H 2 O 2 produce oxidative damage to 2-deoxy-d-ribose, was evaluated using the TBARS method. Additionally, the antioxidant action was quantified through the superoxide dismutase (SOD)-like activity, using a protocol based on the inhibitory effect of SOD on the reduction of nitrobluetetrazolium (NBT) by the superoxide anion generated by the xanthine/xanthine oxidase system. Our findings show that Cu-amino acid complexes are strong ROS producers and moderate SOD mimics. Conversely, Cu-dipeptide-phen complexes are good SOD mimics but poor ROS producers. The activity of Cu-dipeptide complexes was strongly dependent on the dipeptide. A DFT computational analysis revealed that complexes with high SOD-like activity tend to display a large dipole moment and condensed-to-copper charge, softness and LUMO contribution. Moreover, good ROS producers have higher global hardness and copper electrophilicity, lower copper softness and flexible and freely accessible coordination polyhedra.

This work presents the synthesis and characterization of eight copper complexes [Cu(L-dipeptide)(neo)]·nH 2 O (neo = neocuproine) and their cytotoxic activities against tumor cell lines. The crystalline structure of [Cu(gly-val)(neo)]·3H 2 O, [Cu(gly-leu)(neo)]·H 2 O, [Cu(ala-gly)(neo)]·4H 2 O, [Cu(val-phe)(neo)]·4.5H 2 O and [Cu(phe-phe)(neo)]·3H 2 O were determined by single crystal X-ray diffraction. In all of them, the Cu(II) is pentacoordinated, in a square pyramidal environment. The coordination observed in solid state was retained in the major species in aqueous solution, as suggested by Electronic Paramagnet Resonance and UV-vis spectroscopies. The complexes were shown to have affinity for isolated DNA, as determined by Circular Dichroism experiments. Furthermore, biological experiments showed that all the complexes present high cytotoxic activity against the cell lines: MDA-MB-231, MCF-7 (human metastatic breast adenocarcinomas, the first triple negative), MCF-10A (human normal breast cells), A549 (human lung epithelial carcinoma) and MRC-5 (human lung epithelial cells). Together, these results suggest that these compounds are promising steps towards new effective drugs to treat cancer., (Copyright © 2019. Published by Elsevier Inc.)

We report on chemistry and cytotoxic studies of four new ruthenium (II) complexes containing uracil derivatives. All compounds are neutral, presenting the formula [Ru(PPh 3 ) 2 (2TU) 2 ] (1), [Ru(PPh 3 ) 2 (6m2TU) 2 ] (2), [Ru(dppb)(2TU) 2 ] (3) and [Ru(dppb)(6m2TU) 2 ] (4), where PPh 3  = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane, 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil. They were characterized using NMR, UV-vis and IR spectroscopies, microanalytical analysis and mass spectrometry. Furthermore, the crystal structures of 1-4 were determined by single-crystal X-ray diffraction. The coordination of 2-thiouracil derivatives with ruthenium increases regions able to carry out hydrogen bonds with the biological targets, such as DNA. We evaluated the interaction of the complexes with DNA by UV/Vis spectrophotometric titration, and as a result, the values of DNA-binding constants are in the range of 0.8-1.8 × 10 4  M -1 . Moreover, the interaction of the complexes with BSA was investigated. In vitro, activities against B16-F10 (mouse melanoma), HepG2 (human hepatocellular carcinoma), HL-60 (human promyelocytic leukemia) and K562 (human chronic myelocytic leukemia) and non-tumor cells: PBMC (human peripheral blood mononuclear cells activated with concanavalin A - human lymphoblast) were carried out. Cytotoxicity assays revealed that complexes (2) and (4) present biological activity against tumor cells comparable with oxaliplatin, the reference platinum drug, revealing that they are promising molecules for developing new antitumor compounds., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In this paper, four new ruthenium complexes, [Ru(N-S)(dppm)2]PF6 (1), [Ru(N-S)(dppe)2]PF6 (2), [Ru(N-S)2(dppp)] (3) and [Ru(N-S)2(PPh3)2] (4) [dppm = 1,1-bis(diphenylphosphino)methane, dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, PPh3 = triphenylphosphine and N-S = 2-mercaptopyrimidine anion] were synthesized and characterized using spectroscopy techniques, molar conductance, elemental analysis, electrochemical techniques and X-ray diffraction. The DNA binding studies were investigated using voltammetry and spectroscopy techniques. The results show that all complexes exhibit a weak interaction with DNA. HSA interaction with the complexes was studied using fluorescence emission spectroscopy, where the results indicate a spontaneous interaction between the species by a static quenching mechanism. The cytotoxicity of the complexes was evaluated against A549, MDA-MB-231 and HaCat cells by MTT assay. Complexes (1) and (2), which are very active against triple negative MDA-MB-231, were subjected to further biological tests with this cell line. The cytotoxic activity triggered by the complexes was confirmed by clonogenic assay. Cell cycle analyses demonstrated marked anti-proliferative effects, especially at the G0/G1 and S phases. The morphological detection of apoptosis and necrosis - HO/PI and Annexin V-FITC/PI assay, elucidated that the type of cell death triggered by these complexes was probably by apoptosis. The in vivo toxicological assessment performed on zebrafish embryos revealed that complexes (1) and (2) did not present embryotoxic or toxic effects during embryonic and larval development showing that they are promising new prototypes of safer and more effective drugs for triple negative breast cancer treatment.

