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Herein we report the synthesis of gold(i) and gold(iii) complexes of tris(4-methoxyphenyl)phosphine and tris(2,6-dimethoxyphenyl)phosphine and their anticancer activity towards 2D and 3D cancer models. Show less

Gold compounds have been proven to be novel and versatile tools for biological applications, including as anticancer agents. Recently, we explored the potential of Au(III) complexes with bi-dentate N-donor ligands as inhibitors of the membrane water and glycerol channels aquaporins (AQPs), involved in different physiological and pathophysiological pathways. Here, eight new Au(III) complexes featuring a pyridine-benzimidazole scaffold have been synthesized and characterized via different methods. The stability of all the compounds in aqueous solution and their reactivity with glutathione have been investigated by UV–visible spectroscopy. The Au(III) compounds, tested for their AQPs inhibition properties in human Red Blood Cells (hRBC), are potent and selective inhibitors of AQP3. Furthermore, the compounds’ antiproliferative effects have been studied in a small panel of human cancer cells expressing AQP3. The complexes show only very moderate anticancer effects in vitro and are mostly active against the melanoma A375 cells, with marked expression of AQP3 at the level of the nuclear membrane. In general, the AQP3 inhibition properties of these complexes hold promises to develop them as chemical probes to study the function of this protein isoform in biological systems. Show less

AbstractA structurally diverse library of 14 gold(I) cationic bis(NHC) and neutral mono(NHC) complexes (NHC: N‐heterocyclic carbene) was synthesized and characterized in this work. Four of them were new cationic gold(I) complexes containing functionalized NHCs, and their X‐ray crystal structures are presented herein. All of the complexes were investigated for their anticancer activities in four cancer cell lines, including a cisplatin‐resistant variant, and a noncancerous cell line. Seven of the cationic gold(I) complexes were found to display high and specific cytotoxic activities toward cancer cells. Two of them were even able to overcome cisplatin resistance. Two highly potent cationic complexes (11 and 15) were also submitted to the NCI‐60 cancer panel for further cytotoxicity evaluation. Complex 15 showed a surprisingly high potency toward leukemia among the nine examined cancer subtypes, particularly toward the CCRF‐CEM leukemia cell line with a concentration for 50 % inhibition of growth down to 79.4 nm. In addition, cationic complex 13, which demonstrated a remarkable cytotoxicity against hepatocellular carcinoma, was selected to obtain insight into the mechanistic aspects in HepG2 cells. Cellular uptake measurements were indicative of good bioavailability. By various biochemical assays, this complex was found to effectively inhibit thioredoxin reductase and its cytotoxicity toward HepG2 cells was found to be reactive oxygen species dependent. TLDR: A structurally diverse library of 14 gold(I) cationic bis(N HC) and neutral mono(NHC) complexes (NHC: N‐heterocyclic carbene) was synthesized and characterized in this work, and their X‐ray crystal structures are presented herein. Show less

Purpose

Oxaliplatin causes disabling acute and chronic peripheral neuropathy. We explored the preventive effects of calmangafodipir, mimicking the mitochondrial enzyme manganese superoxide dismutase, thereby protecting cells from oxidative stress, in a placebo-controlled, double-blinded randomised phase II study (ClinicalTrials.gov.NCT01619423) in patients with metastatic colorectal cancer (mCRC).

Patient and methods

mCRC patients treated with modified FOLFOX-6 (folinic acid 200 mg/m², 5-fluorouracil bolus 400 mg/m², oxaliplatin 85 mg/m² and 5-fluorouracil 2400 mg/m² continuous infusion for 46 h) every fortnight for 8 cycles in first or second line were eligible. Calmangafodipir was given in a phase I dose-finding and in a phase II placebo-controlled study, as a 5-min infusion 10 min prior to oxaliplatin. Neurotoxicity was evaluated by the physician using the Oxaliplatin Sanofi Specific Scale and by the patient using the cold allodynia test and the Leonard scale.

Results

Eleven patients were included in phase I without any detectable toxicity to calmangafodipir. In the phase II study, 173 patients were randomised to placebo (n = 60), calmangafodipir 2 µmol/kg (n = 57) and calmangafodipir 5 µmol/kg (n = 45, initially 10 µmol/kg, n = 11). Calmangafodipir-treated patients (all three doses pooled) had less physician graded neurotoxicity (odds ratio (90% confidence interval one-sided upper level) 0.62(1.15), p = .16), significantly less problems with cold allodynia (mean 1.6 versus 2.3, p < .05) and significantly fewer sensory symptoms in the Leonard scale (cycle 1-8 mean 1.9 versus 3.0, p < .05 and during follow-up after 3 and 6 months, mean 3.5 versus 7.3, p < .01). Response rate, progression-free and overall survival did not differ among groups.

