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Eight new ruthenium(II) complexes of N,N-chelating pyrazolylbenzimidazole ligands of the general formula [RuII(p-cym)(L)X]+ [where the ligand L is 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole (L1) substituted at the 4 position of the pyrazole ring by Cl (L2), Br (L3), or I (L4) and X = Cl- and I-] were synthesized and characterized using various analytical techniques. Complexes 1 and 3 were also characterized by single-crystal X-ray crystallography, and they crystallized as a monoclinic crystal system in space groups P21/n and P21/c, respectively. The complexes display good solution stability at physiological pH 7.4. The iodido-coordinated pyrazolylbenzimidazole ruthenium(II) p-cymene complexes (2, 4, 6, and 8) are more resistant toward hydrolysis and have less tendency to form monoaquated complexes in comparison to their chlorido analogues (1, 3, 5, and 7). The halido-substituted 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole ligands, designed as organic-directing molecules, inhibit vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation. In addition, the ruthenium(II) complexes display a potential to bind to DNA bases. The cytotoxicity profile of the complexes (IC50 ca. 9-12 μM for 4-8) against the triple-negative breast cancer cells (MDA-MB-231) show that most of the complexes are efficient. The lipophilicity and cellular accumulation data of the complexes show a good correlation with the cytotoxicity profile of 1-8. The representative complexes 3 and 7 demonstrate the capability of arresting the cell cycle in the G2/M phase and induce apoptosis. The inhibition of VEGFR2 phosphorylation with the representative ligands L2 and L4 and the corresponding metal complexes 3 and 7 in vitro shows that the organic-directing ligands and their complexes inhibit VEGFR2 phosphorylation. Besides, L2, L4, 3, and 7 inhibit the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and proto-oncogene tyrosine-protein kinase (Src), capable of acting downstream of VEGFR2 as well as independently. Compounds L2, L4, 3, and 7 have a lesser effect on ERK1/2 and more prominently affect Src phosphorylation. We extended the study for L2 and 3 in the Tg(fli1:gfp) zebrafish model and found that L2 is more effective in vivo compared to 3 in inhibiting angiogenesis.

Morpholine motif is an important pharmacophore and, depending on the molecular design, may localize in cellular acidic vesicles. To understand the importance of the presence of pendant morpholine in a metal complex, six bidentate N,O-donor ligands with or without a pendant morpholine unit and their corresponding ruthenium(II) p-cymene complexes (1-6) are synthesized, purified, and structurally characterized by various analytical methods including X-ray diffraction. Complexes 2-4 crystallized in the P21/c space group, whereas 5 and 6 crystallized in the P1 space group. The solution stability studies using 1H NMR support instantaneous hydrolysis of the native complexes to form monoaquated species in a solution of 3:7 (v/v) dimethyl sulfoxide-d6 and 20 mM phosphate buffer (pH* 7.4, containing 4 mM NaCl). The monoaquated complexes are stable for at least up to 24 h. The complexes display excellent in vitro antiproliferative activity (IC50 ca. 1-14 μM) in various cancer cell lines, viz., MDA-MB-231, MiaPaCa2, and Hep-G2. The presence of the pendant morpholine does not improve the dose efficacy, but rather, with 2-[[(2,6-dimethylphenyl)imino]methyl]phenol (HL1) and its pendant morpholine analogue (HL3) giving complexes 1 and 3, respectively, the antiproliferative activity was poorer with 3. MDA-MB-231 cells treated with the complexes show that the acidic vesicles remain acidic, but the population of acidic vesicles increases or decreases with time of exposure, as observed from the dispersed red puncta, depending on the complex used. The presence of the 2,6-disubstituted aniline and the naphthyl group seems to improve the antiproliferative dose. The complex treated MDA-MB-231 cells show that cathepsin D, which is otherwise present in the cytosolic lysosomes, translocates to the nucleus as a result of exposure to the complexes. Irrespective of the presence of a morpholine motif, the complexes do not activate caspase-3 to induce apoptosis and seem to favor the necrotic pathway of cell killing.

Sulfonamides have a broad range of therapeutic applications, which include the inhibition of various isoforms of carbonic anhydrases (CAs). Among the various CA isoforms, CA IX is overexpressed in ...