The rational design of anticancer agents that acts in specific biological targets is one of the most effective strategies for developing chemotherapeutic agents. Aiming at obtaining new ruthenium (II) compounds with good cytotoxicity against tumor cells, a series of new complexes of general formula [RuCl(PPh 3 )(Hdpa)(NN)]Cl [PPh 3  = triphenylphosphine, N-N = 2,2'-dipyridylamine (Hdpa) (1), 1,2-diaminoethane (en) (2), 2,2'-bipyridine (bipy) (3), 5,5'-dimethyl-2,2'-bipyridine (dmbipy) (4), 1,10-phenanthroline (phen) (5) and 4,7-diphenyl-1,10-phenanthroline (dphphen) (6)] were synthesized. The complexes were characterized by elemental analysis and spectroscopic techniques (IR, UV/Visible, and 1D and 2D NMR) and three of their X-ray structures were determined: [RuCl(PPh 3 )(Hdpa) 2 ]Cl, [RuCl(PPh 3 )(Hdpa)(en)]Cl and [RuCl(PPh 3 )(Hdpa)(dmbipy)]Cl. All the complexes are more cytotoxic against the cancer cell line than against the non-tumor cell line, highlighting complexes 1 and 5, which have an index selectivity of 18 and 15, respectively. The binding constants of compounds 1-6 with human serum albumin (HSA) were determined by tryptophan fluorescence quenching, indicating moderate to strong interactions. The binding mode of the complexes to calf thymus (CT) DNA was explored by several techniques, which reveal that only the dphphen compound 6 causes distortions in the secondary and tertiary structures of DNA. The studies demonstrated that the nature of the NN co-ligand and the presence of the PPh 3 and Hdpa ligands are features that can influence the binding affinity of the complexes by the biomolecules and in the cytotoxic activity of the complexes. Overall, the complexes with diimine co-ligand are much more cytotoxic than compound 2 with the aliphatic diamine., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Thirteen new ruthenium amino acid complexes were synthesized and characterized. They were obtained by the reaction of α-amino acids (AA) with [RuCl 2 (P-P)(N-N)], where P-P=1,4-bis(diphenylphosphino)butane (dppb) or 1,3-bis(diphenylphosphino)propane (dppp) and N-N=4,4'-dimethyl-2,2'-bipyridine (4'-Mebipy), 5,5'-dimethyl-2,2'-bipyridine (5'-Mebipy) or 4,4'-Methoxy-2-2'-bipyridine (4'-MeObipy). This afforded a family of complexes formulated as [Ru(AA-H)(P-P)(N-N)]PF 6 , where AA=glycine (Gly), L-alanine (Ala), L-valine (Val), L-tyrosine (Tyr), L-tryptophan (Trp), L-histidine (His) and L-methionine (Met). All compounds were characterized by elemental analysis, spectroscopic and electrochemical techniques. The [Ru(AA-H)(P-P)(N-N)]PF 6 complexes are octahedral (the AA-H ligand binding involves N-amine and O-carboxylate), diamagnetic (low-spin d 6 , S=0) and present bands due to electronic transitions in the visible region. 1 H, 13 C{ 1 H} and 31 P{ 1 H} NMR spectra of the complexes indicate the presence of C 2 symmetry, and the identification of diastereoisomers. In vitro cytotoxicity assays of the compounds and cisplatin were carried out using MDA-MB-231 (human breast) tumor cell line and a non-tumor breast cell line (MCF-10A). Most complexes present promising results with IC 50 values comparable with the reference drug cisplatin and high selectivity indexes were found for the complexes containing L-Trp. The binding of two Ru-precursors of the type [RuCl 2 (dppb)(NN)] (N-N=4'-MeObipy or 4'-Mebipy) to the blood transporter protein human serum albumin (HSA) was evaluated by fluorescence and circular dichroism spectroscopy. Both complexes bind HSA, probably in the hydrophobic pocket near Trp214, and the Ru-complex containing 4'-MeObipy shows higher affinity for HSA than the 4'-Mebipy one., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru) complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1) [Ru(SO4)(dppb)(bipy)], (2) [Ru(CO3)(dppb)(bipy)], (3) [Ru(C2O4)(dppb)(bipy)] and (4) [Ru(CH3CO2)(dppb)(bipy)]PF6 [where dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine], on proliferation of TNBC (MDA-MB-231), estrogen-dependent breast tumor cells (MCF-7) and a non-tumor breast cell line (MCF-10A). Complex (4) was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4) was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4) was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4) should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment.

