Phenanthroline and phenyl carboxylate mixed ligand copper complexes in developing drugs to treat cancer.

The success of a classic inorganic coordination compound, Cisplatin, cis-[Pt(NH3)2Cl2], 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 [Cu2(3-(4-hydroxyphenyl)propanoate)3(phenanthroline)2]Cl·H2O. 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.

Ruthenium(II) complexes of curcumin and ß-diketone derivatives: effect of structural modifications on their cytotoxicity.

Ruthenium(II) complexes (Ru1-Ru3) with the general formula [Ru(O-O)(PPh3)2(bipy)]PF6, bearing two triphenylphosphine (PPh3), bipyridine (bipy) and a series of natural and synthetic ß-diketones (O,O) ligands were synthesized and characterized using various analytical techniques. The interaction between the complexes and calf thymus DNA (CT-DNA) was investigated and demonstrated a weak interaction. The cytotoxicity of the complexes was investigated against breast cancer cells (MDA-MB-231 and MCF-7), lung cancer cells (A549), cisplatin-resistant ovarian cancer cells (A2780cis), as well as non-tumour lung (MRC-5) and non-tumour breast (MCF-10A) cell lines. All complexes exhibited cytotoxic activity against all the cell lines studied, with half maximal inhibitory concentration (IC50) values ranging from 0.39 to 13 µM. Notably, the three complexes demonstrated selectivity against the A2780cis cell line, with IC50 ranging from 0.39 to 0.82 µM. Among them, Ru2 exhibited the highest cytotoxicity, with an IC50 value of 0.39 µM. Consequently, this new class of complexes shows good selectivity towards cisplatin-resistant ovarian cancer cells and it is promising for further investigation as anti-cancer agents.

Ruthenium complex containing 1,3-thiazolidine-2-thione inhibits hepatic cancer stem cells by suppressing Akt/mTOR signalling and leading to apoptotic and autophagic cell death.

Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF6, to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133+ and CD44high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs.

Minimal Functionalization of Ruthenium Compounds with Enhanced Photoreactivity against Hard-to-Treat Cancer Cells and Resistant Bacteria.

Metallocompounds have emerged as promising new anticancer agents, which can also exhibit properties to be used in photodynamic therapy. Here, we prepared two ruthenium-based compounds with a 2,2'-bipyridine ligand conjugated to an anthracenyl moiety. These compounds coded GRBA and GRPA contain 2,2'-bipyridine or 1,10-phenathroline as auxiliary ligands, respectively, which provide quite a distinct behavior. Notably, compound GRPA exhibited remarkably high photoproduction of singlet oxygen even in water (Ï•Δ = 0.96), almost twice that of GRBA (Ï•Δ = 0.52). On the other hand, this latter produced twice more superoxide and hydroxyl radical species than GRPA, which may be due to the modulation of their excited state. Interestingly, GRPA exhibited a modest binding to DNA (Kb = 4.51 × 104), while GRBA did not show a measurable interaction only noticed by circular dichroism measurements. Studies with bacteria showed a great antimicrobial effect, including a synergistic effect in combination with commercial antibiotics. Besides that, GRBA showed very low or no cytotoxicity against four mammalian cells, including a hard-to-treat MDA-MB-231, triple-negative human breast cancer. Potent activities were measured for GRBA upon blue light irradiation, where IC50 of 43 and 13 nmol L-1 were seen against hard-to-treat triple-negative human breast cancer (MDA-MB-231) and ovarian cancer cells (A2780), respectively. These promising results are an interesting case of a simple modification with expressive enhancement of biological activity that deserves further biological studies.

Exploring the potential of ruthenium(II)-phosphine-mercapto complexes as new anticancer agents.