Conclusions

Calmangafodipir at a dose of 5 µmol/kg appears to prevent the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumour outcomes. Show less

Ruthenium-based compounds represent a class of potential antineoplastic drugs. Recently, we designed, synthesized, and identified the Ru(II)-thymine complex [Ru(PPh₃)₂(Thy)(bipy)]PF₆ (where PPh = triphenylphosphine, Thy = thymine and bipy = 2,2'-bipyridine) as a potent cytotoxic agent with the ability to bind to DNA and human and bovine serum albumins. In this study, the underlying cytotoxic mechanism of the [Ru(PPh₃)₂(Thy)(bipy)]PF₆ complex was assessed. This complex displayed potent cytotoxicity in different cancer cell lines; the morphology that is associated with apoptotic cell death, increased internucleosomal DNA fragmentation without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization, and caspase-3 activation were observed in human promyelocytic leukemia HL-60 cells that were treated with the complex. Moreover, pretreatment of HL-60 cells with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, partially reduced the apoptosis that was induced by the complex, indicating that the apoptotic cell death occurred through a caspase-mediated pathway. In conclusion, the [Ru(PPh₃)₂(Thy)(bipy)]PF₆ complex displays potent cytotoxicity to different cancer cells and induces caspase-mediated apoptosis in HL-60 cells. Show less

New ruthenium methyl-cyclopentadienyl compounds bearing bipyridine derivatives with the general formula [Ru(η⁵-MeCp)(PPh₃)(4,4'-R-2,2'-bpy)]⁺ (Ru1, R = H; Ru2, R = CH₃; and Ru3, R = CH₂OH) have been synthesized and characterized by spectroscopic and analytical techniques. Ru1 crystallized in the monoclinic P2₁/ c, Ru2 in the triclinic P1̅, and Ru3 in the monoclinic P2₁/ n space group. In all molecular structures, the ruthenium center adopts a "piano stool" distribution. Density functional theory calculations were performed for all complexes, and the results support spectroscopic data. Ru1 and Ru3 were poor substrates of the main multidrug resistance human pumps, ABCB1, ABCG2, ABCC1, and ABCC2, while Ru2 displayed inhibitory properties of ABCC1 and ABCC2 pumps. Importantly, all compounds displayed a very high cytotoxic profile for ovarian cancer cells (sensitive and resistant) that was much more pronounced than that observed with cisplatin, making them very promising anticancer agents. Show less

In this study, six half-sandwich luminescent iridium (Ir) and ruthenium (Ru) anticancer complexes bearing P^P-chelating ligands 1,2-bis(diphenylphosphino)benzene (dppbz) and 1,8-bis(diphenylphosphino)naphthalene (dppn) were synthesized and characterized via1H-NMR spectroscopy, 31P-NMR spectroscopy, mass spectrometry, elemental analysis and X-ray crystallography. All the complexes displayed more potent anticancer activity than cisplatin towards A549 lung cancer cells and HeLa cervical cancer cells, especially the most potent iridium complex Ir3, which was 73 times more potent than cisplatin against A549 cells. Different from cisplatin, no nucleobase adducts of Ir3 were detected. With the help of the self-luminescence of complex Ir3 and confocal microscopy, it was observed that Ir3 efficiently penetrated into the A549 cells via energy-dependent active transport, and specifically accumulated in lysosomes, affected the permeabilization of the lysosomal membranes and induced caspase-dependent cell death through lysosomal damage. Both apoptosis and autophagy of the A549 cells were observed. The reactive oxygen species (ROS) elevation, reduction of the mitochondrial membrane potential and cell cycle arrest at the G0/G1 phase also contributed to the observed cytotoxicity of Ir3. We demonstrate that these half-sandwich Ir and Ru anticancer complexes have different anticancer mechanism of action from that of cisplatin, which can be developed as potential multifunctional theranostic platforms that combine bioimaging and anticancer capabilities. Show less

The ligands L¹ and L² both form separable dinuclear double-stranded helicate and mesocate complexes with Ru^II . In contrast to clinically approved platinates, the helicate isomer of [Ru₂ (L¹ )₂ ]⁴⁺ was preferentially cytotoxic to isogenic cells (HCT116 p53^-/- ), which lack the critical tumour suppressor gene. The mesocate isomer shows the reverse selectivity, with the achiral isomer being preferentially cytotoxic towards HCT116 p53^+/+ . Other structurally similar Ru^II -containing dinuclear complexes showed very little cytotoxic activity. This study demonstrates that alterations in ligand or isomer can have profound effects on cytotoxicity towards cancer cells of different p53 status and suggests that selectivity can be "tuned" to either genotype. In the search for compounds that can target difficult-to-treat tumours that lack the p53 tumour suppressor gene, [Ru₂ (L¹ )₂ ]⁴⁺ is a promising compound for further development. Show less

