Structure-activity relationship of anticancer and antiplasmodial gold bis(dithiolene) complexes.

Monoanionic gold bis(dithiolene) complexes were recently shown to display activity against ovarian cancer cells, Gram-positive bacteria, Candida strains and the rodent malaria parasite, P. berghei. To date, only monoanionic gold(III) bis(dithiolene) complexes with a thiazoline backbone substituted with small alkyl chains have been evaluated for biomedical applications. We now analyzed the influence of the length and the hydrophobicity vs. hydrophilicity of these complexes' alkyl chain on their anticancer and antiplasmodial properties. Isomer analogues of these monoanionic gold(III) bis(dithiolene) complexes, this time with a thiazole backbone, were also investigated in order to assess the influence of the nature of the heterocyclic ligand on their overall chemical and biological properties. In this report we present the total synthesis of four novel monoanionic gold(III) bis(dithiolene) complexes with a long alkyl chain and a polyoxygenated (PEG) chain aiming to improve their solubility and biological properties. Our results showed that the complexes with a PEG chain showed promising anticancer and antiplasmodial activities beside improved solubility, a key parameter in drug discovery and development.

Post-craniotomy coronal suture diastases in a transformed lower grade glioma.

Cranial suture diastases are an uncommon clinical entity, with post craniotomy diastases being a previously undescribed finding in literature to our best knowledge. Herein, we report a case of a 28-year-old adult who underwent a second-stage low-grade glioma surgery 7 months after initial surgery. This study presents coronal suture diastases adjacent to the previously performed craniotomy. After literature and pathophysiology review, we found it to be unique and that the craniotomy can resemble the mechanical stress of trauma.

Copper(I)-Thiosemicarbazone Complexes with Dual Anticancer and Antiparasitic Activity.

Four new Cu(I) complexes of the general formula [Cu(PP)(LL)][BF4 ], in which PP is a phosphane ligand (triphenylphosphane or 1,2-bis(diphenylphosphano)ethane (dppe)) and LL is a bioactive thiosemicarbazone ligand (4-(methyl)-1-(5-nitrofurfurylidene)thiosemicarbazone) or 4-(ethyl)-1-(5-nitrofurfurylidene)thiosemicarbazone) were synthesized and fully characterized by classical analytical and spectroscopic methods. The anti-trypanosome and anticancer activities were investigated in vitro on Trypanosoma cruzi and in two human cancer cell lines (ovarian OVCAR3 and prostate PC3). To test the selectivity toward parasites and cancer cells, the cytotoxicity on normal monkey kidney VERO and human dermal fibroblasts HDF cells was also evaluated. The new heteroleptic complexes were more cytotoxic on T. cruzi and chemoresistant prostate PC3 cells than the benchmark drugs nifurtimox and cisplatin. The compounds also showed a high level of cellular internalization by the OVCAR3 cells and, in particular, those containing the dppe phosphane showed activation of the cell death mechanism via apoptosis. On the other hand, the production of reactive oxygen species induced by these complexes was not evident.

Antitumoral and Antimicrobial Activities of Block Copolymer Micelles Containing Gold Bisdithiolate Complexes.

Gold(III) bisdithiolate complexes have been reported as potential antimicrobial and antitumoral agents. The complex [Au(cdc)2]- (cdc=cyanodithioimido carbonate) displayed antimicrobial and outstanding antitumor activity against the ovarian cancer cells A2780 and A2780cisR, which are sensitive and resistant to cisplatin, respectively. However, poor water solubility may hamper its clinical use. Block copolymer micelles (BCMs) may solubilize hydrophobic drugs, improving their bioavailability and circulation time in blood. Aiming to provide water solubility, prolonged availability, and enhanced therapeutic indexes, BCMs loaded with [Au(cdc)2]- were synthesized and characterized. The BCM-[Au(cdc)2] micelles were prepared with a loading efficiency of 64.6% and a loading content of 35.3 mg [Au(cdc)2]-/gBCM. A hydrodynamic diameter of 77.31 ± 27.00 nm and a low polydispersity index of 0.18 indicated that the micelles were homogenous and good candidates for drug delivery. Cytotoxic activity studies against A2780/A2780cisR cells showed that BCM-[Au(cdc)2] maintained relevant cytotoxic activity comparable to the cytotoxicity observed for the same concentration of gold complexes. The Au uptake in A2780 cells, determined by PIXE, was ca. 17% higher for BCMs-[Au(cdc)2] compared to [Au(cdc)2]-. The BCMs-[Au(cdc)2] presented antimicrobial activity against S. aureus Newman and C. glabrata CBS138. These results evidenced the potential of BCM-[Au(cdc)2] for drug delivery and its promising anticancer and antimicrobial activities.