A series of copper(I)-phosphine polypyridyl complexes have been investigated as potential antitumor agents. The complexes [Cu(PPh 3 ) 2 dpq]NO 3 (2), [Cu(PPh 3 ) 2 dppz]NO 3 (3), [Cu(PPh 3 ) 2 dppa]NO 3 (4), and [Cu(PPh 3 ) 2 dppme]NO 3 (5) were synthesized by the reaction of [Cu(PPh 3 ) 2 NO 3 ] with the respective planar ligand under mild conditions. These copper complexes were fully characterized by elemental analysis, molar conductivity, FAB-MS, and NMR, UV-vis, and IR spectroscopies. Interactions between these copper(I)-phosphine polypyridyl complexes and DNA have been investigated using various spectroscopic techniques and analytical methods, such as UV-vis titrations, thermal denaturation, circular dichroism, viscosity measurements, gel electrophoresis, and competitive fluorescent intercalator displacement assays. The results of our studies suggest that these copper(I) complexes interact with DNA in an intercalative way. Furthermore, their high protein binding affinities toward human serum albumin were determined by fluorescence studies. Additionally, cytotoxicity analyses of all complexes against several tumor cell lines (human breast, MCF-7; human lung, A549; and human prostate, DU-145) and non-tumor cell lines (Chinese hamster lung, V79-4; and human lung, MRC-5) were performed. The results revealed that copper(I)-phosphine polypyridyl complexes are more cytotoxic than the corresponding planar ligand and also showed to be more active than cisplatin. A good correlation was observed between the cytostatic activity and lipophilicity of the copper(I) complexes studied here.

The motivation to use ruthenium complexes in cancer treatment has led our research group to synthesize complexes with this metal and test them against several types of tumor cells, yielding promising results. In this paper the results of biological tests, assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, were carried out on the complexes cis-[RuCl(BzCN)(bipy)(dppe)]PF6 (1), cis-[RuCl(BzCN)(bipy)(dppb)]PF6 (2), cis-[RuCl(BzCN)(bipy)(dppf)]PF6 (3) and cis-[RuCl(BzCN)(phen)(dppb)]PF6 (4) which are described [BzCN = b enzonitrile; bipy = 2,2'-bipyridine; phen = 1,10-phenanthroline; dppe = 1,2-bis(diphenylphosphino) ethane; dppb = 1,4-bis-(diphenylphosphino)butane; dppf = 1,1'-bis(diphenylphosphino)ferrocene]. The present study is focused on the cytotoxic activity of complexes (1)-(4) against four tumor cell lines and on the apoptosis and changes in the cell cycle and gene expression observed in the sarcoma 180 (S180) tumor cell line treated with complex (1). The results demonstrated that this complex inhibits S180 cell growth, with an IC50 of 17.02 ± 8.21 μM, while exhibiting lower cytotoxicity (IC50 = 53.73 ± 5.71 μM) towards lymphocytes (normal cells). Flow cytometry revealed that the complex inhibits the growth of tumor cells by inducing apoptosis as evidenced by an increase in the proportion of cells positive for annexin V staining and G0/G1 phase cell-cycle arrest. Further investigation showed that complex (1) induces a drop in the mitochondrial membrane potential and provokes a decrease in Bcl-2 protein expression and increase in caspase 3 activation, while the increased activation of caspase 8 caused a decrease in the gene expression in caspases 3 and 9. Increases in Tp53 and Bax expressions were also observed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