Platinum-based complexes are one of the most successful chemotherapeutic agents having a significant ground in cancer chemotherapy despite their side effects. During the past few decades, Ru(II) complexes have been emerging as efficient alternatives owing to their promising activities against platinum-resistant cancer. The pathway of action, lipophilicity, and cytotoxicity of a Pt or Ru complex may be tuned by varying the attached ligands, the coordination mode, and the leaving group. In this work, we report a family of Pt(II) and Ru(II) complexes (1-5) of three N,O and N,N donor-based trimethoxyanilines containing Schiff bases with the general formula [PtII(L)(DMSO)Cl], [RuII(L)(p-cymene)Cl], [RuII(L)(p-cymene)Cl]+, and [PtII(L)Cl2]. All of the complexes are characterized by different analytical techniques. 1H NMR and electrospray ionization mass spectrometry (ESI-MS) data suggest that the N,O-coordinated Pt(II) complexes undergo slower aquation compared to the Ru(II) analogues. The change of the coordination mode to N,N causes the Ru complexes to be more inert to aquation. The N,O-coordinating complexes show superiority over N,N-coordinating complexes by displaying excellent in vitro antiproliferative activity against different aggressive cancer cells, viz., triple-negative human metastatic breast adenocarcinoma MDA-MB-231, human pancreatic carcinoma MIA PaCa-2, and hepatocellular carcinoma Hep G2. In vitro cytotoxicity studies suggest that Pt(II) complexes are more effective than their corresponding Ru(II) analogues, and the most cytotoxic complex 3 is 10-15 times more toxic than the clinical drugs cisplatin and oxaliplatin against MDA-MB-231 cells. Cellular studies show that all of the N,O-coordinated complexes (1-3) initiate disruption of the microtubule network in MDA-MB-231 cells in a dose-dependent manner within 6 h of incubation and finally lead to the arrest of the cell cycle in the G2/M phase and render apoptotic cell death. The disruption of the microtubule network affects the agility of the cytoskeleton rendering inhibition of tyrosine phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), a key step in angiogenesis. Complexes 1 and 2 inhibit VEGFR2 phosphorylation in a dose-dependent fashion. Among the Pt(II) and Ru(II) complexes, the former displays higher cytotoxicity, a stronger effect on the cytoskeleton, better VEGFR2 inhibition, and strong interaction with the model nucleobase 9-ethylguanine (9-EtG).

We report [RuII(L)(η6-p-cym)Cl] (1 and 2) and [PtII(L)(DMSO)Cl] (3 and 4) complexes, where L is a chelate imine ligand derived from chloroethylamine and salicylaldehyde (HL1) or o-vanillin (HL2). T...

Ruthenium compounds are promising anticancer candidates owing to their lower side-effects and encouraging activities against resistant tumors. Half-sandwich piano-stool type RuII compounds of general formula [(L)RuII(η6-arene)(X)]+ (L = chelating bidentate ligand, X = halide) have exhibited significant therapeutic potential against cisplatin-resistant tumor cell lines. In RuII (p-cymene) based complexes, the change of the halide leaving group has led to several interesting features, viz., hydrolytic stability, resistance toward thiols, and alteration in pathways of action. Tyramine is a naturally occurring monoamine which acts as a catecholamine precursor in humans. We synthesized a family of N,N and N,O coordinated RuII (p-cymene) complexes, [(L)RuII(η6-arene)(X)]+ (1-4), with tyramine and varied the halide (X = Cl, I) to investigate the difference in reactivity. Our studies showed that complex 2 bearing N,N coordination with an iodido leaving group shows selective in vitro cytotoxicity against the pancreatic cancer cell line MIA PaCa-2 (IC50 ca. 5 μM) but is less toxic to triple-negative breast cancer (MDA-MB-231), hepatocellular carcinoma (Hep G2), and the normal human foreskin fibroblasts (HFF-1). Complex 2 displays stability toward hydrolysis and does not bind with glutathione, as confirmed by 1H NMR and ESI-HRMS experiments. The inert nature of 2 leads to enhancement of cytotoxicity (IC50 = 5.3 ± 1 μM) upon increasing the cellular treatment time from 48 to 72 h.

