👤 Banerjee M

Four triphenylamine (TPA)-appended cyclometallated iridium(III) complexes were designed and synthesized. Photophysical properties of these complexes were studied, and density functional theory (DFT) was utilized to analyze the influence of the ancillary ligands (TPA-modified bipyridine) to these complexes. The introduction of TPA units could effectively adjust the lipid solubility of complexes (logP), and endowed complexes with potential bioactivity (anticancer, antibacterial and bactericidal activity), especially in the field of anticancer (the best value of IC₅₀ is 4.34±0.01μM). Interestingly, complexe 4 show some selectivity for cancer cells versus normal cells. Meanwhile, complexes could effectively prevent the metastasis of cancer cells. Complexes can be transported by serum albumin and followed by the static quenching mechanism (K_q: 10¹³M^-1s^-1), disturb cell cycle at G₀/G₁ phase, and induce apoptosis. The favorable fluorescence property confirmed these complexes followed by an energy-dependent cellular uptake mechanism, effectively accumulated in lysosomes (PCC: >0.95) and induced lysosomal damage, and eventually leaded to cell death. Our study demonstrates that these complexes are potential anticancer agents with dual functions, including metastasis inhibition and lysosomal damage. Show less

Cisplatin and its analogs have been used for the treatment of various cancers, but their serious side effect has limited clinical application. Presently, scientists are developing other metal drugs as an alternative of cisplatin. In this paper, three new iridium(III) complexes [Ir(ppy)₂(adppz)](PF₆) (adppz = 7-aminodipyrido[3,2-a:2',3'-c]phenazine; ppy = 2-phenylpyridine 1), [Ir(bzq)₂(adppz)](PF₆) (bzq = benzo[h]quinolone 2) and [Ir(piq)₂(adppz)](PF₆) (piq = 1-phenylisoquinoline 3) were synthesized and characterized. The complexes can effectively inhibit the cell colonies. The cytotoxicity in vitro of the complexes against A549, HepG2, SGC-7901, BEL-7402 and normal NIH3T3 cells was evaluated by 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) methods. The intracellular reactive oxygen species (ROS) levels and Ca²⁺ concentrations were assayed. The mitochondrial membrane potential, a release of cytochrome c and the expression of B-cell lymphoma/leukemia-2 (Bcl-2) family protein have been investigated. The data reveal that the complexes 1-3 can effectively inhibit the cell proliferation in A549 cells with low IC₅₀ value of 3.2 ± 0.4 μM, 4.8 ± 0.5 μM and 1.2 ± 0.2 μM, respectively. The antitumor in vivo shows that complex 3 can inhibit tumor growth with an inhibitory rate of 76.34%. The studies on the mechanism indicate that these complexes cause apoptosis in A549 cell via a ROS-mediated lysosomal-mitochondrial dysfunction pathway. In addition, the interaction of the complexes with BSA was explored. Show less

This work mainly introduces the synthesis and characterization of three iridium(III) complexes [Ir(ppy)₂(adppz)](PF₆) (Ir-1), [Ir(bzq)₂(addpz)](PF₆) (Ir-2) and [Ir(piq)₂(adppz)](PF₆) (Ir-3). The complexes are more cytotoxic than cisplatin against tumor cell lines such as SGC-7901, A549, HeLa, Eca-109, HepG2 and BEL-7402. The toxicity test results indicated that complexes Ir-1, Ir-2 and Ir-3 can effectively inhibit the cell growth of SGC-7901 cells, and the measured IC₅₀ values are 1.8 ± 0.4, 1.6 ± 0.3 and 0.8 ± 0.1 μM, respectively. AO/EB staining and flow apoptosis confirmed that SGC-7901 cells were caused apoptosis after being treated with the complexes. Along with the increase of endogenous ROS and Ca²⁺ levels, mitochondrial membrane potential collapse and massive release of cytochrome c, it is fully demonstrated that these complexes induce apoptosis through ROS-mediated mitochondrial pathway. At the same time, the complex Ir-3 is outstanding in the inhibition of tumor growth in vivo. Combined with the above results, it provides a favorable foundation for the future development of more effective anti-tumor drugs. Show less