The search for new metal-based anticancer drug candidates is a fundamental task in medicinal inorganic chemistry. In this work, we assessed the potential of two new Ru(II)-phosphine-mercapto complexes as potential anticancer agents. The complexes, with the formula [Ru(bipy)(dppen)(Lx)]PF6 [(1), HL1 = 2-mercapto-pyridine and (2), HL2 = 2-mercapto-pyrimidine, bipy = 2,2'-bipyridine, dppen = cis-1,2-bis(diphenylphosphino)-ethylene] were synthesized and characterized by nuclear magnetic resonance (NMR) [1H, 31P(1H), and 13C], high resolution mass spectrometry (HR-MS), cyclic voltammetry, infrared and UV-Vis spectroscopies. Complex 2 was obtained as a mixture of two isomers, 2a and 2b, respectively. The composition of these metal complexes was confirmed by elemental analysis and liquid chromatography-mass spectrometry (LC-MS). To obtain insights into their lipophilicity, their distribution coefficients between n-octanol/PBS were determined. Both complexes showed affinity mainly for the organic phase, presenting positive log P values. Also, their stability was confirmed over 48 h in different media (i.e., DMSO, PBS and cell culture medium) via HPLC, UV-Vis and 31P{1H} NMR spectroscopies. Since enzymes from the P-450 system play a crucial role in cellular detoxification and metabolism, the microsomal stability of 1, which was found to be the most interesting compound of this study, was investigated using human microsomes to verify its potential oxidation in the liver. The analyses by LC-MS and ESI-MS reveal three main metabolites, obtained by oxidation in the dppen and bipy moieties. Moreover, 1 was able to interact with human serum albumin (HSA). The cytotoxicity of the metal complexes was tested in different cancerous and non-cancerous cell lines. Complex 1 was found to be more selective than cisplatin against MDA-MB-231 breast cancer cells when compared to MCF-10A non-cancerous cells. In addition, complex 1 affects cell morphology and migration, and inhibits colony formation in MDA-MB-231 cells, making it a promising cytotoxic agent against breast cancer.

Exploring the BSA- and DNA-binding, cytotoxicity, and cell cycle evaluation of ternary copper(II)/diimine complexes with N,N-dibenzyl-N'-benzoylthiourea as promising metallodrug candidates.

Four new copper(II) complexes were synthesized and characterized with the general formula [Cu(N-N)(Th)(NO3)], where N-N corresponds to the N-heterocyclic ligands 1,10-phenanthroline (phen), 2,2'-bipyridine (bipy), 4,7-diphenyl-1,10-phenanthroline (dpp), and 4,4-dimethyl-2,2'-bipyridine (dmbp) and Th represents the N,N-dibenzyl-N'-benzoylthiourea. Cytotoxic activities of the complexes against HCT116 (human colon carcinoma), HepG2 (human hepatocellular carcinoma), and non-tumor MRC-5 (human lung fibroblast) cells were investigated. The copper(II) complexes 1-4 were characterized by spectroscopic techniques while complexes 1 and 2 were studied using single-crystal X-ray diffraction as well. The complexes possessed a five-coordinated structure with one nitrate ligand as a monodentate at the axial position and two bidentate ligands N-heterocyclic and N,N-dibenzyl-N'-benzoylthiourea. The complexes showed promising IC50 values, ranging from 0.3 to 9.0 µM. Furthermore, interaction studies with biomolecules such as calf thymus DNA (ct-DNA) and Bovine Serum Albumin (BSA), which can act as possible biological targets of the complexes, were carried out. The studies suggested that the compounds interact moderately with ct-DNA and BSA. Complexes 1, 2, and 4 did not lead to cell accumulation at any stage of the cell cycle but caused a significant increase in internucleosomal DNA fragmentation. Whereas, compound 3 caused cell cycle arrest in the S phase while doxorubicin caused cell cycle arrest in the G2/M phase. The effect of structural modifications on the metal compounds was correlated with their biological properties and it was concluded that an increase in biological activity occurred with increasing the extension of the diimine ligands. Thus, complex 3 was the most promising one.

Ru(II)-based complexes containing 2-thiouracil derivatives suppress liver cancer stem cells by targeting NF-κB and Akt/mTOR signaling.

Cancer stem cells (CSCs) are defined as a rare population of cancer cells related to tumor initiation and maintenance. These cells are primarily responsible for tumor growth, invasion, metastasis, recurrence, and resistance to chemotherapy. In this paper, we demonstrated the ability of Ru(II)-based complexes containing 2-thiouracil derivatives with the chemical formulas trans-[Ru(2TU)(PPh3)2(bipy)]PF6 (1) and trans-[Ru(6m2TU)(PPh3)2(bipy)]PF6 (2) (where 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil) to suppress liver CSCs by targeting NF-κB and Akt/mTOR signaling. Complexes 1 and 2 displayed potent cytotoxic effects on cancer cell lines and suppressed liver CSCs from HepG2 cells. Increased phosphatidylserine exposure, loss of mitochondrial transmembrane potential, increased PARP (Asp214) cleavage, DNA fragmentation, chromatin condensation and cytoplasmic shrinkage were detected in HepG2 cells treated with these complexes. Mechanistically, complexes 1 and 2 target NF-κB and Akt/mTOR signaling in HepG2 cells. Cell motility inhibition was also detected in HepG2 cells treated with these complexes. Complexes 1 and 2 also inhibited tumor progression in mice with HepG2 cell xenografts and exhibited tolerable systemic toxicity. Taken together, these results indicate that these complexes are new anti-HCC drug candidates that can suppress liver CSCs.