Image-Guided Nanodelivery of Pt(IV) Prodrugs to GRP-Receptor Positive Tumors.

Over the last decades, gold nanoparticles (AuNPs) have proven to be remarkable tools for drug delivery and theranostic applications in cancer treatment. On the other hand, Pt(IV) prodrugs have been employed as an interesting alternative to the more common Pt(II) complexes, such as cisplatin, for cancer chemotherapy. Searching to design an image-guided nanocarrier to deliver selectively Pt(IV) prodrugs to tumors expressing the gastrin releasing peptide receptor (GRPR), we have synthesized small core AuNPs carrying a thiolated DOTA derivative, a GRPR-targeting bombesin analog (BBN[7-14]) and a Pt(IV) prodrug attached to the AuNPs without (AuNP-BBN-Pt1) or with a PEGylated linker (AuNP-BBN-Pt2 and AuNP-BBN-Pt3). In the GRPR+ prostate cancer PC3 cell line, the cytotoxic activity of the designed AuNP-BBN-Pt nanoparticles is strongly influenced by the presence of the PEGylated linker. Thus, AuNP-BBN-Pt1 displayed the lowest IC50 value (9.3 ± 2.3 µM of Pt), which is comparable to that exhibited by cisplatin in the same cell line. In contrast, AuNP-BBN-Pt1 showed an IC50 value of 97 ± 18 µM of Pt in the non-tumoral RWPE-1 prostate cells with a much higher selective index (SI) towards PC3 cells (SI = 10) when compared with cisplatin (SI = 1.3). The AuNPs were also successfully labeled with 67Ga and the resulting 67Ga-AuNP-BBN-Pt were used to assess their cellular uptake in PC3 cells, with AuNP-BBN-Pt1 also displaying the highest cellular internalization. Finally, intratumoral administration of 67Ga-AuNP-BBN-Pt1 in a PC3 tumor-bearing mice showed a prolonged retention of the nanoparticle compared to that of cisplatin, with optimal in vivo stability and 20% of the injected platinum remaining in the tumor after 72 h post-injection. Furthermore, microSPECT imaging studies confirmed the uptake and considerable retention of the 67Ga-labeled AuNPs in the tumors. Overall, these results show the potential of these targeted AuNPs loaded with Pt(IV) prodrugs for prostate cancer theranostics.

Boron clusters (ferrabisdicarbollides) shaping the future as radiosensitizers for multimodal (chemo/radio/PBFR) therapy of glioblastoma.