Two iridium(III) polypyridyl complexes [Ir(ppy)₂(HPIP)](PF₆) (Ir-1), [Ir(ppy)₂(BHPIP)](PF₆) (Ir-2) and their liposomes Ir-1-Lipo and Ir-2-Lipo were synthesized and characterized by elemental analysis, IR, ¹H NMR and ¹³C NMR. The anticancer activity in vitro and in vivo was evaluated. The cytotoxic activity in vitro of the complexes and their liposomes Ir-1-Lipo and Ir-2-Lipo against cancer cells was investigated by MTT methods. Ir-1 and Ir-2 show no cytotoxic activity, while Ir-1-Lipo and Ir-2-Lipo exhibit high cytotoxic effect. The IC₅₀ values range from 5.2 ± 0.8 to 22.3 ± 1.8 μM. The apoptosis, reactive oxygen species, the change of mitochondrial membrane potential, intracellular Ca²⁺ levels and a release of cytochrome c were investigated. The effect of Ir-1-Lipo and Ir-2-Lipo on microtubules was also explored. In the C57BL/6 mice model, Ir-1 only displays a tumor inhibitory rate of 23.21%, while lr-1-Lipo exhibits satisfactory in vivo antitumor efficacy with tumor inhibitory rate of 72.55%. This study demonstrates that complexes encapsulated in liposomes induce apoptosis in B16 through ROS-mediated lysosomal-mitochondria dysfunction, inhibition of polymerization of microtubules and induce cell cycle arrest at S phase. Show less

Three iridium(III) complexes ([Ir(Hppy)₂(L)](PF₆) (Hppy = 2-phenylpyridine, L = 5-nitrophenanthroline, NP), 1; 5-nitro-6-amino-phenanthroline (NAP), 2; and 5,6-diamino-phenanthroline (DAP) 3 were synthesized and characterized. The cytotoxicities of Ir(III) complexes 1-3 against cancer cell lines SGC-7901, A549, HeLa, Eca-109, HepG2, BEL-7402, and normal NIH 3T3 cells were investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) method. The results showed that the three iridium(III) complexes had moderate in vitro anti-tumor activity toward SGC-7901 cells with IC₅₀ values of 3.6 ± 0.1 µM for 1, 14.1 ± 0.5 µM for 2, and 11.1 ± 1.3 µM for 3. Further studies showed that 1-3 induce cell apoptosis/death through DNA damage, cell cycle arrest at the S or G0/G1 phase, ROS elevation, increased levels of Ca²⁺, high mitochondrial membrane depolarization, and cellular ATP depletion. Transwell and Colony-Forming assays revealed that complexes 1-3 can also effectively inhibit the metastasis and proliferation of tumor cells. These results demonstrate that 1-3 induce apoptosis in SGC-7901 cells through ROS-mediated mitochondrial damage and DNA damage pathways, as well as by inhibiting cell invasion, thereby exerting anti-tumor cell proliferation activity in vitro. Show less

We report the synthesis and characterization of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4'-carboxy-2,2'-bipyridine)Cl]PF6 (Ir-I), the product (Ir-II) from amide coupling of Ir-I to dibenzocyclooctyne-amine, and its conjugate (Ir-CP) with the cyclic nona-peptide c(CRWYDENAC). The familiar three-legged 'piano-stool' configuration for complex Ir-I was confirmed by its single crystal X-ray structure. Significantly, copper-free click strategy has been developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. The approach consisted of two steps: (i) the carboxylic acid group of the bipyridine ligand in complex Ir-I was first attached to an amine functionalized dibenzocyclooctyne group via amide formation to generate complex Ir-II; and (ii) the alkyne bond of dibenzocyclooctyne in complex Ir-II underwent a subsequent strain-promoted copper-free cycloaddition with the azide group of the modified peptide. Interestingly, while complex Ir-I was inactive towards A2780 human ovarian cancer cells, complex Ir-II exhibited moderate cytotoxic activity. Targeted complexes such as Ir-CP offer scope for enhanced activity and selectivity of this class of anticancer complexes. Show less

Rhenium(i) di- and tri-carbonyl complexes of the form fac-[Re(CO)₃(L,L'-Bid)X] and [Re(CO)₂(L,L'-Bid)X₂], where X = aqua (H₂O), methanol (CH₃OH), triphenylphosphine (PPh₃), 1,3,5-triaza-7-phosphaadamantane (PTA), tricyclohexylphosphine (PCy₃) and L,L'-Bid = O,O' bidentate ligands (tropolone = TropH and 3-hydroxyflavone = FlavH) and N,O bidentate ligands (8-hydroxyquinoline = QuinH, 5,7-chloro-8-hydroxyquinoline = diCl-QuinH and quinoline-2,4-dicarboxylic acid = QuinH₂), were synthesized and unambiguously characterized by ¹H-, ¹³C-and ³¹P-NMR, IR, UV/Vis and micro-analysis. The crystal structures of four complexes, namely fac-[Re(CO)₃(QuinH)(H₂O)]·H₂O (5), fac-[Re(CO)₃(Quin)(PPh₃)] (11), fac-[Re(CO)₃(diCl-Quin)(PPh₃)] (12) and [Re(CO)₂(Trop)(PPh₃)₂]·2C₆H₅CH₃ (20) were obtained. Re-P bonding distances for 11 and 12 are 2.4948(8) and 2.4908(8) Å, respectively, indicating the effect of the electron-withdrawing substituents of the diCl-Quin^- ligand. The second-order rate constants for the substitutions of methanol at 25.1 °C in fac-[Re(CO)₃(L,L'-Bid)(CH₃OH)] (L,L'-Bid = Trop, Flav and QuinH) type complexes by different entering phosphine ligands (PPh₃, PCy₃, and PTA) varied between 7.23(7) × 10^-5 and 1.32(3) × 10^-3 M^-1 s^-1 and were found to depend on the coordinated bidentate ligand (in general k₁ (QuinH) < k₁ (Trop) < k₁ (Flav)). The toxicity of fac-[Re(CO)₃(QuinH)(PTA)], fac-[Re(CO)₃(Trop)(PTA)], fac-[Re(CO)₃(Trop)(PPh₃)] and fac-[Re(CO)₃(Flav)(PPh₃)] on the cervical cancer HeLa and epithelial RPE-1 cell lines was then evaluated. Complex fac-[Re(CO)₃(Flav)(PPh₃)] (16) and fac-[Re(CO)₃(Trop)(PPh₃)] (13) displayed the highest cytotoxicity with IC₅₀ values of 12.21 ± 0.17 μM and 13.35 ± 0.94 μM, respectively in HeLa cells. Interestingly, a small selectivity towards cancer over non-cancerous cells was observed for these compounds (IC₅₀ = 18.41 ± 3.16 μM and >25 μM in RPE-1 cells). Show less