Combination of multifunctionalities into one compound is a rational strategy in medicinal chemical design, and have often been used with metallodrug-based compounds. In the present study, we synthesized a novel ruthenium-based 5-fluorouracil complex [Ru(5-FU)(PPh₃)₂(bipy)]PF₆ (PPh₃ = triphenylphosphine; and bipy = 2,2'-bipyridine) with enhanced cytotoxicity in different cancer cells, and assessed its apoptosis induction action in human colon carcinoma HCT116 cells. The complex was characterized by infrared, cyclic voltammetry, molar conductance measurements, elemental analysis, NMR experiments and X-ray crystallographic analysis. In both 2D and 3D cell culture models, the complex presented cytotoxicity to cancer cells more potent than 5-FU. A typical morphology of apoptotic cell death, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HCT116 cells. Moreover, the pre-treatment with Z-DEVD-FMK, a caspase-3 inhibitor, reduced the apoptosis induced by the complex, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. The complex failed to induce reactive oxygen species production and DNA intercalation. In conclusion, the novel complex displays enhanced cytotoxicity to different cancer cells, and is able to induce caspase-mediated apoptosis in HCT116 cells. Show less

Ru(arene) compounds have many desirable features making them promising candidates for further development in anticancer drug research. While a lot of emphasis has been placed on the modification of the ancillary ligands, there are not many examples of arene ligands bearing functional groups. Herein, we report the preparation of [Ru(arene)(8-oxyquinolinato)Cl] complexes with the arene being a protected form of the amino acid l-phenylalanine and 8-oxyquinolinato ligand substituted with halogens. With this approach we aimed to alter the pharmacological properties of the complexes and address issues with the aqueous solubility of the analogous p-cymene complexes. The complexes were shown to be stable in DMSO and water and reacted readily with l-histidine and 9-ethylguanine as protein and DNA models, respectively. Assaying the antiproliferative activity in cancer cells gave IC₅₀ values in the low μM range. While the lipophilicity of the p-cymene analogues correlated well with their in vitro cytotoxicity, the potency of the complexes with the l-phenylalanine-derived arene was independent of lipophilicity. Show less

Organometallic Ru(II)-cymene complexes linked to ferrocene (Fc) via nitrogen heterocycles have been synthesized and studied as cytotoxic agents. These compounds are analogues of Ru(II)-arene piano-stool anticancer complexes such as RAPTA-C. The Ru center was coordinated by pyridine, imidazole, and piperidine with 0-, 1-, or 2-carbon bridges to Fc to give six bimetallic, dinuclear compounds, and the properties of these complexes were compared with their non-Fc-functionalized parent compounds. Crystal structures for five of the compounds, their Ru-cymene parent compounds, and an unusual trinuclear compound were determined. Cyclic voltammetry was used to determine the formal M^III/II potentials of each metal center of the Ru-cymene-Fc complexes, with distinct one-electron waves observed in each case. The Fc-functionalized complexes were found to exhibit good cytotoxicity against HT29 human colon adenocarcinoma cells, whereas the parent compounds were inactive. Similarly, antibacterial activity from the Ru-cymene-Fc compounds was observed against Bacillus subtilis, but not from the unfunctionalized complexes. In both cases, the IC₅₀ values correlated quantitatively with the Fc^+/0 reduction potentials. This is consistent with more facile oxidation to give ferrocenium, and subsequent generation of toxic reactive oxygen species, leading to greater cytotoxicity. The antioxidant properties of the complexes were quantified by a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. EC₅₀ values indicate that linking of the Ru and Fc centers promotes antioxidant activity. Show less