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, and is highly resistant to conventional radiotherapy and chemotherapy. Therefore, the development of multidrug resistance and tumor recurrence are frequent. Given the poor survival with the current treatments, new therapeutic strategies are urgently needed. Radiotherapy (RT) is a common cancer treatment modality for GBM. However, there is still a need to improve RT efficiency, while reducing the severe side effects. Radiosensitizers can enhance the killing effect on tumor cells with less side effects on healthy tissues. Herein, we present our pioneering study on the highly stable and amphiphilic metallacarboranes, ferrabis(dicarbollides) ([o-FESAN]- and [8,8'-I2-o-FESAN]-), as potential radiosensitizers for GBM radiotherapy. We propose radiation methodologies that utilize secondary radiation emissions from iodine and iron, using ferrabis(dicarbollides) as iodine/iron donors, aiming to achieve a greater therapeutic effect than that of a conventional radiotherapy. As a proof-of-concept, we show that using 2D and 3D models of U87 cells, the cellular viability and survival were reduced using this treatment approach. We also tested for the first time the proton boron fusion reaction (PBFR) with ferrabis(dicarbollides), taking advantage of their high boron (11B) content. The results from the cellular damage response obtained suggest that proton boron fusion radiation therapy, when combined with boron-rich compounds, is a promising modality to fight against resistant tumors. Although these results are encouraging, more developments are needed to further explore ferrabis(dicarbollides) as radiosensitizers towards a positive impact on the therapeutic strategies for GBM.

Tuning the Biological Activity of Camphorimine Complexes through Metal Selection.

The cytotoxic activity of four sets of camphorimine complexes based on the Cu(I), Cu(II), Ag(I), and Au(I) metal sites were assessed against the cisplatin-sensitive A2780 and OVCAR3 ovarian cancer cells. The results showed that the gold complexes were ca. one order of magnitude more active than the silver complexes, which in turn were ca. one order of magnitude more active than the copper complexes. An important finding was that the cytotoxic activity of the Ag(I) and Au(I) camphorimine complexes was higher than that of cisplatin. Another relevant aspect was that the camphorimine complexes did not interact significantly with DNA, in contrast with cisplatin. The cytotoxic activity of the camphorimine complexes displayed a direct relationship with the cellular uptake by OVCAR3 cells, as ascertained by PIXE (particle-induced X-ray emission). The levels of ROS (reactive oxygen species) formation exhibited an inverse relationship with the reduction potentials for the complexes with the same metal, as assessed by cyclic voltammetry. In order to gain insight into the toxicity of the complexes, their cytotoxicity toward nontumoral cells (HDF and V79 fibroblasts) was evaluated. The in vivo cytotoxicity of complex 5 using the nematode Caenorhabditis elegans was also assessed. The silver camphorimine complexes displayed the highest selectivity coefficients (activity vs. toxicity).

Dose Rate Effects on the Selective Radiosensitization of Prostate Cells by GRPR-Targeted Gold Nanoparticles.

For a while, gold nanoparticles (AuNPs) have been recognized as potential radiosensitizers in cancer radiation therapy, mainly due to their physical properties, making them appealing for medical applications. Nevertheless, the performance of AuNPs as radiosensitizers still raises important questions that need further investigation. Searching for selective prostate (PCa) radiosensitizing agents, we studied the radiosensitization capability of the target-specific AuNP-BBN in cancer versus non-cancerous prostate cells, including the evaluation of dose rate effects in comparison with non-targeted counterparts (AuNP-TDOTA). PCa cells were found to exhibit increased AuNP uptake when compared to non-tumoral ones, leading to a significant loss of cellular proliferation ability and complex DNA damage, evidenced by the occurrence of multiple micronucleus per binucleated cell, in the case of PC3 cells irradiated with 2 Gy of γ-rays, after incubation with AuNP-BBN. Remarkably, the treatment of the PC3 cells with AuNP-BBN led to a much stronger influence of the dose rate on the cellular survival upon γ-photon irradiation, as well as on their genomic instability. Overall, AuNP-BBN emerged in this study as a very promising nanotool for the efficient and selective radiosensitization of human prostate cancer PC3 cells, therefore deserving further preclinical evaluation in adequate animal models for prostate cancer radiotherapy.

In vitro toxicity of particulate matter emissions from residential pellet combustion.