Thioredoxin reductase (TrxR) is often overexpressed in different types of cancer cells including hepatocellular carcinoma (HCC) cells and regarded as a target with great promise for anticancer drug research and development. Here, we have synthesized and characterized nine new designed rhodium(I) N-heterocyclic carbene (NHC) complexes. All of them were effective towards cancer cells, especially complex 1e was more active than cisplatin and manifested strong antiproliferative activity against HCC cells. In vivo anticancer studies showed that 1e significantly repressed tumor growth in an HCC nude mouse model and ameliorated liver lesions in a chronic HCC model caused by CCl₄. Notably, a mechanistic study revealed that 1e can strongly inhibit TrxR system both in vitro and in vivo. Furthermore, 1e promoted intracellular ROS accumulation, damaged mitochondrial membrane potential, promoted cancer cell apoptosis and blocked the cells in the G1 phase. Show less

Sensitivity and resistance of cells to platinum drug chemotherapy are to a large extent determined by activity of the DNA damage response (DDR). Combining chemotherapy with inhibition of specific DDR pathways could therefore improve treatment efficacy. Multiple DDR pathways have been implicated in removal of platinum-DNA lesions, but it is unclear which exact pathways are most important to cellular platinum drug resistance. Here, we used CRISPR/Cas9 screening to identify DDR proteins that protect colorectal cancer cells against the clinically applied platinum drug oxaliplatin. We find that besides the expected homologous recombination, Fanconi anemia and translesion synthesis pathways, in particular also transcription-coupled nucleotide excision repair (TC-NER) and base excision repair (BER) protect against platinum-induced cytotoxicity. Both repair pathways are required to overcome oxaliplatin- and cisplatin-induced transcription arrest. In addition to the generation of DNA crosslinks, exposure to platinum drugs leads to reactive oxygen species production that induces oxidative DNA lesions, explaining the requirement for BER. Our findings highlight the importance of transcriptional integrity in cells exposed to platinum drugs and suggest that both TC-NER and BER should be considered as targets for novel combinatorial treatment strategies. Show less

A series of half-sandwich Ir^III pentamethylcyclopentadienyl and Ru^II arene complexes containing P^P-chelating ligands of the type [(Cp^x/arene)M(P^P)Cl]PF₆, where M = Ir, Cp^x is pentamethylcyclopentadienyl (Cp*), or 1-biphenyl-2,3,4,5-tetramethyl cyclopentadienyl (Cp^xbiPh); M = Ru, arene is 3-phenylpropan-1-ol (bz-PA), 4-phenylbutan-1-ol (bz-BA), or p-cymene (p-cym), and P^P is 2,20-bis(diphenylphosphino)-1,10-binaphthyl (BINAP), have been synthesized and fully characterized, three of them by X-ray crystallography, and their potential as anticancer agents explored. All five complexes showed potent anticancer activity toward HeLa and A549 cancer cells. The introduction of a biphenyl substituent on the Cp* ring for the iridium complexes has no effect on the antiproliferative potency. Ruthenium complex [(η⁶-p-cym)Ru(P^P)Cl]PF₆ (5) displayed the highest potency, about 15 and 7.5 times more active than the clinically used cisplatin against A549 and HeLa cells, respectively. No binding to 9-MeA and 9-EtG nucleobases was observed. Although these types of complexes interact with ctDNA, DNA appears not to be the major target. Compared to iridium complex [(η⁵-Cp*)Ir(P^P)Cl]PF₆ (1), ruthenium complex (5) showed stronger ability to interfere with coenzyme NAD⁺/NADH couple through transfer hydrogenation reactions and to induce ROS in cells, which is consistent with their anticancer activities. The redox properties of the complexes 1, 5, and ligand BINAP were evaluated by cyclic voltammetry. Complexes 1 and 5 arrest cell cycles at the S phase, Sub-G₁ phase and G₁ phase, respectively, and cause cell apoptosis toward A549 cells. Show less

