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GaOOH powders of submicron dimensions were synthesized through a simple, surfactant-free hydrothermal synthesis at pH values of 7 and 14. Sn and Cr at concentrations of 2 mol% and 1 mol%, respectively, were successfully incorporated into a GaOOH lattice at pH = 7. The synthesized powders were characterized through XRD, SEM, UV-Vis spectroscopy, XPS, and PL spectroscopy to untangle their structural, morphological, optical, elemental, and compositional- and defect-level analyses, respectively. All samples were individually tested for their in vitro anti-proliferation activities against three human cancer cell line profiles, namely, lung carcinoma (A549), colon adenocarcinoma (LoVo), and hepatocellular carcinoma (HuH-7). The samples showed obtrusive anti-proliferation activity against the three cancer line profiles. An apoptotic cell killing mechanism was found in the studied samples after a successful analysis of various staining assays and flowcytometric analyses in the A549 cancer cell profile. Cr loading at 1 mol% enhanced the cancer cell inhibition property of GaOOH against all cancer cells investigated. Also, the morphology and doping levels were observed to have a collective effect on the anti-proliferation activity of GaOOH with specificity in treating certain cancer cells.

Six different acylthiourea ligands (L1–L6) and their corresponding Ru(II)-p-cymene complexes (P1–P6) were designed to explore the structure–activity relationship of the complexes upon aliphatic chain and aromatic conjugation on the C- and N-terminals, respectively. The compounds were synthesized and adequately characterized using various analytical and spectroscopic techniques. The structures of P2–P6, solved using single crystal X-ray diffraction (XRD), confirmed the neutral monodentate coordination of the S atoms of the acylthiourea ligands to Ru(II) ions. In silico studies showed an increase of lipophilicity for the ligands with an increase in alkyl chain length or aromatic conjugation at the C- or N-terminal, respectively. Subsequently, mitogen-activated protein kinases (MAPK) were predicted as one of the primary targets for the complexes, which showed good binding affinity towards extracellular signal-regulated kinases (ERK1, ERK2 and ERK5), c-Jun N-terminal kinase (JNK) and p38 of the MAPK pathway. Henceforth, the complexes were tested for their anticancer activity in lung carcinoma (A549) and cisplatin-resistant lung carcinoma (cisA549R) cells and human umbilical vein epithelial normal cells (HUVEC). Interestingly, an increase in chain length or aromatic conjugation led to an increase in the activity of the complexes, with P5 (7.73 and 13.04 μM) and P6 (6.52 and 14.45 μM) showing the highest activity in A549 and cisA549R cells, which is better than the positive control, cisplatin (8.72 and 44.28 μM). Remarkably, we report the highest activity yet observed for complexes of the type [(η6-p-cymene)RuIICl2(S-acylthiourea)] in the tested cell lines. Aqueous solution studies showed that complexes P5 and P6 are rapidly hydrolyzed to produce solely aquated species that remained stable for 24 h. Staining assays and flow cytometric analyses of P5 and P6 in A549 cells revealed that the complexes induced apoptosis and arrested the cell cycle predominantly in the S phase. In vivo studies demonstrated the higher toxicity of cisplatin and a comparatively higher survival rate of mice injected with the most active complex P6. Histological analyses revealed that treatment with P6 at high doses of up to 8 mg kg−1 did not cause any palpable damage to the tested organs.

International audience; A panel of six new structurally related organo-metallic arene Ru(II) complexes of general composition [(η 6-benzene)Ru(L)Cl] (1−3) and [(η 6-p-cymene)Ru(L)Cl] (4−6) (L = dimethylaminobenzhydrazones) have been designed and synthesized in search of new ruthenium anticancer drugs. The identities of the synthesized complexes have been well-established by elemental analysis and various spectral (FT-IR, UV−vis, NMR, and HR-MS) methods. The solid-state molecular structures of the ruthenium complexes were determined with the help of X-ray crystallography and confirms the presence of a pseudo-octahedral geometry around ruthenium. Furthermore, cytotoxicity of the complexes has been unveiled with the aid of MTT assay against A549 (lung carcinoma), LoVo (colon adenocarcinoma), HuH-7 (hepato cellular carcinoma) along with the noncancerous 16HBE (human lung bronchial epithelium) cells and compared with the effect of the standard drug cisplatin. Interestingly, complexes 4, 5, and 6 which contain a p-cymene moiety induce a remarkable decrease of cell viability against all the cancer cells tested. The capacity corresponding to the inhibition of A549 cells proliferation was analyzed by 5-ethynyl-2-deoxyuridine (EdU) incorporation assay and indicated a notable effect of p-cymene counterparts 4, 5, and 6 over cisplatin. Further studies such as AO-EB (acridine orange− ethidium bromide) staining, flow cytometry, and Western blot analyses on cell death mechanism signified that the cytotoxicity was associated with apoptosis in cancer cells. This clearly suggests that p-cymene-capped Ru(II) complexes are also one of the propitious cancer therapeutic candidates and are worthy of further investigations.