Particulate matter emissions (PM10) from the combustion, in a residential stove, of two commercial brands of certified (ENplus A1) pellets, a non-certified brand and laboratory made pellets of acacia were tested for their ability to induce ecotoxic, cytotoxic, and mutagenic responses in unicellular organisms and a human cell line. Ecotoxicity was evaluated through the Vibrio fischeri bioluminescence inhibition assay. Moreover, cytotoxicity was assessed at two time points (24- and 48-hr) through two complementary techniques in order to evaluate the cellular metabolic activity and membrane integrity of human lung epithelial cells A549. The Ames test using two Salmonella typhimurium strains (TA100 and TA98) was employed to assess the mutagenic potential of the polycyclic aromatic hydrocarbon fraction extracted from the PM10 samples. Results obtained with the bioluminescent bacteria indicated that only particles from the combustion of acacia pellets were toxic. All samples induced impairment on the A549 cells metabolic activity, while no significant release of lactate dehydrogenase was recorded. PM10 emissions from acacia pellets were the most cytotoxic, while samples from both certified pellets evoked significant cytotoxicity at lower doses. Cytotoxicity time-dependency was only observed for PM10 from the combustion of acacia pellets and one of the brands of certified pellets. Mutagenic activity was not detected in both S. typhimurium strains. This study emphasises the role of the raw material for pellet manufacturing on the toxicological profile of PM emissions. Alternative raw materials should be deeply investigated before their use in pelletisation and combustion in residential appliances.

Sono-Biosynthesis and Characterization of AuNPs from Danube Delta Nymphaea alba Root Extracts and Their Biological Properties.

Root extracts from Danube Delta Nymphaea alba were used to prepare gold nanoparticles (AuNPRn) by reducing HAuCl4 at different pHs (6.4-8.4) using ultrasonic irradiation: an easy, cheap, eco-friendly and green approach. Their antibacterial and anticancer activities were evaluated against Staphylococcus aureus and Escherichia coli, and A2780 ovarian cancer cells, respectively. The AuNPRn were characterized concerning their phytoconstituents (polyphenols, flavonoids and condensed tannins) and gold content. All of the nanoparticles were negatively charged. AuNPRn exhibited a hydrodynamic size distribution ranging from 32 nm to 280 nm, with the larger nanoparticles being obtained with an Au/root extract ratio of 0.56, pH 7 and 10 min of sonication (AuNPR1), whereas the smallest were obtained with an Au/root extract ratio of 0.24, pH 7.8 and 40 min of sonication (AuNPR4). The TEM/SEM images showed that the AuNPRn had different shapes. The ATR-FTIR indicated that AuNPRn interact mainly with hydroxyl groups present in the polyphenol compounds, which also confirm their high antioxidant capacity, except for AuNPR2 obtained at pH 6.4. Among the AuNPRn, the smallest ones exhibited enhanced antimicrobial and anticancer activities.

In vitro toxicity of indoor and outdoor PM10 from residential wood combustion.

Particulate matter with aerodynamic diameter < 10 µm (PM10) was collected, indoors and outdoors, when wood burning appliances (open fireplace and woodstove) were in operation. The PM10 ecotoxicity was assessed with the Vibrio fischeri bioluminescence inhibition assay, while the cytotoxicity was evaluated by the WST-8 and lactate dehydrogenase (LDH) release assays using A549 cells. Extracts of PM10-bound polycyclic aromatic hydrocarbons (PAH) were tested for their mutagenicity through the TA98 and TA100 Ames test. The bioluminescent inhibition assay revealed that indoor particles released from the fireplace were the most toxic. Indoors, the reduction in A549 cell metabolic activity was over two times higher for the fireplace in comparison with the woodstove (32 ± 3.2% and 72 ± 7.6% at the highest dose, respectively). Indoor particles from the fireplace were found to induce greater cytotoxicity than the corresponding outdoor samples. Combined WST-8 and LDH results suggest that PM10 exposure induce apoptotic cell death pathway in which the cell membrane integrity is maintained. Indoor and outdoor samples lacked direct and indirect mutagenic activity in any of the tester strains. For indoor-generated PM10, organic carbon and PAH were significantly correlated with cell viability and bioluminescence reduction, suggesting a role of organic compounds in toxicity.