With the aim of enhancing the biological activity of ruthenium-nitrosyl complexes, new compounds with four equatorially bound indazole ligands, namely, trans-[RuCl(Hind)₄(NO)]Cl₂·H₂O ([3]Cl₂·H₂O) and trans-[RuOH(Hind)₄(NO)]Cl₂·H₂O ([4]Cl₂·H₂O), have been prepared from trans-[Ru(NO₂)₂(Hind)₄] ([2]). When the pH-dependent solution behavior of [3]Cl₂·H₂O and [4]Cl₂·H₂O was studied, two new complexes with two deprotonated indazole ligands were isolated, namely [RuCl(ind)₂(Hind)₂(NO)] ([5]) and [RuOH(ind)₂(Hind)₂(NO)] ([6]). All prepared compounds were comprehensively characterized by spectroscopic (IR, UV-vis, ¹H NMR) techniques. Compound [2], as well as [3]Cl₂·2(CH₃)₂CO, [4]Cl₂·2(CH₃)₂CO, and [5]·0.8CH₂Cl₂, the latter three obtained by recrystallization of the first isolated compounds (hydrates or anhydrous species) from acetone and dichloromethane, respectively, were studied by X-ray diffraction methods. The photoinduced release of NO in [3]Cl₂ and [4]Cl₂ was investigated by cyclic voltammetry and resulting paramagnetic NO species were detected by EPR spectroscopy. The quantum yields of NO release were calculated and found to be low (3-6%), which could be explained by NO dissociation and recombination dynamics, assessed by femtosecond pump-probe spectroscopy. The geometry and electronic parameters of Ru species formed upon NO release were identified by DFT calculations. The complexes [3]Cl₂ and [4]Cl₂ showed considerable antiproliferative activity in human cancer cell lines with IC₅₀ values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru-NO complexes [3]Cl₂ and [4]Cl₂ was studied and p53-independent mode of action was confirmed. The effects of NO release on the cytotoxicity of the complexes with or without light irradiation were investigated using NO scavenger carboxy-PTIO. Show less

α-Diimines are among the most robust and versatile ligands available in synthetic coordination chemistry, possessing finely tunable steric and electronic properties. A series of novel cationic ruthenium(II) p-cymene complexes bearing simple α-diimine ligands, [(η⁶- p-cymene)RuCl{κ² N-(HCNR)₂}]NO₃ (R = Cy, [1]NO₃; R = 4-C₆H₁₀OH, [2]NO₃; R = 4-C₆H₄OH, [3]NO₃), were prepared in near-quantitative yields as their nitrate salts. [2]NO₃ displays high water solubility. The potential of the α-diimine ligand in [3]NO₃ as a carrier of bioactive molecules was investigated via esterification reactions with the hydroxyl groups. Thus, the double-functionalized derivatives [(η⁶- p-cymene)RuCl{κ² N-(HCN(4-C₆H₄OCO-R))₂}]NO₃ (R = aspirinate, [5]NO₃; valproate, [6]NO₃) and also [4]Cl (R = Me) were obtained in good-to-high yields. UV-vis and multinuclear NMR spectroscopy and cyclic voltammetric studies in aqueous solution revealed only minor ruthenium chloride hydrolytic cleavage, biologically accessible reduction potentials, and pH-dependent behavior of [3]NO₃. Density functional theory analysis was performed in order to compare the Ru-Cl bond strength in [1]⁺ with the analogous ethylenediamine complex, showing that the higher stability observed in the former is related to the electron-withdrawing properties of the α-diimine ligand. In vitro cytotoxicity studies were performed against tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK-293) cell lines, with the complexes bearing simple α-diimine ligands ranging from inactive to IC₅₀ values in the low micromolar range. The complexes functionalized with bioactive components, i.e., [5]NO₃ and [6]NO₃, exhibited a marked increase in the cytotoxicity with respect to the precursor [3]NO₃. Show less