Ruthenium complexes with bioactive ligands are becoming promising substitutes for platinum complexes due to their precise action against various cancers. In the present study, the synthesis of three new arene Ru(ii) complexes containing new carbazole-based hydrazone ligands of general formula [(η6-benzene)Ru(L)Cl] (1-3; L = carbazolone benzhydrazone ligands), and their anticancer properties are described. The structural characterization of the ligands and their ruthenium complexes has been realized with the aid of elemental analysis, IR, UV-vis, NMR and HR-MS techniques. The molecular structures of all three complexes have been elucidated by single crystal X-ray crystallography and reveal the existence of pseudo-octahedral geometry around the ruthenium. The in vitro cancer cell growth inhibition property of the complexes against A549 (lung carcinoma), A2780 (ovarian adenocarcinoma) and non-cancerous 16HBE (human lung bronchial epithelium) cells were examined by MTT assay. All the complexes display good cytotoxicity towards both of these types of cancer cell compared to the standard drug cisplatin, with low IC50 values. Remarkably, complex 3, which contains an electron-donating substituent, induces a significant reduction of viability in A2780 cells. The inhibition capacity of the complexes towards A2780 cells proliferation was further confirmed using 5-ethynyl-2-deoxyuridine (EdU) assay via minimal DNA synthesis. The result of the acridine orange-ethidium bromide (AO-EB) fluorescent staining assay establishes that the cytotoxicity of the complexes was mediated by apoptosis in cancer cells. Furthermore, flow cytometry using Annexin V-FITC/propidium iodide (PI) double staining determines the quantitative discrimination of early apoptosis by the externalization of phosphatidylserine. In addition, cell cycle distribution indicates that the complexes block the cell cycle progression in the S-phase. The outcome of our investigation shows the promising scope and potency of tailored arene ruthenium complexes for precise cancer chemotherapy beyond platinum drugs.

Six different acylthiourea ligands (L1-L6) and their corresponding Ru(II)

Ruthenium complexes have attracted a surge of interest as anticancer drug candidates because of their low toxicity, diversity in mode-of-actions and non-cross drug resistance with conventional platinum-based agents. Despite remarkable advances, only a limited number of ruthenium complexes have been demonstrated to kill cancer cells and suppress metastasis simultaneously. Here, two organometallic tetranuclear Ru(II) arene complexes (Ru-1 and Ru-2) have been synthesized and evaluated for their in vitro activity against a panel of human cancer cell lines, including a cisplatin-resistant human lung cancer A549 cell line. A superior cytotoxic activity of the ruthenium complexes compared to cisplatin across distinct cell lines was observed. Further examination of the mechanism indicated that anticancer activity was accomplished by inducing apoptosis in cancer cells. In addition, we found that such compounds exhibited promising antimetastatic activity and reduced the invasiveness of cancer cells. Importantly, choosing Ru-1 as a target compound, a significantly enhanced safety profile relative to cisplatin in animals was validated, suggesting that these complexes can be used as promising candidates for cancer therapy and deserve further investigation.

In this study, we newly designed and synthesized a small library of ten structurally related C,N-cyclometalated ruthenium(II) complexes containing various pyridine-functionalized NHC ligand and chelating bipyridyl ligands (e.g., 2,2'-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, and 1,10-phenanthroline (phen)). The complexes were well characterized by NMR, electrospray ionization-mass spectrometry, and single-crystal X-ray structure analyses. Among the new ruthenium(II) derivatives, we identified that the complex Ru8 bearing bulky moieties (i.e., phen and pentamethyl benzene) had the most potent cytotoxicity against all tested cancer cell lines, generating dose- and cell line-dependent IC50 values at the range of 3.3-15.0 μm. More significantly, Ru8 not only efficiently inhibited the metastasis process against invasion and migration of tumor cells but also exhibited potent antivascular effects by suppressing HUVEC cells migration and tube formation in vitro and blocking vessel generation in vivo (chicken chorioallantoic membrane model). In a metastatic A2780 tumor xenograft-bearing mouse model, administration of Ru8 outperformed antimetastatic agent NAMI-A and clinically approved cisplatin in terms of antitumor efficacy and inhibition of metastases to other organs. Overall, these data provided compelling evidence that the new cyclometalated ruthenium complex Ru8 is an attractive agent because of synergistically suppressing bulky tumors and metastasized tumor nudes. Therefore, the complex Ru8 deserves further investigations.