In the search for new compounds with antitumor activity, coordination complexes with different metals are being studied by our group. This work presents the synthesis and characterization of six copper complexes with general stoichiometry [Cu(L-dipeptide)(phen)]·nH2O (were phen=1,10-phenanthroline) and their cytotoxic activities against tumor cell lines. To characterize these systems, analytical and spectroscopic studies were performed in solid state (by UV-visible, IR, X-ray diffraction) including the crystal structure of four new complexes (of the six complexes studied): [Cu(Ala-Phe)(phen)]·4H2O, [Cu(Phe-Ala)(phen)]·4H2O, [Cu(Phe-Val)(phen)]·4.5H2O and [Cu(Phe-Phe)(phen)]·3H2O. In all of them, the copper ion is situated in a distorted squared pyramidal environment. The phen ligand is perpendicular to the dipeptide, therefore exposed and potentially available for interaction with biological molecules. In addition, for all the studied complexes, structural information in solution using EPR and UV-visible spectroscopies were obtained, showing that the coordination observed in solid state is maintained. The lipophilicity, DNA binding and albumin interaction were also studied. Biological experiments showed that all the complexes induce cell death in the cell lines: HeLa (human cervical adenocarcinoma), MCF-7 (human metastatic breast adenocarcinoma) and A549 (human lung epithelial carcinoma). Among the six complexes, [Cu(Ala-Phe)(phen)] presents the lowest IC50 values. Taken together all these data we hypothesize that [Cu(Ala-Phe)(phen)] may be a good candidate for further studies in vivo., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The synthesis and characterization of ruthenium compounds of the type [RuCl(2)(NO)(dppp)(L)]PF(6) [dppp=1,3-bis(diphenylphosphino)propane; L=pyridine, 4-methylpyridine, 4-phenylpyridine and dimethyl sulfoxide] are described. The complexes were characterized by elemental analysis, UV/Vis and infrared spectroscopy, cyclic voltammetry, and X-ray crystallography for the complexes with the pyridine and 4-methylpyridine ligands. In vitro evaluation of these nitrosyl complexes revealed cytotoxic activity from 7.1 to 19.0 microM against the MDA-MB-231 breast tumor cells and showed that, in this case, they are more active than the reference metallodrug cisplatin. The 1,3-bis(diphenylphosphino)propane and the N-heterocyclic ligands alone failed to show cytotoxic activities at the concentrations tested (maximum concentration utilized=200 microM).

The reaction of cis-[RuCl(2)(dppb)(N-N)], dppb=1,4-bis(diphenylphosphino)butane, complexes with the ligand HSpymMe(2), 4,6-dimethyl-2-mercaptopyrimidine, yielded the cationic complexes [Ru(SpymMe(2))(dppb)(N-N)]PF(6), N-N=bipy (1) and Me-bipy (2), bipy=2,2'-bipyridine and Me-bipy=4,4'-dimethyl-2,2'-bipyridine, which were characterized by spectroscopic and electrochemical techniques and X-ray crystallography and elemental analysis. Additionally, preliminary in vitro tests for antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27264 and antitumor activity against the MDA-MB-231 human breast tumor cell line were carried out on the new complexes and also on the precursors cis-[RuCl(2)(dppb)(N-N)], N-N=bipy (3) and Me-bipy (4) and the free ligands dppb, bipy, Me-bipy and SpymMe(2). The minimal inhibitory concentration (MIC) of compounds needed to kill 90% of mycobacterial cells and the IC(50) values for the antitumor activity were determined. Compounds 1-4 exhibited good in vitro activity against M. tuberculosis, with MIC values ranging between 0.78 and 6.25microg/mL, compared to the free ligands (MIC of 25 to >50microg/mL) and the drugs used to treat tuberculosis. Complexes 1 and 2 also showed promising antitumor activity, with IC(50) values of 0.46+/-0.02 and 0.43+/-0.08microM, respectively, against MDA-MB-231 breast tumor cells.