Three pyrazolone-based hydrazone ligands HL' (HL' in general; in detail, HL1 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl)(phenyl)methylene)-1-(2,4-nitrophenyl)hydrazine, HL2 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl) (phenyl)methylene)-1-(4-nitrophenyl)hydrazine, and HL3 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl)(phenyl)methylene)-1-(pyridin-2-yl)hydrazine) have been prepared starting from 4-benzoyl-3-methyl-1-phenyl-1 H-pyrazol-5(4 H)-one and fully characterized in the solid state and solution, where the existing tautomeric forms were identified by taking advantage of natural abundance ¹H-¹⁵N coupling in {¹H-¹⁵N}-HSQC and {¹H-¹⁵N}-HMBC NMR spectroscopy. Then, six half-sandwich arene-ruthenium(II) derivatives (arene = hexamethylbenzene and p-cymene) of composition [(arene)Ru(L')Cl] have been synthesized and fully characterized by IR, ¹H, and ¹³C NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis, and density functional theory calculations. The crystal structures of three complexes, together with the E configurational isomer (with respect to the C═N double bond) of the free proligand HL2 and the zwitterionic proligand HL3 were determined by X-ray analysis. The anionic ligands L1 and L2 were found bonded to ruthenium in the N,O-form, while L3 coordinates the metal in the N,N-form affording five-membered chelating rings. The cytotoxicity of the complexes was evaluated against human breast adenocarcinoma cells (MCF-7 and MCF-7CR), as well as against nontumorigenic human breast (MCF-10A) cells and compared to the free ligand and cisplatin. Show less

Aims

Ruthenium (II) complexes are promising anticancer molecules due its pharmacological properties and selectivity to cells tumor. The aim of this work was to study the cytotoxic activity, and apoptosis induction of two new ruthenium complexes on a human gastric cancer cell line.

Main methods

Two ruthenium(II) complexes were synthesized: [(H₂pbbzim)Ru(tpy-Ph-COOCH₃)](Cl)₂ (Ru-UCN1), and [(tpy)Ru(tpy-Ph-bzH)](Cl)₂ (Ru-UCN3), and their anticancer capacity determined by cytotoxic assays, gene expression analysis, caspase activation and confocal microscopy.

Key findings

Ru-UCN3 is more notably cytotoxic than cisplatin in human gastric cancer cells AGS at 24 h, while Ru-UCN1 is more active against gastric cancer cells than cisplatin at 48 h. The complexes induce apoptosis as shown by RT-qPCR, protease activity, and confocal microscopy. Ru-UCN1 induces the overexpression of pro-apoptotic genes at 3 and 6 h, whereas Ru-UCN3 induces overexpression of these genes at 12 and 24 h. Ru-UCN1 treatment shows a strong activation of caspases 3/7 at 24 h, which was not observed for Ru-UCN3 treatment in the same timeframe.

Significance

Taken together, this data suggests that Ru-UCN1 and to a lesser extent, Ru-UCN3, may be interesting anticancer agents for gastric cancer. Show less

We present here the first comprehensive study on the lipophilicity of ruthenium anticancer agents encompassing compounds with broad structural diversity, ranging from octahedral Ru^III (azole) through to Ru^II (arene) complexes. MEEKC was used to determine the capacity factors of the Ru complexes, and after a complex peak was unambiguously assigned using MEEKC-ICP-MS, the results were validated through comparison with the log P determined by octanol/water partitioning experiments. Correlation of the two data sets demonstrated a close relationship despite the limited structural overlap of the compounds studied. The capacity factors found by MEEKC allowed for the clustering of complexes based on their structure and this could be used to rationalize the observed cytotoxicity in the human colon carcinoma HCT116 cell line. It was demonstrated that rather than modification of the mono- or bidentate coordinated ligands much tighter control over a complexes lipophilic properties could be achieved through modification of the Ru(arene) ligand, with minimal detriment to cytotoxicity. This demonstrates the flexibility and potential of the Ru piano-stool scaffold. MEEKC proved to be a highly efficient means of screening the anticancer potential of preclinical ruthenium complex candidates for their lipophilic properties and correlate them with their biological activity and structural properties. 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

The designing of metal-based anticancer therapeutic agents can be optimized in a better and rapid way if the ligands utilized have standalone properties. Therefore, even when the organometallic/coordination complex (i.e., metallodrug) gets dissociated in extreme conditions, the ligand can endorse its biological properties. Herein, we have synthesized and characterized ɳ⁶-p-cymene ruthenium diclofenac complex. Furthermore, the ruthenium complex interactions with human serum albumin (HSA) and ct-DNA have been studied using various spectroscopic studies viz., UV, fluorescence, and circular dichroism and exhibited a significant binding propensity. Furthermore, in vitro cytotoxicity assays were carried out against human breast cancer "MCF-7" cell line. The ɳ⁶-p-cymene ruthenium diclofenac complex registered significant cytotoxicity with an IC₅₀ value of ∼25.0 µM which is comparable to the standard drugs. The ɳ⁶-p-cymene ruthenium diclofenac complex was able to decrease the MCF-7 cell proliferation and induced significant levels of apoptosis with relatively low toxicity. Show less