In this study, Ru(II)-arene complexes with acylthiourea ligands of the type [Ru(η⁶‑p‑cymene)(PPh₃)(T)Cl]PF₆(1-5) and [Ru(η⁶‑p‑cymene)(PPh₃)(T)]PF₆(1a, 4a), where PPh₃ = triphenylphosphine and T = N‑acyl‑N'(monosubstituted)thiourea, were synthesized and characterized, and their cytotoxic properties were also evaluated. 1a and 4a were obtained from the hydrolysis reaction of 1 and 4. All complexes showed unusual coordination modes for acylthiourea ligands, which are coordinated in a monodentate fashion (S) in 1-5, while they found to be bidentate (S,N), in 1a and 4a. To the best of our knowledge, 1a and 4a are the first crystallographically reported ruthenium compounds with acylthiourea coordinated via S and N(amide) atoms. The cytotoxicity of the compounds was evaluated in human lung cells, A549 and MRC-5. The IC₅₀ values ranging from 0.25 to 0.61 μM after 48 h incubation in lung cancer cells indicate that the compounds showed high cytotoxicity with values significantly lower than the reference drug, cisplatin (11.84 μM). Interaction studies were carried out using human serum albumin (HSA) and DNA. All complexes showed similar cytotoxic activity, however complex 1a, which is the hydrolysis product of 1, presented the highest activity and selectivity among all seven compounds synthesized here. Complexes 1 and 1a inhibited the colony formation decreasing the colony size and inducing morphology changes in A549 cells. These complexes induced apoptosis cell death and promoted cell cycle arrest in the Sub-G1 phase with a decrease in the cell number at the S phase. Show less

As hypoxia is an important factor to limit chemotherapeutic efficacy in tumors, we herein report three ruthenium(II)-arene complexes containing a hypoxia inducible factor-1α inhibitor (YC-1), which endow the organometallic complexes with potential for hypoxia targeting. In vitro tests showed the resulting complexes had higher anticancer activities in hypoxia than in normoxia against the tested cancer cell lines. Western blot analysis revealed that complexes 1-3 blocked HIF-1α protein accumulation under hypoxic conditions. Moreover, these complexes displayed much less cytotoxicity toward the normal human umbilical vein endothelial cell line (HUVEC), indicating that complexes 1-3 may be selectively cytotoxic for human cancer cell lines. These findings proved that ligation with YC-1 endowed these organometallic ruthenium(II) complexes with potential for hypoxia targeting in addition to enhancing their anticancer activities. Show less

Mononuclear gold(I) acyclic diaminocarbenes (ADCs) were prepared by the reaction of 1,2-cyclohexanediamine with the corresponding isocyanide complexes [AuCl(CNR)] (R = Cy, ^t Bu). The three-component coupling of aldehydes, amines, and alkynes was investigated by using these gold(I) ADC complexes. The new gold(I) metal complexes are highly efficient catalysts for the synthesis of propargylamines and indolizines in the absence of solvent and in mild conditions. This method affords the corresponding final products with excellent yields in short reaction times. Additionally, chiral gold(I) complexes with ADCs have been prepared and tried in the enantioselective synthesis of propargylamines. Show less

Three new compounds have been synthesized and completely characterized by analytical and spectroscopic techniques. The new bipyridine-perfluorinated ligand L1 and the new organometallic complex [Ru(η⁵-MeCp)(PPh₃)₂Cl] (Ru1) crystalize in the centrosymmetric triclinic space group P1¯. Analysis of the phenotypic effects induced by both organometallic complexes Ru1 and [Ru(η⁵-MeCp)(PPh₃)(L1)][CF₃SO₃] (Ru2), on human colorectal cancer cells (SW480 and RKO) survival, showed that Ru2 has a potent anti-proliferative activity, 4-6 times higher than cisplatin, and induce apoptosis in these cells. Data obtained in a noncancerous cell line derived from normal colon epithelial cells (NCM460) revealed an intrinsic selectivity of Ru2 for malignant cells at low concentrations, showing the high potential of this compound as a selective anticancer agent. Show less

Ruthenium(II/III) metal complexes have been widely recognized as the alternative chemotherapeutic agents to overcome the drug resistance and tumor recurrence associated with platinum derivatives. In this work, a novel ruthenium(II) triazine complex namely, 1 ([Ru(bdpta)(tpy)]²⁺) was synthesized and spectroscopically characterized. Drug resistant cancer stem cells (CSCs) were used to evaluate the cytotoxicity of Ru(II) complex 1. The complex 1 showed a greater cytotoxic potential with IC₅₀ values lower than that of cisplatin. The intracellular localization assay confirmed that the complex 1 was effectively distributed into mitochondria as well as endoplasmic reticulum (ER), and executed a ROS-mediated calcium and Bax/Bak dependent intrinsic apoptosis. Interestingly, direct interaction between complex 1 and glucose regulated protein 78 (GRP78), a protein associated with drug resistance caused the ROS-mediated ubiquitination of GRP78. Notably, western blot and confocal microscopy analysis confirmed that complex 1 significantly reduced the protein levels of GRP78. Dose-dependent in vivo antitumor efficacy against CD133+HCT-116 CSCs derived tumor xenograft further validated that complex 1 could be an effective chemotherapeutic agent. Show less