Morpholine motif is an important pharmacophore and, depending on the molecular design, may localize in cellular acidic vesicles. To understand the importance of the presence of pendant morpholine in a metal complex, six bidentate N,O-donor ligands with or without a pendant morpholine unit and their corresponding ruthenium(II)

Ruthenium(II/III) complexes are predicted to be efficient alternatives to platinum drug-resistant cancers but have never been investigated for sequestration and efflux by Cu-ATPases (ATP7A or ATP7B) overexpressed in resistant cancer cells, although a major cause of platinum drug resistance is found to be sequestration of platinum chemotherapeutic agents by thiol donors glutathione (GSH) or the Cys-X-X-Cys (CXXC) motifs in the Cu-ATPases in cytosol. Here, we show for the first time that ATP7B efficiently sequesters ruthenium(II) η6-p-cymene complexes. We present seven complexes, [RuII(η6-p-cym)(L)X](PF6) (1-7; L = L1-L3, X = Cl, Br, and I), out of which two resists deactivation by the cellular thiol, glutathione (GSH). The results show that Ru-I coordination and a moderate steric factor increase resistance to GSH and the CXXC motif. RuII-I-coordinated 3 and 7 showed resistance to sequestration by ATP7B. 3 displays highest resistance against GSH and does not trigger ATP7B trafficking in the liver cancer cell line. It escapes ATP7B-mediated sequestration and triggers apoptosis. Thus, with a suitable bidentate ligand and iodido leaving group, RuII(η6-p-cym) complexes may display strong kinetic inertness to inhibit the ATP7B detoxification pathway. Inductively coupled plasma mass spectrometry data show higher retention of 3 and 7 inside the cell with time compared to 4, supporting ATP7B-mediated sequestration.

Four trimethoxy- and dimethoxyphenylamine-based Schiff base (L1-L4)-bearing RuII-p-cymene complexes (1-4) of the chemical formula [RuII(η6-p-cymene)(L)(Cl)] were synthesized, isolated in pure form, and structurally characterized using single-crystal X-ray diffraction and other analytical techniques. The complexes showed excellent in vitro antiproliferative activity against various forms of cancer that are difficult to cure, viz., triple negative human metastatic breast carcinoma MDA-MB-231, human pancreatic carcinoma MIA PaCa-2, and hepatocellular carcinoma Hep G2. The 1H nuclear magnetic resonance data in the presence of 10% dimethylformamide-d7 or dimethyl sulfoxide-d6 in phosphate buffer (pD 7.4, containing 4 mM NaCl) showed that the complexes immediately generate the aquated species that is stable for at least 24 h. Electrospray ionization mass spectrometry data showed that they do not bind with guanine nitrogen even in the presence of 5 molar equivalents of 9-EtG, during a period of 24 h. The best complex in the series, 1, exhibits an IC50 of approximately 10-15 μM in the panel of tested cancer cell lines. The complexes do not enhance the production of reactive oxygen species in the cells. Docking studies with a tubulin crystal structure (Protein Data Bank entry 1SAO ) revealed that 1 and 3 as well as L1 and L3 have a high affinity for the interface of the α and β tubulin dimer in the colchicine binding site. The immunofluorescence studies showed that 1 and 3 strongly inhibited microtubule network formation in MDA-MB-231 cells after treatment with an IC20 or IC50 dose for 12 h. The cell cycle analysis upon treatment with 1 showed that the complexes inhibit the mitotic phase because the arrest was observed in the G2/M phase. In summary, 1 and 3 are RuII half-sandwich complexes that are capable of disrupting a microtubule network in a dose-dependent manner. They depolarize the mitochondria, arrest the cell cycle in the G2/M phase, and kill the cells by an apoptotic pathway.

Sulfonamides have a broad range of therapeutic applications, which include the inhibition of various isoforms of carbonic anhydrases (CAs). Among the various CA isoforms, CA IX is overexpressed in tumors and regulates the pH of the tumor microenvironment. Herein we present five new ruthenium(II)

Platinum-based complexes are one of the most successful chemotherapeutic agents having a significant ground in cancer chemotherapy despite their side effects. During the past few decades, Ru(II) complexes have been emerging as efficient alternatives owing to their promising activities against platinum-resistant cancer. The pathway of action, lipophilicity, and cytotoxicity of a Pt or Ru complex may be tuned by varying the attached ligands, the coordination mode, and the leaving group. In this work, we report a family of Pt(II) and Ru(II) complexes (

