A new copper(II) complex containing long-chain aliphatic hydrazide and 1,10-phenanthroline upregulates ADP hydrolysis in triple-negative breast cancer cells.

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)(H2O)](NO3)21, [Cu(dech)(1,10-phen)(H2O)](NO3)22 and [Cu(dodh)(1,10-phen)(H2O)](NO3)2.H2O 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 (IC50) 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.

Structural and Anticancer Studies of Methoxyflavone Derivative from Strychnos pseudoquina A.St.-Hil. (Loganiaceae) from Brazilian Cerrado.

The Cerrado biome is the world's largest and most diversified tropical savanna. Despite its diversity, there remains a paucity of scientific discussion and evidence about the medicinal use of Cerrado plants. One of the greatest challenges is the complexity of secondary metabolites, such as flavonoids, present in those plants and their extraction, purification, and characterization, which involves a wide range of approaches, tools, and techniques. Notwithstanding these difficulties, the search for accurately proven medicinal plants against cancer, a leading cause of death worldwide, has contributed to this growing area of research. This study set out to extract, purify, and characterize 3-O-methylquercetin isolated from the plant Strychnos pseudoquina A.St.-Hil. (Loganiaceae) and to test it for antiproliferative activity and selectivity against different tumor and nontumor human cell lines. A combined-method approach was employed using 1H and 13C nuclear magnetic resonance, thermogravimetric analysis, differential scanning calorimetry, single-crystal X-ray diffraction, Hirshfeld surface analysis, and theoretical calculations to extensively characterize this bioflavonoid. 3-O-methylquercetin melts around 275 °C and crystallizes in a nonplanar conformation with an angle of 18.02° between the pyran ring (C) and the phenyl ring (B), unlike quercetin and luteolin, which are planar. Finally, the in vitro cytotoxicity of 3-O-methylquercetin was compared with data from quercetin, luteolin, and cisplatin, showing that structural differences influenced the antiproliferative activity and the selectivity against different tumor cell lines.

Development of Copper Complexes with Diimines and Dipicolinate as Anticancer Cytotoxic Agents.

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.

"Half-Sandwich" Ruthenium Complexes with Alizarin as Anticancer Agents: In Vitro and In Vivo Studies.

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(η6-p-cymene)] (C1), [Ru(L)(η6-p-cymene)(PPh3)]PF6 (C2), and [Ru(L)(η6-p-cymene)(PEt3)]PF6 (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 (IC50 = 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-G1 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.

It Takes Two to Tango, Part II: Synthesis of A-Ring Functionalised Quinones Containing Two Redox-Active Centres with Antitumour Activities.

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!

New Copper(II)-L-Dipeptide-Bathophenanthroline Complexes as Potential Anticancer Agents-Synthesis, Characterization and Cytotoxicity Studies-And Comparative DNA-Binding Study of Related Phen Complexes.

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 [CuCl2(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.

New ruthenium complexes containing salicylic acid and derivatives induce triple-negative tumor cell death via the intrinsic apoptotic pathway.

In this work we present the synthesis and characterization of six new ruthenium compounds with general formulae [Ru(L)(dppb)(bipy)]PF6 and [Ru(L)(dppe)2]PF6 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 31P{1H} NMR spectra of the complexes with the general formula [Ru(L)(dppe)2]PF6 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]PF6 were the most cytotoxic, and the complex [Ru(AmSal)(dppe)2]PF6 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.

Tetramethyl-phenanthroline copper complexes in the development of drugs to treat cancer: synthesis, characterization and cytotoxicity studies of a series of copper(II)-L-dipeptide-3,4,7,8-tetramethyl-phenanthroline complexes.

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 H2O and [Cu2Cl4(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.

Comparative Study of Antioxidant and Pro-Oxidant Properties of Homoleptic and Heteroleptic Copper Complexes with Amino Acids, Dipeptides and 1,10-Phenanthroline: The Quest for Antitumor Compounds.

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 ([Cu3(AlaLeu)3(H2O)3(CO3)]·PF6·H2O), 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 H2O2 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.

meso-Tetra-(4-pyridyl)porphyrin/palladium(II) complexes as anticancer agents.

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.