The Proinflammatory Soluble CD40 Ligand Is Associated with the Systemic Extent of Stable Atherosclerosis.

Background and objectives: Polyvascular atherosclerosis is frequent and associated with a high cardiovascular risk, although the mechanisms regulating the atherosclerosis extent to single or multiple arterial territories are still poorly understood. Inflammation regulates atherogenesis and soluble CD40 ligand (sCD40L) is an inflammatory mediator associated with the presence of single-territorial atherosclerosis. We assessed whether the sCD40L expression is associated with the atherosclerosis extent to single or multiple arterial territories and with the atherosclerosis severity in different territories. Materials and Methods: We prospectively enrolled 94 participants with no atherosclerosis (controls, n = 26); isolated coronary atherosclerosis (group 1, n = 20); coronary and lower extremity (LE) atherosclerosis (group 2, n = 18); coronary and carotid atherosclerosis (group 3, n = 12); and coronary, LE, and carotid atherosclerosis (group 4, n = 18). Serum sCD40L levels were quantified. Results: The sCD40L levels (ng/mL, mean (standard deviation)) were 4.0 (1.5), 5.6 (2.6), 7.2 (4.2), 5.9 (3.7), and 5.1 (2.4) in controls and groups 1 to 4, respectively (ANOVA p = 0.012). In nonrevascularized patients, the sCD40L levels were significantly higher in group 2 than in group 1 and were correlated with the number of LE diseased segments. Prior LE bypass surgery was associated with lower sCD40L levels. Coexistence of coronary and LE atherosclerosis was independently associated with the sCD40L levels. Conclusions: The sCD40L levels were increased in stable atherosclerosis, particularly in polyvascular coronary and LE atherosclerosis. The number of LE diseased segments and prior LE revascularization were associated with sCD40L expression. To our knowledge, these are novel data, which provide insights into the mechanisms underlying multi-territorial atherosclerosis expression. sCD40L may be a promising noninvasive tool for refining the stratification of the systemic atherosclerotic burden.

Therapeutic potential of vanadium complexes with 1,10-phenanthroline ligands, quo vadis? Fate of complexes in cell media and cancer cells.

VIVO-complexes formulated as [VIVO(OSO3)(phen)2] (1) (phen = 1,10-phenanthroline), [VIVO(OSO3)(Me2phen)2] (2) (Me2phen = 4,7-dimethyl-1,10-phenanthroline) and [VIVO(OSO3)(amphen)2] (3) (amphen = 5-amino-1,10-phenanthroline) were prepared and stability in cell incubation media evaluated. Their cytotoxicity was determined against the A2780 (ovarian), MCF7 (breast) and PC3 (prostate) human cancer cells at different incubation times. While at 3 and 24 h the cytotoxicity differs for complexes and corresponding free ligands, at 72 h incubation all compounds are equally active presenting low IC50 values. Upon incubation of A2780 cells with 1-3, cellular distribution of vanadium in cytosol, membranes, nucleus and cytoskeleton, indicate that the uptake of V is low, particularly for 1, and that the uptake pattern depends on the ligand. Nuclear microscopic techniques are used for imaging and elemental quantification in whole PC3 cells incubated with 1. Once complexes are added to cell culture media, they decompose, and with time most VIV oxidizes to VV-species. Modeling of speciation when [VIVO(OSO3)(phen)2] (1) is added to cell media is presented. At lower concentrations of 1, VIVO- and phen-containing species are mainly bound to bovine serum albumin, while at higher concentrations [VIVO(phen)n]2+-complexes become relevant, being predicted that the species taken up and mechanisms of action operating depend on the total concentration of complex. This study emphasizes that for these VIVO-systems, and probably for many others involving oxidovanadium or other labile metal complexes, it is not possible to identify active species or propose mechanisms of cytotoxic action without evaluating speciation occurring in cell media.

Soluble CD40 ligand expression in stable atherosclerosis: A systematic review and meta-analysis.