New half sandwich arene ruthenium(II) complexes of the type [Ru(arene)Cl(L)] (where arene = benzene and p-cymene, L = thiophene benzhydrazone ligands) have been synthesized from the reactions of the neutral precursor [Ru(arene) (μ-Cl) Cl]2 and the corresponding benzhydrazone ligand. All the complexes were completely characterized by elemental analysis and additionally by IR, UV–Vis, 1H NMR and ESI-MS spectroscopic methods. The solid state structures of the complexes 6 and 7 were determined by single-crystal X-ray diffraction analysis, which exhibit typical pseudo-octahedral geometry around the metal centre. The antiproliferative activity of the complexes was evaluated on cancerous (HeLa, MDA-MB-231, and Hep G2) and noncancerous (NIH3T3) cell lines. In general, complexes containing electron releasing OCH3 substituent have potential anticancer activity than those incorporating H, Cl and Br substituents. Moreover, the p-cymene complexes show more cytotoxicity than benzene derivatives, suggesting that the substituent at arene plays a vital role in the biological activity of the compounds. Further, an apoptotic mechanism of cell death in MDA-MB-231 was confirmed by AO-EB, Hoechst 33258 staining and annexin-V/PI double-staining techniques. In addition, the extent of DNA fragmentation in cancer cells was studied by comet assay.

A suitable method for the synthesis of ruthenium(II) arene benzhydrazone complexes (1–6) of the general formula [(η6-arene)Ru(L)Cl] (arene-benzene or p-cymene; L-monobasic bidentate substituted 9-anthraldehyde benzhydrazone derivatives) has been described. The composition of the complexes has been established by elemental analysis, IR, UV-Vis, emission, NMR and ESI-MS spectral methods. The solid state molecular structure of a representative complex was determined by a single-crystal X-ray diffraction study and indicates the presence of pseudo-octahedral (piano stool) geometry. All the complexes have been thoroughly screened for their cytotoxicity against human cervical cancer cells (HeLa), human breast cancer cell line (MDA-MB-231) and human liver carcinoma cells (Hep G2) under in vitro conditions. Interestingly, the cytotoxic activity of complex 6 is much more potent than cisplatin with low IC50 values against all the cancer cell lines tested. Furthermore, the results of AO–EB, Hoechst 33258 and flow cytometry analyses reveal that these complexes induce cell death only through apoptosis. The comet assay has been employed to determine the extent of DNA fragmentation in cancer cells. A hemolysis assay with human erythrocytes demonstrated good blood biocompatibility of all the ruthenium(II) arene benzhydrazone complexes. These results highlight the strong possibility to develop highly active ruthenium complexes as anticancer agents.

A convenient method for the synthesis of ruthenium(II) arene benzhydrazone complexes (1–6) of the general formula [(η6-arene)Ru(L)Cl] (arene-benzene or p-cymene; L-monobasic bidentate substituted indole-3-carboxaldehye benzhydrazone derivatives) has been described. The complexes have been fully characterized via elemental analysis, IR, UV-vis, NMR and ESI-MS spectral methods. The solid-state molecular structures of the representative complexes were determined using a single-crystal X-ray diffraction study and the results indicated the presence of a pseudo octahedral (piano stool) geometry. All the complexes were thoroughly screened for their cytotoxicity against human cervical cancer cells (HeLa), human breast cancer cell line (MDA-MB-231) and human liver carcinoma cells (Hep G2) under in vitro conditions. Interestingly, the cytotoxic activity of complexes 3, 4 and 6 is much more potent than cis-platin with low IC50 values against all the cancer cell lines tested. Furthermore, the mode of cell death in the MDA-MB-231 cells was assessed via AO–EB staining, Hoechst 33258 staining, flow cytometry and comet assay. Furthermore, the results of Western blot analyses suggest that complexes 3 and 6 accumulate preferentially in the mitochondria of MDA-MB-231 cells and induce apoptosis via mitochondrial pathways by up-regulating p53 and Bax, and down-regulating Bcl-2.