Estudio estructural y supramolecular del ácido 2-E-((4-hidroxifenil) diazenil) benzoico / Structural and supramolecular study of 2- E -((4-hy-droxyphenyl) diazenyl) benzoic acid / Estudo estrutural e supramolecular do composto ácido 2- E -((4-hidroxifenil) diazenil) benzoico

Resumen La estructura cristalina del compuesto ácido 2-E-((4-hidroxifenil) diazenil) benzoico se resolvió por medio del método de fase intrínseca usando datos de difracción de rayos X de monocristal, encontrando que la molécula cristaliza en el sistema cristalino ortorrómbico con grupo espacial Pbca. Dentro de su celda unidad hay cuatro moléculas por unidad asimétrica que son confórmeros moleculares. Estos confórmeros forman hélices beta a lo largo de la dirección [010]. A partir de los datos estructurales se realizó el cálculo de superficies de Hirshfeld determinando, a partir de ellas, sus correspondientes diagramas de huellas dactilares bidimensionales, lo que permitió estudiar las interacciones intermoleculares que más contribuyen al empaquetamiento cristalino. Así, se pudo determinar que la principal contribución a la superficie general está dada por los contactos H•••H (34,8%), seguida de interacciones O•••H/ H•••O (27%) y C•••H/H•••C (18,6%). También fueron calculadas las redes energéticas de interacción con un nivel de teoría DFT/B3LYP/6-31G(d,p), permitiendo cuantificar los valores de cada componente que aportan a la energía total, siendo las interacciones de dispersión (-57,5 kJ/mol) las que más contribuyen en la formación del empaquetamiento cristalino para este compuesto.

Abstract The crystalline structure of 2-E-((4-hydroxyphenyl) diazenil) benzoic acid compound was solved by intrinsic phase method using single-crystal X-ray diffraction data. The molecule crystallizes in the orthorhombic Pbca space group. in the unit cell four molecular conformers of the compound per asymmetric unit are observed, which are forming beta helix arrangement along [010] direction. Hirshfeld surface calculation was performed to determine the intermolecular interactions that contribute to the crystal packing. it was possible to observe that the main contribution to the general surface is given by the contacts H ••• H (34.8%), followed by interactions O ••• H/H ••• O (27%) and C ••• H/H ••• C (18.6%). The energy interaction networks were calculated at a DFT/B3LYP/6-31G(d,p) level, allowing to quantify the high participation of dispersion interactions (-57.5 kJ/mol) in the formation of crystal packing.

Resumo A estrutura cristalina do composto ácido 2-E-((4-hidroxifenil) diazenil) benzóico foi resolvida pelo método da fase intrínseca usando dados de difração de raios X de cristal único, constatando que a molécula cristaliza no sistema cristalino ortorrômbico com grupo espacial Pbca. Dentro de sua cela unitária, existem quatro moléculas por unidade assimétrica, que são isômeros moleculares. Esses isômeros formam hélices beta na direção [010]. A partir dos dados estruturais, foi realizado o cálculo das superfícies de Hirshfeld determinando a partir delas seus respetivos diagramas bidimensionais das impressões digitais, o que permitiu estudar as interações intermoleculares que mais contribuem para o empacotamento cristalino. Assim, foi determinado que a principal contribuição para a superfície geral é dada pelos contatos H ••• H (34,8%), seguidos pelas interações O ••• H / H••• O (27%) e C ••• H / H ••• C (18,6%). Também foram calculadas as redes de energia de interação com um nível de teoria DFT/B3LYP/6-31G(d,p), permitindo quantificar a alta participação de interações de dispersão (-57,5 kJ / mol) na formação do empacotamento cristalino para este composto.

Vibrational and conformational analysis of structural phase transition in Estradiol 17ß valerate with temperature.

Estradiol 17ß valerate (E2V) is a hormonal medicine widely used in hormone replacement therapy. E2V undergoes a reversible isosymmetric structural phase transition at low temperature (Ì´ 250 K) which results from the reorientation of the valerate chain. The reversible isosymmetric structural phase transition follows Ehrenfest's classification when described as first-order and Buerger's classification when classified as order-disorder. The conformational difference also induces changes in molecular torsional angles and on the hydrogen bond pattern. In combination with density functional theory (DFT) calculations, vibrational spectroscopy has been used to correlate the valerate chain modes with the modifications of the dihedral angles on phase transition. We are expecting improvement in our understanding of the phase transition mechanism driven by the temperature. The Conformational analysis reveals the feasible structures corresponding to changes in the dihedral angles associated with the valerate chain. The infrared spectra of calculated conformers are in good agreement with the experimental spectra of E2V structure recorded at room temperature revealing that the changes in valerate chain modes at 1115 cm-1, 1200 cm-1and 1415 cm-1 fingerprint the molecular conformation. An investigation made to determine the ligand-protein interaction of E2V through docking against estrogen receptor (ER) reveals the inhibitive and agonist nature of E2V.

Electrochemical, mechanistic, and DFT studies of amine derived diphosphines containing Ru(II)-cymene complexes with potent in vitro cytotoxic activity against HeLa and triple-negative breast cancer cells MDA-MB-231.