Ruthenium compounds are promising anticancer candidates owing to their lower side-effects and encouraging activities against resistant tumors. Half-sandwich piano-stool type Ru

Ruthenium(II/III) complexes are predicted to be effcient alternatives to platinum drug-resistant cancers but have never been investigated for sequestration and efflux by Cu-ATPases (ATP7A or ATP7B) overexpressed in resistant cancer cells, although a major cause of platinum drug resistance is found to be sequestration of platinum chemotherapeutic agents by thiol donors glutathione (GSH) or the Cys−X−X−Cys (CXXC) motifs in the Cu-ATPases in cytosol. Here, we show for the first time that ATP7B effciently sequesters ruthenium(II) η(6)-p-cymene complexes. We present seven complexes, [Ru(II)(η(6)-p-cym)(L)X](PF(6)) (1−7; L = L1−L3, X = Cl, Br, and I), out of which two resists deactivation by the cellular thiol, glutathione (GSH). The results show that Ru−I coordination and a moderate steric factor increase resistance to GSH and the CXXC motif. Ru(II)−I-coordinated 3 and 7 showed resistance to sequestration by ATP7B. 3 displays highest resistance against GSH and does not trigger ATP7B trafficking in the liver cancer cell line. It escapes ATP7B-mediated sequestration and triggers apoptosis. Thus, with a suitable bidentate ligand and iodido leaving group, Ru(II)(η(6)-p-cym) complexes may display strong kinetic inertness to inhibit the ATP7B detoxification pathway. Inductively coupled plasma mass spectrometry data show higher retention of 3 and 7 inside the cell with time compared to 4, supporting ATP7B-mediated sequestration.

Four trimethoxy- and dimethoxyphenylamine-based Schiff base (L1−L4)-bearing Ru(II)−p-cymene complexes (1−4) of the chemical formula [Ru(II)(η(6)-p-cymene)(L)(Cl)] were synthesized, isolated in pure form, and structurally characterized using single-crystal X-ray diffraction and other analytical techniques. The complexes showed excellent in vitro antiproliferative activity against various forms of cancer that are difficult to cure, viz., triple negative human metastatic breast carcinoma MDA-MB-231, human pancreatic carcinoma MIA PaCa-2, and hepatocellular carcinoma Hep G2. The (1)H nuclear magnetic resonance data in the presence of 10% dimethylforma-mide-d(7) or dimethyl sulfoxide-d(6) in phosphate buffer (pD 7.4, containing 4 mM NaCl) showed that the complexes immediately generate the aquated species that is stable for at least 24 h. Electrospray ionization mass spectrometry data showed that they do not bind with guanine nitrogen even in the presence of 5 molar equivalents of 9-EtG, during a period of 24 h. The best complex in the series, 1, exhibits an IC(50) of approximately 10−15 μM in the panel of tested cancer cell lines. The complexes do not enhance the production of reactive oxygen species in the cells. Docking studies with a tubulin crystal structure (Protein Data Bank entry 1SAO) revealed that 1 and 3 as well as L1 and L3 have a high affinity for the interface of the α and β tubulin dimer in the colchicine binding site. The immunofluorescence studies showed that 1 and 3 strongly inhibited microtubule network formation in MDA-MB-231 cells after treatment with an IC(20) or IC(50) dose for 12 h. The cell cycle analysis upon treatment with 1 showed that the complexes inhibit the mitotic phase because the arrest was observed in the G2/M phase. In summary, 1 and 3 are Ru(II) half-sandwich complexes that are capable of disrupting a microtubule network in a dose-dependent manner. They depolarize the mitochondria, arrest the cell cycle in the G2/M phase, and kill the cells by an apoptotic pathway.