Ru^II(η⁶-arene) compounds carrying bioactive flavonol ligands have shown promising anticancer activity against tumor cells via a multitargeting mode of action, i.e., through interaction with DNA and inhibition of topoisomerase IIα. By introducing a novel arene ligand based on the amino acid l-phenylalanine (Phe), we aimed to alter the pharmacological properties of the complexes. We report here a series of novel Ru^II(η⁶-arene)Cl complexes with different substituents on the phenyl ring of the flavonol which should maintain the multitargeting capability of the parent η⁶- p-cymene (cym) complexes. Studies with selected examples revealed stability in aqueous solution after quickly forming aqua complexes but rapid decomposition in pure DMSO. The reactions with protein and DNA models proceeded quickly and resulted in cleavage of the flavonol or adduct formation, respectively. The compounds were found to be cytotoxic with significant antiproliferative activity in cancer cells with IC₅₀ values in the low μM range, while not following the same trends as observed for the cym analogues. Notably, the cellular accumulation of the new derivatives was significantly higher than for their respective cym complexes, and they induced DNA damage in a manner similar to that of cisplatin but to a lesser extent. Show less

Anticancer-active Ru^II -η⁶ -p-cymene complexes of bioactive 2-pyridinecarbothioamide ligands have been shown to have high selectivity for plectin and can be administered orally. Reported herein is the functionalization of a 2-pyridinecarbothioamide with a sulfonamide group and its conversion into M-η⁶ -p-cymene complexes (M = Ru, Os). The presence of a sulfonamide moiety in many organic drugs and metal complexes endows these agents with interesting biological properties and can transform the latter into multi-targeted agents. The compounds were characterized with standard methods and the in vitro anticancer activity data was compared with studies on the hydrolytic stability of the complexes and their reactivity to small biomolecules. A molecular modeling study revealed plausible modes of binding of the complexes in the catalytic pocket of carbonic anhydrase II. 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

A new family of neutral ruthenium(II) arene complexes of the type [Ru(η⁶-arene)X(κ²- O, N-L)] (η⁶-arene = p-cym, bz; X = Cl^-, SCN^-; HL1 = 2-(2'-hydroxyphenyl)benzimidazole, HL2 = 2-(2'-hydroxyphenyl)benzothiazole) has been synthesized and characterized. The cytotoxic activity of the Ru(II) complexes was evaluated in several tumor cell lines (A549, HepG2 and SW480) both in the dark and after soft irradiation with UV and blue light. None of the complexes bearing benzimidazole (HL1) as a ligand displayed phototoxicity, whereas the complexes with a benzothiazole ligand (HL2) exhibited photoactivation; the sensitivity observed for UV was higher than for blue light irradiation. The interesting results displayed by HL2 and [Ru(η⁶- p-cym)(NCS)(κ²- O, N-L2)], [3a], in terms of photo cytotoxicity prompted us to analyze their interaction with DNA, both in the dark and under irradiation conditions, in an effort to shed some light on their mechanism of action. The results of this study revealed that HL2 interacts with DNA by groove binding, whereas [3a] interacts by a dual mode of binding, an external groove binding, and covalent binding of the metal center to the guanine moiety. Interestingly, both HL2 and [3a] display a clear preference for AT base pairs, and this causes fluorescence enhancement. Additionally, cleavage of the pUC18 plasmid DNA by the complex is observed upon irradiation. The study of the irradiated form demonstrates that the arene ligand is released to yield species such as [Ru(κ²- O, N-L2)(κ¹- S-DMSO)₂(μ-SCN)]₂ [3c] and [Ru(κ²- O, N-L2)(κ¹- S-DMSO)₃(SCN)] [3d]. Such photo dissociation occurs even in the absence of oxygen and leads to cytotoxicity enhancement, an effect attributed to the presence of [3d], thus revealing the potential of [3a] as a pro-drug for photoactivated anticancer chemotherapy (PACT). Show less

Three new bis(2,2'-bipyridine)-heteroleptic Ru(II) dyads incorporating thienyl groups (n = 1-3, compounds 1, 2 and 3, respectively) appended to 1,10-phenanthroline were synthesized and characterized to investigate the impact of n on the photophysical and photobiological properties within the series. All three complexes showed unstructured emission near 618 nm from a triplet metal-to-ligand charge transfer (³ MLCT) state with a lifetime (τ_em ) of approximately 1 μs. Transient absorption measurements revealed an additional excited state that was nonemissive and long-lived (τ_TA  = 43 μs for 2 and 27 μs for 3), assigned as a triplet intraligand (³ IL) state that was accessible only in 2 and 3. All three complexes were strong singlet oxygen (¹ O₂ ) sensitizers, with quantum yields (Φ_∆ ) for 2 and 3 being the largest (74-78%), and all three were photocytotoxic to cancer cells with visible light activation in the order: 3 > 2 > 1. Cell-free DNA photodamage followed the same trend, where potency increased with decreasing ³ IL energy. Compounds 2 and 3 also showed in vitro photobiological effects with red light (625 nm), where their molar absorptivities were <100 m^-1  cm^-1 . These findings highlight that Ru(II) dyads derived from α-oligothiophenes directly appended to 1,10-phenanthroline-namely 2 and 3-possess low-lying ³ IL states that are highly photosensitizing, and they may therefore be of interest for photobiological applications such as photodynamic therapy (PDT). Show less