Complexes with general formula [RuCl(η6-p-cymene)(P-NR-P)]X (R = CH2Py (Py = pyridine) - [1a]+, CH2Ph (Ph = phenyl) - [1b]+, Ph - [1c] and p-tol (p-tol = p-tolyl) - [1d]+; X = PF6- or BF4-) were evaluated as cytotoxic agents against two cancer cell lines (HeLa and MDA-MB-231). All metal complexes are active in the range of concentrations tested (up to 100 µmol L-1). The IC50 (µmol L-1) values for the metal complexes are lower than that found for cisplatin. The activities are up to 6- and 15-fold higher than cisplatin for HeLa and MDA-MB-231 cancer cell lines, respectively. Studies of DNA binding and DNA cleavage were performed. DNA binding studies revealed a modest hypochromic shift in the metal complexes electronic spectra, indicating a weak interaction with Kb values in the range of 1.7 × 103-1.6 × 104. Although the cleavage tests revealed that in the dark DNA is not a biological target for these metal complexes, upon blue light irradiation they are activated causing DNA cleavage. Electrochemical studies showed the presence of two independent redox processes, one attributed to the oxidation process of Ru2+ → Ru3+ (EC process) and the other one to the reduction of Ru2+ → Ru1+, which is further reduced to Ru0 (ECE mechanism). In both processes, coupled chemical reactions were observed. DFT calculations were performed to support the electrochemical/chemical behavior of the complexes. The reactivity of complex [1b]BF4 with CH3CN was evaluated and two complexes were isolated [2b]BF4 and [3b]BF4. The complex mer-[RuCl(CH3CN)3(P-NCH2Ph-P)]BF4 ([2b]BF4) was isolated after refluxing the precursor [1b]BF4 in CH3CN. Isomerization of [2b]BF4 in CH3CN resulted in the formation of fac-[RuCl(CH3CN)3(P-NCH2Ph-P)]BF4. An attempt to isolate the fac-isomer by adding diethyl ether was unsuccessful, and the complex [3b]BF4 was observed as the major component. The complex [Ru2(µ-Cl3)(CH3CN)2(P-NCH2Ph-P)2]BF4 ([3b]BF4) proved to be very stable and can be obtained from both the mer- and the fac-isomers. The molecular structures of [1b]BF4 and [3b]BF4 were solved by single-crystal X-ray diffraction.

Silver(I) complexes of 3-methoxy-4-hydroxybenzaldehyde thiosemicarbazones and triphenylphosphine: structural, cytotoxicity, and apoptotic studies.

Novel silver(i) complexes of the type [AgCl(PPh3)2(L)] {PPh3 = triphenylphosphine; L = VTSC = 3-methoxy-4-hydroxybenzaldehyde thiosemicarbazone (1); VMTSC = 3-methoxy-4-[2-(morpholine-1-yl)ethoxy]benzaldehyde thiosemicarbazone (2); VPTSC = 3-methoxy-4-[2-(piperidine-1-yl)ethoxy]benzaldehyde thiosemicarbazone (3)} were synthesized and fully characterized by spectroscopic techniques. The molecular structures of complexes 2 and 3 were determined by single crystal X-ray diffraction. Compounds 1-3 exhibited appreciable cytotoxic activity against human tumor cells (lung A549, breast MDA-MB-231 and MCF-7) with IC50 values in 48 h of incubation ranging from 5.6 to 18 µM. Cellular uptake studies showed that complexes 1-3 were efficiently internalized after 3 hours of treatment in MDA-MB-231 cells. The effects of complex 1 on the cell morphology, cell cycle, induction of apoptosis, mitochondrial membrane potential (Δψm), and reactive oxygen species (ROS) production have been evaluated in triple negative breast cancer (TNBC) cells MDA-MB-231. Our results showed that complex 1 induced typical morphological alterations of cell death, an increase in cells at the sub-G1 phase, apoptosis, and mitochondrial membrane depolarization. Furthermore, DNA binding studies evidenced that 1 can bind to ct-DNA and does so without modifying the B-structure of the DNA, but that the binding is weak compared to that of Hoechst 33258.

Biguanide-transition metals complexes as potential drug for hyperglycemia treatment.