New Pd(II) and Pt(II) complexes [ML2] (HL=a substituted 2,5-dihydro-5-oxo-1H-pyrazolone-1-carbothioamide) have been synthesized by reacting K2MCl4 (M=Pd, Pt) or Pd(OAc)2 with beta-ketoester thiosemicarbazones. The structures of seven of these complexes were determined by X-ray diffraction. Although all exhibit a distorted square-planar coordination with trans- or (in one case) cis-[MN2S2] kernels, their supramolecular arrangements vary widely from isolated molecules to 3D-networks. The in vitro antitumoral assays performed with two HL ligands and their metal complexes showed significant cytostatic activity for the latter, with the most active [ML2] derivative (a palladium complex) being about sixteen times more active than cis-DDP against the cisplatinum-resistant cell line A2780cisR.

Coordination complexes may act as anticancer agents. Among others, the formation of the complex may facilitate the ligand uptake by the cell. Searching for new copper compounds with cytotoxic activity, the complex Cu-dipicolinate was studied as a neutral scaffold to form ternary complexes with diimines. A series of [Cu(dipicolinate)(diimine)] complexes (where diimine: Phenanthroline, phen, 5-NO2-phenanthroline, 4-methyl-phenanthroline, neocuproine, 3,4,7,8-tetramethyl-phenanthroline, tmp, bathophenanthroline, bipyridine, dimethyl-bipyridine, as well as the ligand 2,2-dipyridil-amine, bam) were synthesized and characterized both in the solid state, including a new crystal structure of [Cu2(dipicolinate)2(tmp)2]·7H2O. Their chemistry in aqueous solution was explored by UV/vis spectroscopy, conductivity, cyclic voltammetry, and electron paramagnetic resonance studies. Their DNA binding was analyzed by electronic spectroscopy (determining Kb values), circular dichroism, and viscosity methods. The cytotoxicity of the complexes was assessed on human cancer cell lines MDA-MB-231, MCF-7 (breast, the first triple negative), A549 (lung epithelial) and A2780cis (ovarian, Cisplatin-resistant), and non-tumor cell lines MRC-5 (lung) and MCF-10A (breast). The major species are ternary, in solution and solid state. Complexes are highly cytotoxic as compared to Cisplatin. Complexes containing bam and phen are interesting candidates to study their in vivo activity in triple-negative breast cancer treatment. [ABSTRACT FROM AUTHOR]

In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres (ortho-quinone/para-quinone or quinone/selenium-containing triazole) through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The combination of two naphthoquinoidal substrates towards a synergetic product was indicated, but not fully explored. Herein, we report the synthesis of 15 new quinone-based derivatives prepared from click chemistry reactions and their subsequent evaluation against nine cancer cell lines and the murine fibroblast line L929. Our strategy was based on the modification of the A-ring of para-naphthoquinones and subsequent conjugation with different ortho-quinoidal moieties. As anticipated, our study identified several compounds with IC50 values below 0.5 µM in tumour cell lines. Some of the compounds described here also exhibited an excellent selectivity index and low cytotoxicity on L929, the control cell line. The antitumour evaluation of the compounds separately and in their conjugated form proved that the activity is strongly enhanced in the derivatives containing two redox centres. Thus, our study confirms the efficiency of using A-ring functionalized para-quinones coupled with ortho-quinones to obtain a diverse range of two redox centre compounds with potential applications against cancer cell lines. Here as well, it literally takes two for an efficient tango! [ABSTRACT FROM AUTHOR]

This study reports the synthesis, structural characterization and cytotoxic activity of four new palladium/pyridylporphyrin complexes, with the general formula {TPyP[PdCl(P–P)]4}(PF6)4, where P–P is 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)butane (dppb) or 1,1′-bis(diphenylphosphino)ferrocene (dppf). The complexes were characterized by elemental analysis, and by FT-IR, UV/Vis, 1H and 31P{1H} NMR (1D/2D) spectroscopy. The slow evaporation of a methanolic solution of {TPyP[PdCl(dppb)]4}(PF6)4 (in an excess of NaBF4 salt) resulted in single crystals suitable for X ray diffraction, allowing the determination of the tridimensional structure of this complex, which crystallized in the P21/a space group. The cytotoxicity of the complexes against MDA-MB-231 (breast cancer cells) and MCF-10A (non-tumor breast cancer cells), was determined by the colorimetric MTT method, which revealed that all four complexes show selective indexes close to 1.2, lower than that of cisplatin for the same cells (12.12). The interaction of the complexes with CT-DNA was evaluated by UV-visible and viscosity measurements and it was determined that the complexes interact moderately with CT-DNA, probably by H-bonding/π–π stacking and electrostatic interactions. [ABSTRACT FROM AUTHOR]