A novel 16-member metallamacrocyclic octanuclear copper(II) complex of formulation [Cu 8 L 4 (OH) 4 ] (1) has been prepared from a reaction of [Cu 2 L(O 2 CMe)] and NaOH in methanol, where L is a pentadentate trianionic Schiffbase ligand N,N'-(2-hydroxypropane-1,3-diyl)bis(salicylaldimine). The complex has been characterized by analytical, structural, and spectral methods. It crystallizes in the monoclinic space group C2/c with the following unit cell dimensions: a = 30.365(3) A; b = 14.320(2) A; c = 19.019(2) A; β = 125.33(2)°; V = 6746.7(13) A 3 ; Z = 4. A total of 4589 unique data with l > 2σ(l) were used to refine the structure to R1(F o ) = 0.0525 and wR2 = 0.1156. The structure consists of four binuclear {Cu 2 L} + units linked covalently by four hydroxide ligands to form an octanuclear core which is stabilized by strong hydrogen-bonding interactions involving the hydroxide ligands. Each binuclear unit has a pentadentate ligand L showing N 2 O 3 coordination with an endogenous alkoxide bridging atom. The magnetic susceptibility data of 1, obtained in the temperature range 14-306 K, show the presence of antiferromagnetic exchange interactions between adjacent spin-½ Cu(II) ions. The μ e f f values are 1.54 and 0.26 μ B (per copper) at 295 and 15 K, respectively. The magnetic data have been theoretically fitted using a Heisenberg spin-½ Hamiltonian with nearest-neighbor antiferromagnetic interactions. The spin coupling in the metallamacrocyclic ring has been modeled using four different coupling constants (J) on the basis of the structural parameters of the octanuclear core. The coupling constants obtained are J 1 = -318.8, J 2 = -293.3, J 3 = -111.6, and J 4 = -63.8 cm - 1 . The theoretical modeling of the susceptibility data gives a higher magnitude of the antiferromagnetic interaction within the binuclear {Cu 2 L} + unit compared to those involving adjacent dimeric units.

Two new angular trinuclear copper(II) complexes of formulation [Cu(3)(HL)LL'](ClO(4)), where L' is imidazole (Him, 1) or 1-methylimidazole (1-MeIm, 2) and H(3)L is a Schiff base obtained from the condensation of salicylaldehyde and 1,3-diaminopropan-2-ol (2:1 mole ratio), are prepared from a reaction of [Cu(2)L(mu-Br)] and [Cu(HL)] in the presence of L' and isolated as perchlorate salts. The crystal structures of 1 and 2 consist of a trinuclear copper(II) unit formed by the covalent linkage of monomeric type-2 mimic and dimeric type-3 mimic precursor complexes to give an angular arrangement of the metal atoms in the core which is a model for the active site structure of blue multicopper oxidases. In 1 and 2, the coordination geometry of two terminal copper atoms is distorted square-planar. The central copper has a distorted square-pyramidal (4 + 1) geometry. The mean Cu...Cu distance is approximately 3.3 A. The complex has a diphenoxo-bridged dicopper(II) unit with the phenoxo oxygen atoms showing a planar geometry. In addition, the complex has an endogenous alkoxo-bridged dicopper(II) unit showing a pyramidal geometry for the oxygen atom. The 1:1 electrolytic complexes show a d-d band at 607 nm. Cyclic voltammetry of the complexes in MeCN containing 0.1 M TBAP using a glassy carbon working electrode displays a Cu(3)(II)/Cu(2)(II)Cu(I) couple near -1.0 V (vs SCE). The variable temperature magnetic susceptibility measurements in the range 300-18 K show antiferromagnetic coupling in the complexes giving magnetic moments of approximately 3.0 mu(B) at 300 K and approximately 2.1 mu(B) at 18 K for the tricopper(II) unit. The experimental susceptibility data are theoretically fitted using a model with Heisenberg spin-(1)/(2) Hamiltonian for a trimer of spin-(1)/(2) copper(II) ions having two exchange parameters involving the alkoxo-bridged dicopper(II) (J1) and the diphenoxo-bridged dicopper(II) (J2) units, giving J1 and J2 values of -82.7, -73 cm(-1) for 1 and -98.3, -46.1 cm(-1) for 2, respectively. The structural features indicate a higher magnitude of anitiferromagnetic coupling in the alkoxo-bridged unit based on the greater value of the Cu-O-Cu angle in comparison to the diphenoxo-bridged unit. The core structures of 1 and 2 compare well with the first generation model complexes for the active site structure of multicopper oxidases in the oxidized form. The crystal structure of 1 exhibits a lamellar structure with a gap of approximately 7 A containing water molecules in the interlamellar space. Complex 2 forms a hexanuclear species due to intermolecular hydrogen bonding interactions involving two trimeric units. The crystal packing diagram of 2 displays formation of a three-dimensional framework with cavities containing the perchlorate anions.