Pd(II)/diphosphine/curcumin complexes as potential anticancer agents.

Palladium(II) complexes have stimulated research interest mainly due to their in vitro cytotoxicity against various cancer cell lines and their low cytotoxicity in healthy cells. Thus, in this work, we combined Pd(II)/phosphine systems with the natural product curcumin as a ligand, obtaining a series of complexes, [Pd(cur)(PPh3)2]PF6 (A1), [Pd(cur)(dppe)]PF6 (A2), [Pd(cur)(dppp)]PF6 (A3), [Pd(cur)(dppb)]PF6 (A4) and [Pd(cur)(dppf)]PF6 (A5), where dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, dppb = 1,4-bis(diphenylphosphino)butane, and dppf = 1,1'-bis(diphenylphosphino)ferrocene (P-P), which were characterized by elemental analysis, molar conductivity analysis, and mass, NMR (1H, 13C, 31P{1H}), UV-vis, and IR spectroscopies, and four of them (A1, A2, A4, and A5) by X-ray crystallography. The in vitro cell viability of the complexes A1-A5, cisplatin, and the free ligand curcumin against MDA-MB-231 (human triple-negative breast tumor cells), SK-BR-3 (human breast tumor cells), A549 (human lung tumor cells), MRC-5 (non-tumor human lung cells), A2780 (human ovarian carcinoma cells), and A2780cis (cisplatin-resistant human ovarian carcinoma cells), was evaluated by the MTT colorimetric assay. For the tumor cell lines tested, the complexes showed good anticancer activities. The results showed that in general the complexes had lower IC50 values than free curcumin and the precursors [PdCl2(P-P)]. IC50 results obtained for the A1-A5 complexes, in the MCF-7 cell line, are similar to those that had already been observed for some Pd/bipy/curcumin complexes. In the MDA-MB-231 cell line, complexes A1 and A5 stood out, with their lowest IC50 values, around 5 µmol L-1, and the complexes appeared to be more active (lower IC50 values) against the ovarian cell lines. Complex A1 was 23 and 22-fold more cytotoxic than cisplatin, against the A2780 and A2780cis cells, respectively. The complex A1 was studied on A2780cis cells and it was found that this complex inhibits colony formation and induces cell cycle arrest in the sub-G1 phase in a concentration-dependent manner and leads to cell death by apoptosis. The DCFDA assay revealed a potent ROS induction for complex A1.

A novel ruthenium complex with 5-fluorouracil suppresses colorectal cancer stem cells by inhibiting Akt/mTOR signaling.

[Ru(5-FU)(PPh3)2(bipy)]PF6 (Ru/5-FU) is a novel ruthenium complex with 5-fluorouracil with promising potential against colorectal cancer (CRC). In the present study, we investigated the molecular mechanism of Ru/5-FU action in HCT116 CRC cells. Ru/5-FU exhibited potent cytotoxicity on a panel of cancer cell lines and on primary cancer cells and induced apoptosis in HCT116 CRC cells. Ru/5-FU reduced AKT1 gene transcripts, as well as the expression of Akt1 and Akt (pS473) and downstream Akt proteins mTOR (pS2448), S6 (pS235/pS236), 4EBP1 (pT36/pT45), GSK-3ß (pS9) and NF-κB p65 (pS529), but not Akt upstream proteins Hsp90 and PI3K p85/p55 (pT458/pT199), indicating an inhibitory action of Akt/mTOR signaling. Ru/5-FU increased LC3B expression and reduced p62/SQSTM1 levels, indicating autophagy induction. Curiously, the autophagy inhibitors 3-methyladenine and chloroquine increased Ru/5-FU-induced cell death, indicating an induction of cytoprotective autophagy by this compound. Ru/5-FU also reduced clonogenic survival, as well as the percentage of CD133+ cells and colonosphere formation, indicating that Ru/5-FU can suppress stem cells in HCT116 cells. Ru/5-FU inhibited cell migration and invasion in wound healing assays and Transwell cell invasion assays, along with a reduction in vimentin expression and an increase in E-cadherin levels, indicating that Ru/5-FU can interfere with epithelial-mesenchymal transition. Ru/5-FU also inhibited in vivo HCT116 cell development and experimental lung metastases in mouse xenograft models. Altogether, these results indicate that Ru/5-FU is an anti-CRC chemotherapy drug candidate with the ability to suppress stemness in CRC cells by inhibiting Akt/mTOR signaling.

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.