Abiraterone acetate is a first choice prodrug to treat prostate cancer. New higher-solubility multicomponent crystal forms of the active compound abiraterone could substitute for the commonly used acetate prodrug. Here we prepare abiraterone hydrochloride monohydrate, which is the first multicomponent crystal form of this striking prostate anticancer agent. Its solid state characterization by single-crystal X-ray diffraction (SCXRD), infrared (IR) spectroscopy and thermogravimetry (TG) was performed. The only conformational difference in the molecular backbone common to the literature related crystal forms (abiraterone acetate and the free base abiraterone) and our salt resides in the 3-pyridil rotation upon protonation. If the neutral molecules found in the two literature structures are taken as references, this motif is rotated by almost exactly 180° in our protonated abiraterone. Crystal packing also follows the protonation pattern. While in both prodrug and free base there is formation of head-to-tail fashioned one-dimensional chains as the main supramolecular entities, hydrogen bonded sheets are the main supramolecular motifs of abiraterone hydrochloride monohydrate. In addition, the IR spectrum and the TG thermogram of the hydrochloride salt monohydrate are present with characteristics absorption bands and thermal events, being therefore useful as analytical data for control quality purposes of this promising active pharmaceutical ingredient. Image 1 • Abiraterone hydrochloride monohydrate prepared from the prodrug abiraterone acetate. • There is a 180° rotation of 3-pyridil in its first multicomponent crystal form. • Infrared and thermogravimetric data for this promising alternative drug source. [ABSTRACT FROM AUTHOR]

Copper coordination complexes are increasingly recognized as potential drugs for therapeutic use in various diseases, especially in cancer. In an attempt to find new leaders for the development of antitumor Cu compounds, heteroleptic Cu(I) complexes with triphenylphosphine (PPh 3 ) and dimethylbipyridine (dmbpy), phenanthroline (phen) or neocuproine (neo) were prepared and characterized. The compounds [CuCl(dmbpy)(PPh 3 )] ( 1 ), [CuCl(phen)(PPh 3 )]⋅0,25H 2 O ( 2 ) and [CuCl(neo)(PPh 3 )] ( 3 ) were obtained. The crystal structures of compounds 2 and 3 were determined. In both complexes, the Cu(I) centre presents distorted tetrahedral coordination. All complexes present cytotoxic activity, against tumor cell lines, being more active than Cisplatin, with IC 50 in the low micromolar range. This activity augments in the order 1 < 2 < 3 , following the same order as the lipophilicity. [ABSTRACT FROM AUTHOR]

Amino acid/diphosphine ruthenium complexes, of general formula [Ru(AA-H)(dppb)(bipy)]PF 6 [AA = amino acid: glycine (gly), l -alanine (ala), l -tyrosine (tyr), l -methionine (met), l -leucine (leu), l -valine (val), l -serine (ser), l -tryptophan (trp), and l -lysine(lys); dppb = 1,4-bis(diphenylphosphino)butane; bipy = 2,2′-bipyridine], were synthesized and characterized. The X-ray structures of the glycine and leucine complexes showed that the amino acids are coordinated to the metal center through the carboxylate and amine groups. The complexes, except for the glycine ligand, form two different conformational isomers, as suggested by X-ray structure determination of the complex with leucine, and shown by 31 P{ 1 H} NMR analysis. The cyclic and differential pulse voltammograms of the complexes exhibited an oxidation potential (Ru II /Ru III ) close to 1.0 V, against Ag/AgCl. Toxicity tests against the MDA-MB-231 and DU 145 human tumor cell lines and the Ehrlich mouse cell line indicated a high degree of cytotoxicity for the amino acid complexes. The intrinsic binding constants ( K b ) for the amino acid complexes were determined and found to be in the range of 1.40 × 10 4 –1.80 × 10 4 M −1 , suggesting weak interactions of the complexes with DNA. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis and characterization of ruthenium compounds of the type [RuCl2(P)2(N–N)] [(P)2 =(PPh3)2, dppb=1,4-bis(diphenylphosphino)butano; dppp=1,3-bis(diphenylphosphino)propane; N–N=5,5′-dimethyl-2,2′dipyridyl (5,5′-mebipy) or 4,4′-dimethyl-2,2′dipyridyl (4,4′-mebipy)] are described. The complexes were characterized using elemental analysis, UV–Vis and infrared spectroscopies, cyclic voltammetry, and X-ray crystallography. In vitro evaluation of the complexes, using the MTT methodology, revealed their cytotoxic activities in a range of 5.4–15.7μM against the MDA-MB-231 breast tumor cells and showed that, in this case, they are more active than the reference metallodrug cisplatin. The in vitro antimycobacterial activities of the complexes had their Minimum Inhibitory Concentration (MIC) for MTB cell growth measured, by the REMA method. The MICs for these complexes were found to be between 12.5 and 25.0μg/mL. The results are comparable with the “second line” drug cycloserine (MIC=12.5–50.0μg/mL), commonly used in the treatment of TB. [Copyright &y& Elsevier]