The copper(II) complexes, [Cu(tscpy)(MeOH)](Cl) (1), [CuCl(mtscpy)] (2) and [CuCl(ptscpy)] (3) (where, Htscpy = pyridoxal thiosemicarbazone, Hmtscpy = pyridoxal N4-methyl thiosemicarbazone and Hptscpy = pyridoxal N4-phenylthiosemicarbazone) have been isolated and characterized by the aid of various analytical and spectral methods. The molecular structure of the cationic complex 1 and the neutral complex 3 were characterized by single crystal X-ray diffraction studies which revealed that the thiosemicarbazone ligands coordinated to the copper(II) centre as monoanionic tridentate (ONS−) forming five and six membered rings. The interaction of the new complexes with DNA has been explored using spectral and viscosity studies, indicating the complexes bind to DNA via partial intercalation. A predominantly hydrolytic cleavage of supercoiled pUC19 plasmid DNA was confirmed through an experiment performed in the presence of T4 ligase. Furthermore, the interactions of the complexes with serum albumin (BSA) were also investigated using fluorescence spectroscopic methods. The efficiency of the complexes in arresting the growth of human cervical cancer cells (HeLa), human breast cancer cell line (MCF-7) and human liver carcinoma cells (Hep G2) has also been studied along with the cell viability assay against the noncancerous NIH 3T3 mouse embryonic fibroblast cell lines under in vitro conditions. The cationic complex 1 has higher cytotoxic activity than the other two neutral complexes and cisplatin. AO–EB/DAPI staining assays, Annexin V-FITC and FACS analyses indicated that the complex 1 induces cell death only by apoptosis.

Four low spin d8 nickel(II) square planar complexes with general formula [Ni(L)2] (where L = monobasic N, S bidentate thiocarboxamides) have been synthesized from the reaction of Ni(OAc)2·4H2O with 2 equivalent of thiocarboxamide ligands in ethanol. The complexes have been fully characterized by analytical, spectral (FT-IR, UV-Vis, 1H and 13C NMR) and single crystal X-ray methods. Molecular structure of one of the complexes indicates a mono anionic bidendate coordination of thiocarboxamide ligands to the nickel via pyridine nitrogen and thiolate sulphur and reveal a square planar geometry. The binding interaction of nickel(II) thiocarboxamide complexes with calf-thymus DNA (CT-DNA) was studied by electronic and emission spectroscopic methods revealed that complexes 1–4 could interact with CT-DNA via intercalation mode. DNA cleavage experiment shows that all the complexes cleave pUC19 supercoiled DNA in the presence of an activator like H2O2. The CD spectral study shows that binding of the complexes to DNA does not lead to any significant changes in the conformation of CT-DNA. Further, the protein binding ability of the nickel(II) thiocarboxamide complexes with the BSA was investigated by UV-Vis, fluorescence and synchronous fluorescence methods and a static quenching mechanism was observed for their interaction with BSA. The free radical scavenging ability of all the complexes was evaluated by in vitro antioxidant assays involving DPPH radical, hydroxyl radical and nitric oxide radical and was found to be excellent. Moreover, the efficiency of complexes 1–4 to arrest the growth of HeLa and MG-63 cell lines has been studied along with the cell viability test against the non-cancerous cells NIH-3T3 under in vitro condition. Complex 3 was found to be the highest anticancer activity among the nickel complexes.

A new series of binuclear ruthenium(III) thiosemicarbazone complexes of general formula [(EPh3)2(X)2Ru-L-Ru(X)2(EPh3)2] (where E = P or As; X = Cl or Br; L = NS chelating bis(thiosemicarbazone ligands) has been synthesized and characterized by analytical and spectral (FT-IR, UV–Vis and EPR). IR spectra show that the thiosemicarbazones behave as monoanionic bidentate ligands coordinating through the azomethine nitrogen and thiolate sulphur. The electronic spectra of the complexes indicate that the presence of d–d and intense LMCT transitions in the visible region. The complexes are paramagnetic (low spin d5) in nature and all the complexes show rhombic distortion around the ruthenium ion with three different ‘g’ values (gx ≠ gy ≠ gz) at 77 K. All the complexes are redox active and exhibit an irreversible metal centered redox processes (RuIII–RuIII/RuIV–RuIV; RuIII–RuIII/RuII–RuII) within the potential range of 0.38–0.86 V and −0.39 to −0.66 V respectively, versus Ag/AgCl. Further, the catalytic efficiency of one of the complexes [Ru2Cl2(AsPh3)4(L1)] (4) has been investigated in the case of oxidation of primary and secondary alcohols into their corresponding aldehydes and ketones in the presence of N-methylmorpholine-N-oxide(NMO) as co-oxidant. The formation of high valent RuV O species is proposed as catalytic intermediate for the catalytic cycle.