The photophysical and photobiological properties of a new class of cyclometalated ruthenium(II) compounds incorporating π-extended benzo[ h]imidazo[4,5- f]quinoline (IBQ) cyclometalating ligands (C^N) bearing thienyl rings ( n = 1-4, compounds 1-4) were investigated. Their octanol-water partition coefficients (log P_o/w) were positive and increased with n. Their absorption and emission energies were red-shifted substantially compared to the analogous Ru(II) diimine (N^N) complexes. They displayed C^N-based intraligand (IL) fluorescence and triplet excited-state absorption that shifted to longer wavelengths with increasing n and N^N-based metal-to-ligand charge transfer (MLCT) phosphorescence that was independent of n. Their photoluminescence lifetimes (τ_em) ranged from 4-10 ns for ¹IL states and 12-18 ns for ³MLCT states. Transient absorption lifetimes (τ_TA) were 5-8 μs with 355 nm excitation, ascribed to ³IL states that became inaccessible for 1-3 with 532 nm excitation (1-3, τ_TA = 16-17 ns); the ³IL of 4 only was accessible by lower energy excitation, τ_TA = 3.8 μs. Complex 4 was nontoxic (EC₅₀ > 300 μM) to SK-MEL-28 melanoma cells and CCD1064-Sk normal skin fibroblasts in the dark, while 3 was selectively cytotoxic to melanoma (EC₅₀= 5.1 μM) only. Compounds 1 and 2 were selective for melanoma cells in the dark, with submicromolar potencies (EC₅₀ = 350-500 nM) and selectivity factors (SFs) around 50. The photocytotoxicities of compounds 1-4 toward melanoma cells were similar, but only compounds 3 and 4 displayed significant phototherapeutic indices (PIs; 3, 43; 4, >1100). The larger cytotoxicities for compounds 1 and 2 were attributed to increased cellular uptake and nuclear accumulation, and possibly related to the DNA-aggregating properties of all four compounds as demonstrated by cell-free gel mobility-shift assays. Together, these results demonstrate a new class of thiophene-containing Ru(II) cyclometalated compounds that contain both highly selective chemotherapeutic agents and extremely potent photocytotoxic agents. Show less

Fluorescent 4-ethylthio-1,8-naphthalimides containing rhodium(I) N-heterocyclic carbene (NHC) and ruthenium (II) NHC fragments were synthesised and evaluated for their antiproliferative effects, cellular uptake and DNA-binding activity. Both types of organometallics triggered ligand dependent efficient cytotoxic effects against tumor cells with the rhodium(I) NHC derivatives causing stronger effects than the ruthenium (II) NHC analogues. Antiproliferative effects could also be observed against several pathogenic Gram-positive bacterial strains, whereas the growth of Gram-negative bacteria was not substantially affected. Cellular uptake was confirmed by atomic absorption spectroscopy as well as by fluorescence microscopy indicating a general ligand dependent accumulation in the cells. An in-depth study on the interaction with DNA confirmed insertion of the naphthalimide moiety between the planar bases of B-DNA via an intercalation mechanism, as well as its stacking on top of the quartets of G-quadruplex structures. Furthermore, additional coordinative binding of the organometallic complexes to the model DNA base 9-ethylguanine could be detected. The studied compounds thus represent promising bioorganometallics featuring strong pharmacological effects in combination with excellent cellular imaging properties. Show less

New cyclometallated ruthenium(ii) complexes of 3-acetyl-7-methoxycoumarin-4N-substituted thiosemicarbazones were synthesized and characterized by analytical and spectral techniques. The crystal structures of the ligands H₂L^1-3 and complexes (1, 2 and 4) were confirmed by X-ray crystallography. The analysis showed that the ligands have undergone C-H activation at the C(4) carbon of the pyrone ring and acted in a tridentate fashion by binding through C, N and S atoms. CT-DNA and protein (BSA/HSA) binding studies were carried out to analyze their interaction with biomolecules. Good binding affinity with DNA was observed with intercalative binding mode, which was further confirmed by EB displacement and viscosity measurement studies. The quenching mechanism with BSA/HSA was found to be static. Three dimensional (3D) fluorescence measurements were carried out to validate the micro environmental changes in the serum albumins. Their antioxidant propensity and antimicrobial study insisted that the compounds displayed good spectrum of activity. Evaluation of their anticancer potential against MCF-7 (human breast cancer) and A549 (human lung carcinoma) cell lines revealed that the complexes exhibited better activity than the ligands and cisplatin. Further, the results of LDH and NO release assays supported the cytotoxic nature of the compounds. The non-toxic nature of the compounds was established by testing against the non-cancerous cell line HaCaT (human normal keratinocyte). Show less