Herein, novel ruthenium(II) complexes containing 1-methylimidazole as a ligand were obtained with the following formulas: [RuCl(1Meim)(dppb)(bpy)]Cl (1), [RuCl(1Meim)(dppb)(4,4'-DMbpy)]Cl (2), [RuCl(1Meim)(dppb)(5,5'-DMbpy)]Cl (3) and [RuCl(1Meim)(dppb)(phen)]Cl (4) where, 1Meim = 1-methylimidazole, dppb = 1,4-Bis(diphenylphosphino)butane, bpy = 2,2'-bipyridine, 4,4'-DMbpy = 4,4'-dimethyl-2,2'-bipyridine, 5,5'-DMbpy = 5,5'-dimethyl-2,2'-bipyridine and phen = 1,10-phenanthroline. Additionally, crystal structures containing the cations of (1) and (3) were obtained when the counter ion was exchanged, leading to the formation of [RuCl(1Meim)(dppb)(bpy)]PF₆ (5) and [RuCl(1Meim)(dppb)(5,5'-DMbpy)]PF₆ methanol solvate (6) where PF₆ = hexafluorophosphate, showing one 1-methylimidazole molecule coordinated through the imidazole nitrogen, as expected. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-Vis spectroscopy, ¹H, ¹³C{¹H} and ³¹P{¹H} NMR, mass spectrometry and cyclic voltammetry. The interactions of complexes 1-4 with DNA and human serum albumin (HSA) were evaluated, and the cytotoxicity profiles of compounds 1-4 were determined using four different tumor cell lines derived from human cancers (melanoma: HT-144, colon: HCT-8, breast: MDA-MB-231 and lung: A549). A higher cytotoxic activity was observed for compound (3) against non-small cell lung cancer (A549). Complex (3) inhibited the clonogenic capacity and cell cycle progression of A549 cells and induced apoptosis involving mitochondrial pathway activation. Therefore, the data obtained in the present study support further investigations concerning molecular targets of complex (3) in non-small cell lung cancer. 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

We report the synthesis and characterization of four neutral organometallic tethered complexes, [Ru(η⁶-Ph(CH₂)₃-ethylenediamine-N-R)Cl], where R = methanesulfonyl (Ms, 1), toluenesulfonyl (Ts, 2), 4-trifluoromethylbenzenesulfonyl (Tf, 3), and 4-nitrobenzenesulfonyl (Nb, 4), including their X-ray crystal structures. These complexes exhibit moderate antiproliferative activity toward human ovarian, lung, hepatocellular, and breast cancer cell lines. Complex 2 in particular exhibits a low cross-resistance with cisplatin. The complexes show potent catalytic activity in the transfer hydrogenation of NAD⁺ to NADH with formate as hydride donor in aqueous solution (310 K, pH 7). Substituents on the chelated ligand decreased the turnover frequency in the order Nb > Tf > Ts > Ms. An enhancement of antiproliferative activity (up to 22%) was observed on coadministration with nontoxic concentrations of sodium formate (0.5-2 mM). Complex 2 binds to nucleobase guanine (9-EtG), but DNA appears not to be the target, as little binding to calf thymus DNA or bacterial plasmid DNA was observed. In addition, complex 2 reacts rapidly with glutathione (GSH), which might hamper transfer hydrogenation reactions in cells. Complex 2 induced a dose-dependent G₁ cell cycle arrest after 24 h exposure in A2780 human ovarian cancer cells while promoting an increase in reactive oxygen species (ROS), which is likely to contribute to its antiproliferative activity. Show less

Here and for the first time, we show that the organometallic compound [Ru(η⁵-C₅H₅)(PPh₃)₂Cl] (RuCp) has potential to be used as a metallodrug in anticancer therapy, and further present a new approach for the cellular delivery of the [Ru(η⁵-C₅H₅)(PPh₃)₂]⁺ fragment via coordination on the periphery of low-generation poly(alkylidenimine) dendrimers through nitrile terminal groups. Importantly, both the RuCp and the dendrimers functionalized with [Ru(η⁵-C₅H₅)(PPh₃)₂]⁺ fragments present remarkable toxicity towards a wide set of cancer cells (Caco-2, MCF-7, CAL-72, and A2780 cells), including cisplatin-resistant human ovarian carcinoma cell lines (A2780cisR cells). Also, RuCp and the prepared metallodendrimers are active against human mesenchymal stem cells (hMSCs), which are often found in the tumor microenvironment where they seem to play a role in tumor progression and drug resistance. Show less