BACKGROUND AND AIMS: The role of inflammation in atherosclerosis development and expression in different arterial territories is unclear. Soluble CD40 ligand (sCD40L) mediates inflammation and atherogenesis. Through a systematic review and meta-analysis, we assessed whether sCD40L was dysregulated in stable atherosclerosis, irrespective of the diseased arterial territory, and whether this dysregulation differed according to the specific territory. METHODS: Systematic literature searches were performed in MEDLINE, Cochrane Library, Web of Science, and Embase for studies reporting circulating sCD40L levels in individuals with and without stable atherosclerosis. sCD40L levels were compared using random-effects meta-analysis, weighted by the inverse variance method (study protocol: PROSPERO CRD42020181392). RESULTS: Fifty-four studies (59 estimates) including 7705 patients and 7841 controls were analyzed. sCD40L levels were found to be increased in patients with atherosclerosis, irrespective of the territory (standardized mean difference [SMD] 0.43, 95% CI 0.29-0.57; 59 estimates; χ2 heterogeneity p < 0.001; I2 = 92%). SMD was greatest in carotid atherosclerosis (SMD 0.58, 95% CI 0.30-0.86; 17 estimates), followed by coronary (SMD 0.43, 95% CI 0.24-0.62; 33 estimates), lower extremity (SMD 0.26, 95% CI -0.02-0.54; 7 estimates), and renal atherosclerosis (SMD -0.07, 95% CI -2.77-2.64; 2 estimates) (χ2 heterogeneity p < 0.001; I2 ≥ 80% for all). Subgroup analysis revealed that sCD40L levels were increased in clinical, but not subclinical, atherosclerosis. CONCLUSIONS: sCD40L levels were increased in stable atherosclerosis, particularly in the carotid and coronary territories. These novel data support sCD40L as a marker of systemic atherosclerosis, possibly with differential roles in specific territories.

Inflammation is associated with the presence and severity of chronic coronary syndrome through soluble CD40 ligand.

INTRODUCTION: Inflammation contributes to the initiation and progression of atherosclerosis, although the underlying inflammatory pathways are not entirely known. Specifically, the role of the proinflammatory soluble CD40 ligand (sCD40L) on the expression of chronic coronary syndrome (CCS) is not completely understood. We evaluated whether sCD40L expression is associated with the presence of CCS and with the clinical and anatomical severity of CCS. METHODS: We prospectively recruited 94 participants, assigned to two groups matched by age and sex, without coronary artery disease (n=26) and with CCS (n=68). Clinical, laboratory and anatomical data were prospectively collected, and serum levels of sCD40L were measured. RESULTS: In patients with CCS, classic cardiovascular risk factors were more prevalent, and the sCD40L levels, leukocyte and neutrophil counts, and neutrophil/lymphocyte ratio, but not the C-reactive protein levels, were significantly higher than those in controls. sCD40L was independently associated with the presence of obstructive coronary artery disease in multivariate analysis. Regarding CCS severity, sCD40L levels showed a significant stepwise increase with increasing angina severity (ANOVA P=0.001). In addition, sCD40L was independently associated with the anatomical severity of coronary artery disease, as assessed by the Gensini score. Among patients with CCS, those with previous coronary artery bypass grafting (n=23) had lower sCD40L levels than patients waiting for revascularization (n=45) [4.3 (2.1) ng/mL vs. 6.8 (3.5) ng/mL, P=0.001]. CONCLUSIONS: The expression of the proinflammatory sCD40L was associated with the presence of CCS and reflected the clinical and anatomical severity of CCS. In addition, we describe for the first time the association between prior CABG and reduced sCD40L levels in patients with CCS.

Mechanisms underlying the cytotoxic activity of syn/anti-isomers of dinuclear Au(I) NHC complexes.