Abstract: The reaction of cis-[RuCl2(dppb)(N–N)], dppb=1,4-bis(diphenylphosphino)butane, complexes with the ligand HSpymMe2, 4,6-dimethyl-2-mercaptopyrimidine, yielded the cationic complexes [Ru(SpymMe2)(dppb)(N–N)]PF6, N–N=bipy (1) and Me-bipy (2), bipy=2,2′-bipyridine and Me-bipy=4,4′-dimethyl-2,2′-bipyridine, which were characterized by spectroscopic and electrochemical techniques and X-ray crystallography and elemental analysis. Additionally, preliminary in vitro tests for antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27264 and antitumor activity against the MDA-MB-231 human breast tumor cell line were carried out on the new complexes and also on the precursors cis-[RuCl2(dppb)(N–N)], N–N=bipy (3) and Me-bipy (4) and the free ligands dppb, bipy, Me-bipy and SpymMe2. The minimal inhibitory concentration (MIC) of compounds needed to kill 90% of mycobacterial cells and the IC50 values for the antitumor activity were determined. Compounds 1–4 exhibited good in vitro activity against M. tuberculosis, with MIC values ranging between 0.78 and 6.25μg/mL, compared to the free ligands (MIC of 25 to >50μg/mL) and the drugs used to treat tuberculosis. Complexes 1 and 2 also showed promising antitumor activity, with IC50 values of 0.46±0.02 and 0.43±0.08μM, respectively, against MDA-MB-231 breast tumor cells. [Copyright &y& Elsevier]

• Two new bi and tri thiazolyl derivatives were synthesized and characterized. • The corresponding Cu(II) complexes were synthesized and characterized. • The crystal structure of both complexes is shown. • The cytotoxicity of ligands and complexes was evaluated on breast cancer cell lines. • The complexes show higher cytotoxicity than the free ligands and cisplatin. • Both complexes interact with DNA. New thiazolyl derivatives (BT and TT) and their copper (II) complexes [Cu 2 Cl 2 (BT) 2 (Cu-BT) and [Cu 4 ClO 2 (TT) 2 PF 6 ⋅3.5H 2 O (Cu-TT) were synthesized and characterized by elemental analysis, 1H NMR and 13C NMR, HRMS, X-ray diffraction, IR and UV–Vis spectroscopies. The crystal structure of Cu-BT shows the formation of a dinuclear complex where each copper(II) center is bonded to two thiazol N atoms, from different BT ligands, one deprotonated amide N atom, an O atom from the ester terminal groups and a chlorine atom. The structure found for Cu-TT is a positively charged tetranuclear moiety containing two deprotonated TT ligands, a chlorine anion, two hydroxide anions acting as bridges between the copper centers and a water molecule. The cytotoxic activity of both copper complexes was evaluated on metastatic breast cancer cell lines, characterized for its rapidly dividing behavior. Both, Cu-BT and Cu-TT, show higher cytotoxic activity against these tumor cells than free BT and TT and also than cisplatin. In addition, we found that both complexes interact with DNA. Consistently, they also show cytotoxicity against a rapidly dividing non-tumor cell line, although with higher IC 50, being such interaction and selectivity an indicator of the possible coexistence of more than one mechanism of action. [ABSTRACT FROM AUTHOR]

Abstract: Reaction of the vitamin K3 derivative menadione sodium bisulfite thiosemicarbazone (NaK3TSC) with chloro(triethylphosphine)gold(I) afforded the complex [AuPEt3(K3TSC)]. This compound consists of discrete molecules in which the metal is almost linearly coordinated to P and S. Preliminary in vitro screening showed significant anti-cancer activity, notably against the cisplatin-resistant cell line A2780cis. [Copyright &y& Elsevier]