Ruthenium(II) complexes are currently considered a viable alternative to the widely used platinum complexes as efficient anticancer agents. We herein present the synthesis and characterization of half-sandwich ruthenium compounds with the general formula [Ru( p-cymene)(L-N,N)Cl][CF₃SO₃] (L = 3,6-di-2-pyridyl-1,2,4,5-tetrazine (1) 6,7-dimethyl-2,3-bis(pyridin-2-yl)quinoxaline (2)), which have been synthesized by substitution reactions from the precursor dimer [Ru( p-cymene)(Cl)(μ-Cl)]₂ and were characterized by elemental analysis, mass spectrometry, ¹H NMR, UV-vis, and IR spectroscopy, conductivity measurements, and cyclic voltammetry. The molecular structure for complex 2 was determined by single-crystal X-ray diffraction. The cytotoxic activity of these compounds was evaluated against human tumor cells, namely ovarian carcinoma A2780 and breast MCF7 and MDAMB231 adenocarcinoma cells, and against normal primary fibroblasts. Whereas the cytotoxic activity of 1 is moderate, IC₅₀ values found for 2 are among the lowest previously reported for Ru( p-cymene) complexes. Both compounds present no cytotoxic effect in normal human primary fibroblasts when they are used at the IC₅₀ concentration in A2780 and MCF7 cancer cells. Their antiproliferative capacity is associated with a combined mechanism of apoptosis and autophagy. A strong interaction with DNA was observed for both with a binding constant value of the same magnitude as that of the classical intercalator [Ru(phen)₂(dppz)]²⁺. Both complexes bind to human serum albumin with moderate to strong affinity, with conditional binding constants (log K_b) of 4.88 for complex 2 and 5.18 for complex 1 in 2% DMSO/10 mM Hepes pH7.0 medium. The acute toxicity was evaluated in zebrafish embryo model using the fish embryo acute toxicity test (FET). Remarkably, our results show that compounds 1 and 2 are not toxic/lethal even at extremely high concentrations. The novel compounds reported herein are highly relevant antitumor metallodrug candidates, given their in vitro cytotoxicity toward cancer cells and the lack of in vivo toxicity. Show less

The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the Ru^II(arene) pharmacophore and even less with an Os^II(arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M-C_NHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal-NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η⁶-p-cymene)ruthenium(II) 1b^I was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future. Show less

Series of half-sandwich Ir^IIIN-heterocyclic carbene (NHC) antitumor complexes [(η⁵-Cp*)Ir(C^C)Cl] have been synthesized and characterized (Cp* is pentamethyl cyclopentadienyl, and C^C are four NHC chelating ligands containing phenyl rings at different positions). Ir^III complexes showed potent antitumor activity with IC₅₀ values ranged from 3.9 to 11.8 μM against A549 cells by the MTT assay. Complexes can catalyze the conversion of the coenzyme NADH to NAD⁺ and induce the production of reactive oxygen species (ROS), and bonding to BSA by static quenching mode. Complexes can arrest the cell cycle in G₁ or S phase and reduce the mitochondrial membrane potential. Confocal microscopy test show complexes could target the lysosome and mitochondria in cells with the Pearson's colocalization coefficient of 0.82 and 0.21 after 12 h, respectively, and followed by an energy-dependent cellular uptake mechanism. Show less

Three new iridium (III) complexes [Ir (ppy)₂ (ipbc)](PF₆) (1), [Ir (bzq)₂ (ipbc)](PF₆) (2) and [Ir (piq)₂ (ipbc)](PF₆) (3) were designed and synthesized. All the complexes were tested for anticancer activity using 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) method. The complexes show no cytotoxic activity toward cancer BEL-7402, SGC-7901, Eca-109, A549, HeLa and HepG2 cells. However, upon irradiation with white light, the complexes display high cytotoxicity against BEL-7402 cells with an IC₅₀ value of 5.5 ± 0.8, 7.3 ± 1.3 and 11.5 ± 1.6 μM for 1, 2 and 3, respectively. AO/EB staining and comet assay show that the complexes can induce apoptosis in BEL-7402 cells. The complexes can increase intracellular ROS and Ca²⁺ levels and cause a decrease in the mitochondrial membrane potential. Autophagic assays exhibit that the complexes can induce autophagy and regulate the expression of Beclin-1 and LC3 proteins. The cell cycle distribution in BEL-7402 cells was carried out by flow cytometry. The expression of Bcl-2 family proteins was studied by western blot. Additionally, the complexes can release cytochrome c and inhibit the polymerization of α-tubulin. Our study reveals that the complexes inhibit the cell growth in BEL-7402 cells through an ROS-mediated mitochondria dysfunction and targeting tubules pathways. These complexes are a promising new entity for the development of multi-target anticancer drugs. Show less