Cytotoxic activity of Ru(II)/DPEPhos/N,S-mercapto complexes (DPEPhos = bis-[(2-diphenylphosphino)phenyl]ether).

We report here on three new ruthenium(II) complexes, [Ru(DPEPhos)(mtz)(bipy)]PF6 (Ru1), [Ru(DPEPhos)(mmi)(bipy)]PF6 (Ru2) and [Ru(DPEPhos)(dmp)(bipy)]PF6 (Ru3). DPEPhos = bis-[(2-diphenylphosphino)phenyl]ether, mtz = 2-mercapto-2-thiazoline, mmi = 2-mercapto-1-methylimidazole, dmp = 4,6-diamino-2-mercaptopyrimidine and bipy = 2,2'-bipyridine. The compounds were characterized by several spectroscopic techniques, and the molecular structure of Ru1 complex was determined by single-crystal X-ray diffraction. The cytotoxicity of Ru1 - Ru3 complexes were tested against the A549 (human lung) and the MDA-MB-231 (human breast) cancer cell lines and against MRC-5 (non-tumor lung) and MCF-10A (non-tumor breast) cell lines through the MTT assay. All three complexes are cytotoxic against the cell lines studied, with IC50 values lower than those found for the cisplatin. Among them, the Ru2 complex has shown the best selectivity against MDA-MB-231 cancer cell lines, with an IC50 value 12 times lower than that on MCF-10A. The complex Ru2 was capable to induce changes in MDA-MB-231 cells morphology, with loss of cellular adhesion, inhibited colony formation and induce an accumulation of cells at the sub-G1 phase, with an increase in S-phase and decrease of cells at G2 phase. Viscosity, electrochemical and Hoechst 33258 displacement experiments for Ru1 - Ru3 complexes with calf thymus DNA (CT-DNA) showed an electrostatic and groove binding mode of interaction. Additionally, the complexes interact with the protein Human Serum Albumin (HSA) by static mechanism. The negative values for ΔH and ΔS indicate that van der Waals forces and hydrogen bonding may occurs between the complexes and HSA. Therefore, this class of complexes are promising anticancer candidates and may be selected to further detailed studies.

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.

Gallium and indium complexes with isoniazid-derived ligands: Interaction with biomolecules and biological activity against cancer cells and Mycobacterium tuberculosis.

Gallium and indium octahedral complexes with isoniazid derivative ligands were successfully prepared. The ligands, isonicotinoyl benzoylacetone (H2L1) and 4-chlorobenzoylacetone isonicotinoyl hydrazone (H2L2), and their respective coordination compounds with gallium and indium [GaL1(HL1)] (GaL1), [GaL2(HL2)] (GaL2), [InL1(HL1)] (InL1) and [InL2(HL2)] (InL2) were investigated by NMR, ESI-MS, UV-Vis, IR, single-crystal X-ray diffraction and elemental analysis. In vitro interaction studies with human serum albumin (HSA) evidenced a moderate affinity of all complexes with HSA through spontaneous hydrophobic interactions. The greatest suppression of HSA fluorescence was caused by GaL2 and InL2, which was associated to the higher lipophilicity of H2L2. In vitro interaction studies with CT-DNA indicated weak interactions of the biomolecule with all complexes. Cytotoxicity assays with MCF-7 (breast carcinoma), PC-3 (prostate carcinoma) and RWPE-1 (healthy human prostate epithelial) cell lines showed that complexes with H2L2 are more active and selective against MCF-7, with the greatest cytotoxicity observed for InL2 (IC50 = 10.34 ± 1.69 µM). H2L1 and H2L2 were labelled with gallium-67, and it was verified that 67GaL2 has a greater lipophilicity than 67GaL1, as well as higher stability in human serum or in the presence of apo-transferrin. Cellular uptake assays with 67GaL1 and 67GaL2 evidenced that the H2L2-containing radiocomplex has a higher accumulation in MCF-7 and PC-3 cells than the non-halogenated congener 67GaL1. The anti-Mycobacterium tuberculosis assays revealed that both ligands and metal complexes are potent growth inhibitors, with MIC90 (µg mL-1) values observed from 0.419 ± 0.05 to 1.378 ± 0.21.

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.

Cytotoxic and antiparasitic activities of diphosphine-metal complexes of group 10 containing acylthiourea as ligands.