The syn- and anti-isomers of dinuclear Au(I) complexes of the type Au2(RLOH)(PF6)2 (R = isopropyl or mesityl) bearing 2-hydroxyethane-1,1-diyl-bridged bisimidazolylidene ligands were separated by reversed phase high performance liquid chromatography (HPLC) and characterized by NMR spectroscopy, elemental analysis, ESI mass spectrometry as well as single crystal X-ray diffraction analysis. Evaluation of the antiproliferative activity of the isolated isomers has shown very small difference in their cytotoxic behavior in various cancer cell lines. Additional counter-anion exchange (hexafluorophosphate to chloride) allows to increase the water solubility of synAu2(MesLOH)(PF6)2 and leads to higher antiproliferative activity when compared to the hexafluorophosphate-complex. Both isomers were treated with l-cysteine as nucleophilic thiol source and only the anti-isomer shows dissociation of one bisimidazolylidene ligand after 24 h. In the case of the syn-isomer, density functional theory calculations indicate a lower reactivity due to the higher steric hindrance of the N-substituents and additional hydrogen bond interaction, which prevents a nucleophilic attack. When the N-substituent is replaced by the bulkier mesityl group, both conformations remain unreactive and result to be the most cytotoxic complexes in the above-mentioned cancer cell lines. Interestingly, synAu2(MesLOH)(PF6)2 exhibits a high selectivity in the MCF-7 cell line with a selectivity index (SI) of 19, which is superior to auranofin (SI < 1), making this compound an ideal candidate for further studies. Preliminary mechanistic studies reveal that the cytotoxic complexes possess mitochondrial-TrxR inhibition properties in the nanomolar range. Additionally, the cellular distribution studies by ICP-MS and nuclear microscopy have shown that the compound accumulates in the membranes. These results suggest that the mitochondrial membrane is the main target for this type of dinuclear complexes, causing oxidative stress by inhibiting mitochondrial thioredoxin reductase.

Antiproliferative Activity of Functionalized Histidine-derived Au(I) bis-NHC Complexes for Bioconjugation.

A series of histidine derived Au(I) bis-NHC complexes bearing different ester, amide and carboxylic acid functionalities as well as wingtip substituents is synthesized and characterized. The stability in aqueous media, in vitro cytotoxicity in a set of cancer cell lines (MCF7, PC3 and A2780/A2780cisR) along with the cellular uptake are evaluated. Stability tests suggest hydrolysis of the ester within 8 h, which might lead to deactivation. Furthermore, the bis-NHC system shows a sufficient stability against cysteine and the thiol containing peptide GSH. The benzyl ester and amide show the highest activity comparable to the benchmark compound cisplatin, with the ester only displaying a slightly lower cytotoxicity than the amide. A cellular uptake study revealed that the benzyl ester and the amide could have different intracellular distribution profiles but both complexes induce perturbations of the cellular physiological processes. The simple modifiability and high stability of the complexes provides a promising system for upcoming post modifications to enable targeted cancer therapy.

Copper Complexes with 1,10-Phenanthroline Derivatives: Underlying Factors Affecting Their Cytotoxicity.

The interpretation of in vitro cytotoxicity data of Cu(II)-1,10-phenanthroline (phen) complexes normally does not take into account the speciation that complexes undergo in cell incubation media and its implications in cellular uptake and mechanisms of action. We synthesize and test the activity of several distinct Cu(II)-phen compounds; up to 24 h of incubation, the cytotoxic activity differs for the Cu complexes and the corresponding free ligands, but for longer incubation times (e.g., 72 h), all compounds display similar activity. Combining the use of several spectroscopic, spectrometric, and electrochemical techniques, the speciation of Cu-phen compounds in cell incubation media is evaluated, indicating that the originally added complex almost totally decomposed and that Cu(II) and phen are mainly bound to bovine serum albumin. Several methods are used to disclose relationships between structure, activity, speciation in incubation media, cellular uptake, distribution of Cu in cells, and cytotoxicity. Contrary to what is reported in most studies, we conclude that interaction with cell components and cell death involves the separate action of Cu ions and phen molecules, not [Cu(phen)n] species. This conclusion should similarly apply to many other Cu-ligand systems reported to date.