Coordination compounds of Cu(ii), Ni(ii), Co(ii), and Zn(ii) with a type of biguanide (known commercially as metformin) have been synthesized and characterized using spectroscopic techniques (FT-IR, UV/VIS), X-ray diffraction techniques and thermal analysis. For all compounds, single crystals were obtained for single-crystal X-ray diffraction. For the first time, an octahedral cobalt compound with the formula [Co(C4H11N5)3]Cl2·2H2O that crystallizes in the monoclinic space group C2/c with one molecule in the asymmetric unit has been obtained. Also, a novel nickel compound with the formula [Ni(C4H11N5) (C4H10N5)]Cl·H2O that crystallizes in the monoclinic space group P21/c with two molecules in the asymmetric unit was obtained. Finally, we obtained copper and zinc compounds that crystallize in the monoclinic space groups P21/n and P21/c with the general formula [Cu(C4H11N5)2]Cl2·H2O and [Zn(C4H12N5)Cl3], respectively. A structural and supramolecular analysis was developed for all compounds using Hirshfeld surface analysis and electrostatic potential maps. The cell viability of the obtained compounds was evaluated in C2C12 (ATCCCRL-1772™) mouse muscle cells and HepG2 (ATCC HB-8065™) human liver carcinoma cells by the MTT assay to determine the potential of the compounds as new safe drugs. The results demonstrate that the compounds exhibit low cytotoxicity at doses less than 250 µg mL-1 with a cell viability greater than 80%.

Synthesis and structural characterization of a series of ternary copper(II)-L-dipeptide-neocuproine complexes. Study of their cytotoxicity against cancer cells including MDA-MB-231, triple negative breast cancer cells.

This work presents the synthesis and characterization of eight copper complexes [Cu(L-dipeptide)(neo)]·nH2O (neo = neocuproine) and their cytotoxic activities against tumor cell lines. The crystalline structure of [Cu(gly-val)(neo)]·3H2O, [Cu(gly-leu)(neo)]·H2O, [Cu(ala-gly)(neo)]·4H2O, [Cu(val-phe)(neo)]·4.5H2O and [Cu(phe-phe)(neo)]·3H2O 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.

Synthesis, spectroscopic (FT-IR and UV-Vis), crystallographic and theoretical studies, and a molecular docking simulation of an imatinib-like template.

The aim of the present study was to report the crystal structure and spectroscopic, electronic, supramolecular and electrostatic properties of a new polymorph of 4-(pyridin-2-yl)pyrimidin-2-amine (C9H8N4). The compound was synthesized under microwave irradiation. The single-crystal X-ray structure analysis revealed an angle of 13.36 (8)° between the planes of the rings, as well as molecules linked by Nsp2-H...N hydrogen bonds forming dimers along the crystal. The material was analyzed by FT-IR vibrational spectroscopy, while a computational approach was used to elucidate the vibrational frequency couplings. The existence of Nsp2-H...N hydrogen bonds in the crystal was confirmed spectroscopically by the IR peaks from the N-H stretching vibration shifting to lower wavenumbers in the solid state relative to those in the gas phase. The supramolecular studies confirmed the formation of centrosymmetric R22(8) rings, which correspond to the formation of dimers that stack parallel to the b direction. Other weak C-H...π interactions, essential for crystal growth, were found. The UV-Vis spectroscopic analysis showed a donor-acceptor process, where the amino group acts as a donor and the pyridine and pyrimidine rings act as acceptors. The reactive sites of the molecule were identified and their quantitative values were defined using the electrostatic potential model proposed in the multifunctional wave function analyzer multiwfn. The calculated interaction energies between pairs of molecules were used to visualize the electrostatic terms as the leading factors against the dispersion factors in the crystal-growth process. The docking results showed that the amino group of the pyrimidine moiety was simultaneously anchored by hydrogen-bonding interactions with the Asp427 and His407 protein residues. This compound could be key for the realization of a series of syntheses of molecules that could be used as possible inhibitors of chronic myelogenous leukemia.

Ru(II) complexes containing uracil nucleobase analogs with cytotoxicity against tumor cells.

We report on chemistry and cytotoxic studies of four new ruthenium (II) complexes containing uracil derivatives. All compounds are neutral, presenting the formula [Ru(PPh3)2(2TU)2] (1), [Ru(PPh3)2(6m2TU)2] (2), [Ru(dppb)(2TU)2] (3) and [Ru(dppb)(6m2TU)2] (4), where PPh3 = 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 × 104 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.

Picraviane A and B: Nortriterpenes with limonoid-like skeletons containing a heptanolide E-ring system from Picramnia glazioviana.

Two highly oxygenated nortriterpenes, picraviane A and B, were isolated from the ethanolic extract of Picramnia glazioviana Engl. The structures were determined by analysis of HRMS and 2D NMR spectroscopic data. Single-crystal X-ray diffraction data was also obtained for picraviane B. The absolute configuration of both compounds were assigned by comparison of experimental and calculated vibrational and electronic circular dichroism spectroscopy, respectively. Picraviane A showed a moderate cytotoxic activity against the triple negative MDA-MB-231 breast cancer cell line. These compounds represent an undescribed class of natural products with limonoid-like skeletons containing a heptanolide as the E-ring.

In vitro cytotoxicity and in vivo zebrafish toxicity evaluation of Ru(ii)/2-mercaptopyrimidine complexes.

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.