In this work, group 10 transition metal complexes bearing dppe [1,2-bis(diphenylphosphino)ethane] and acylthiourea ligands were evaluated for their cytotoxic and antiparasitic activities. Six new complexes with a general formula [M(Ln)(dppe)]BF4 [where M = NiII, PdII or PtII; Ln = N, N'-dimethyl-N-benzoyl thiourea (L1) or N, N'-dimethyl-N-tiofenyl thiourea (L2) were synthesized and characterized by infrared, NMR (31P{1H}, 1H and 13C{1H}) spectroscopies, elemental analysis and molar conductivity. The structures of the complexes were confirmed by X-ray diffraction technique. The biological activity of the complexes was evaluated on breast cancer cells (MDA-MB-231 and MCF-7) and causative agents of chagas disease and leishmaniasis. The complexes presented higher cytotoxicity for breast cancer cell lines compared to non-tumor cells. Nickel complexes stood out when evaluated against the triple-negative breast cancer line (MDA-MB-231), presenting considerably lower IC50 values (about 10 to 22×), when compared to palladium and platinum complexes, and the cisplatin drug. When evaluated on the triple-negative line (MDA-MB-231), the complexes [Ni(L2)(dppe)]BF4(2), [Pd(L2)(dppe)]BF4(4) and [Pt(L2)(dppe)]BF4(6) were able to induce cell morphological changes, influence on the cell colony formation and the size of the cells. The complexes inhibit cell migration and cause changes to the cell cytoskeleton and nuclear arrangement. In the same cell line, the compounds caused cell arrest in the Sub-G1 phase of the cell cycle. The compounds were also tested against the Trypanosom Cruzi (T. cruzi) and Leishmania sp. parasites, which cause Chagas and leishmaniasis disease, respectively. The compounds showed good anti-parasitic activity, mainly for T. cruzi, with lower IC50 values, when compared to the commercial drug, benznidazole. The compounds interact with CT-DNA, indicating that interaction occurs by the minor groove of the biomolecule.

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.

Ruthenium(II)-diphosphine complexes containing acylthiourea ligands are effective against lung and breast cancers.

We have synthesized and characterized three new ruthenium(II) diphosphine complexes containing an acylthiourea ligand, with the general formula [Ru(DPEPhos)(O,S)(bipy)]PF6, where DPEPhos = bis(2-(diphenylphosphino)phenyl)ether, bipy = 2,2'-bipyridine, and O,S = N,N-dimethyl-N'-(benzoyl)thiourea (1), N,N-dimethyl-N'-(furoyl)thiourea (2), and N,N-dimethyl-N'-(thiophenyl)thiourea (3), by several physicochemical techniques. We evaluated the ruthenium complexes for their cytotoxicity against two human cancer cell lines, A549 (lung) and MDA-MB-231 (breast), and two corresponding lines of non-cancer cells, MRC-5 (lung) and MCF-10A (breast). All the complexes are cytotoxic against the cancer cell lines; the IC50 values lie in the micromolar range (0.07-0.70 µM). Ruthenium complex 1 is more selective (7 times more active) toward lung cancer cells (A549) than toward non-cancer cells (MRC-5) and is 160 times more cytotoxic than cisplatin against A549 cells. Investigations of the mechanism of action of complex 1 in A549 cells demonstrated that it inhibits colony formation and promotes cell cycle arrest in the G1 phase and apoptotic cell death. DNA binding studies revealed that complexes 1-3 interact with the biomolecule via minor grooves. These complexes also interact with human serum albumin (HSA) and have affinity for site I by hydrophobic forces. Therefore, this new class of ruthenium complexes can act as cytotoxic agents, mainly for lung cancer treatment.

Ru(II)/amino acid complexes inhibit the progression of breast cancer cells through multiple mechanism-induced apoptosis.

For some cancer subtypes, such as triple-negative breast cancer, there are no specific therapies, which leads to a poor prognosis associated with invasion and metastases. Ruthenium complexes have been developed to act in all steps of tumor growth and its progression. In this study, we investigated the effects of Ruthenium (II) complexes coupled to the amino acids methionine (RuMet) and tryptophan (RuTrp) on the induction of cell death, clonogenic survival ability, inhibition of angiogenesis, and migration of MDA-MB-231 cells (human triple-negative breast cancer). The study also demonstrated that the RuMet and RuTrp complexes induce cell cycle blockage and apoptosis of MDA-MB-231 cells, as evidenced by an increase in the number of Annexin V-positive cells, p53 phosphorylation, caspase 3 activation, and poly(ADP-ribose) polymerase cleavage. Moreover, morphological changes and loss of mitochondrial membrane potential were detected. The RuMet and RuTrp complexes induced DNA damage probably due to reactive oxygen species production related to mitochondrial membrane depolarization. Therefore, the RuMet and RuTrp complexes acted directly on breast tumor cells, leading to cell death and inhibiting their metastatic potential; this reveals the potential therapeutic action of these drugs.