Bioorganometallic Chemistry

Series of tetranuclear arene ruthenium complexes of the general formula [Ru 4 (p-cymene) 4 (µ 2 -N∩N) 2 (µ 4 -OO∩OO) 2 ][CF 3 SO 3 ] 4 (N∩N = 2,5-dipyridyl-thiophene (dptp), 3,6-dipyridyl-1,2,4,5-tetrazine (dptz), 3,6-dipyridyl-1,4-dihydro-1,2,4,5-tetrazine (dpdt)) were prepared by reacting the dinuclear arene ruthenium complexes Ru 2 (p-cymene) 2 (µ 4 -OO∩OO)Cl 2 (OO∩OO = oxalato (oxa), 2,5-dioxido-1,4-benzoquinonato (dobq), 2,5-dichloro-1,4-benzoquinonato (dClbq), 2,5-dioxido-3-undecyl-1,4-benzoquinonato (dubq), 5,8-dioxido-1,4-naphtoquinonato (donq)) with silver trifluoromethanesulfonate, followed by the addition of the corresponding N∩N linkers. All metalla-rectangles were characterized by standard techniques, including infrared, UV-visible, 1 H, 13 C NMR spectroscopy and ESI mass spectrometry: Thus confirming the rectangular structure of the complexes, and showing the facility of forming tetranuclear arene ruthenium metalla-rectangles.

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

The ferrocenyl compound 2-ferrocenyl-1,1-bis(4-hydroxyphenyl)-but-1-ene (3), is very cytotoxic against breast cancer cells (IC 50 = 0.44 µM against MDA-MB-231). We now report the synthesis of a new series of para-and meta-substituted mono-and di-ferrocenyl phenols but-1-ene (8), and 1,2-di-ferrocenyl-1-(3-hydroxyphenyl)-but-1-ene ( )] and their electrochemical and biochemical properties, especially in comparison to the previously reported "standard" compounds [2-ferrocenyl-1-(4-hydroxyphenyl)-1-phenyl-but-1-ene (2) and ( )]. We also report the synthesis and characterization of the diphenyl analogue, 2ferrocenyl-1,1-diphenyl-but-1-ene ( ). This structure-activity relationship study was motivated by our hypothesis that the cytotoxicity of 3 is related to its ability to form a quinone methide structure after two in situ 1-electron oxidations, a process which requires the presence of at least one p-phenol. The mono-ferrocenyl compounds (including those previously reported) are reasonably well recognized by the oestrogen receptors α (RBAs = 0.9-9.6%) and β (RBAs = 0.28-16.3%), although the bulkier di-ferrocenyl compounds show very little affinity. In vitro, the cytotoxic effects of the phenolic complexes are related to the positioning of the hydroxyl group (para-superior to meta-), and to the number of ferrocenyl groups (one superior to two), with IC 50 values against the MDA-MB-231 cell line ranging from 0.44-3.5 µM. On the hormone-dependent breast cancer cell line MCF-7, the observed effect seems to be the result of two components, one cytotoxic (antiproliferative) and one estrogenic (proliferative). Electrochemical studies show that only the compounds with a pphenol engage in proton-coupled intramolecular electron transfer.

A novel dioxo-bridged dinuclear gold(III) complex with two 2,9dimethylphenanthroline ligands was synthesized and thoroughly characterized. Its crystal structure was solved, and its solution behavior assessed. Remarkably, this compound revealed excellent antiproliferative properties in vitro against a wide panel of 36 cancer cell lines, combining a high cytotoxic potency to pronounced tumor selectivity. Very likely, these properties arise from an innovative mode of action (possibly involving histone deacetylase inhibition), as suggested by COM-PARE analysis. In turn, electrospray ionization-mass spectrometry studies provided valuable insight into its molecular mechanisms of activation and of interaction with protein targets. Gold(III) reduction, dioxo bridge disruption, coordinative gold(I) binding to the protein, and concomitant release of the phenanthroline ligand were proposed to occur upon interaction with superoxide dismutase, used here as a model protein. Because of the reported results, this new gold(III) compound qualifies itself as an optimal candidate for further pharmacological testing.

In the present investigation, a series of some synthesis and biological evaluation of some pyrazolone derivatives with imidazole, benzimidazole and benztriazole moiety were synthesized and tested for their anti-inflammatory activity in-vitro using celecoxib as a reference drug. Compound 8d was found to be the most potent derivative of the series with 75 %inhibition of inflammation.

Complexes [Ir(μ-Cl)(η 2-C 8 H 14) 2 ] 2 (1) and [Ir(μ-Cl)(η 4-C 8 H 12)] 2 (2) promote the pyridyl-directed ortho-CH and ortho-CBr activations of the phenyl substituent of 2-(2-bromophenyl)pyridine. The formed products depend upon the olefin of the dimer, which governs the kinetic preference of the activation. The cyclooctene complex 1 reacts with the substituted heterocycle to give (η 2-C 8 H 14) 2 Ir(μ-Cl) 2 Ir{κ 2-C,N-[C 6 BrH 3-py]} 2 (3), in acetone, at room temperature. Treatment of 3 with K(acac) affords Ir(acac)(η 2-C 8 H 14) 2 (4) and Ir(acac){κ 2-C,N-[C 6 BrH 3-py]} 2 (5; acac = acetylacetone). Under more severe conditions, 2-ethoxyethanol under reflux, the reaction of 1 with the heterocycle gives a yellow solid, which yields a 5:82:7 mixture of 5, Ir(acac){κ 2-C,N-[C 6 BrH 3-py]}{κ 2-C,N-[C 6 H 4-py]} (6), and Ir(acac){κ 2-C,N-[C 6 H 4-py]} 2 (7) by reaction with K(acac). In acetone or toluene, at room temperature, 2-(2-bromophenyl)pyridine breaks the chloride bridges of dimer 2 to form IrCl(η 4-C 8 H 12){κ 1-N-[py-C 6 BrH 4 ]} (8), which evolves into IrClBr{κ 2-C,N-[C 6 H 4-py]}(η 4-C 8 H 12) (9) as a result of the oxidative addition of the ortho-CBr of the phenyl substituent to the metal center. Treatment of 9 with Ag 2 O in acetylacetone leads to Ir(acac){κ 2-C,N-[C 6 H 4-py]}{κ 1-C, η 2-[C 8 H 12-(C 3-acac)]} (10), as a consequence of the replacement of the halides by an O,O-chelate acac ligand and the outside to metal nucleophilic attack of a second acac group to the diene C−C double bond disposed trans to bromide.

The heterobimetallic complexes [(dppe)Ni(pdt)Mo(CO) 4 ], [(dcpe)Ni(pdt)Mo(CO) 4 ], [(dppe)Ni(pdt)W(CO) 4 ] and [(dcpe)-Ni(pdt)W(CO) 4 ] {dppe = Ph 2 P(CH 2) 2 PPh 2 ; dcpe = Cy 2 P(CH 2) 2-PCy 2 ; pdt 2-=-S(CH 2) 3 S-} have been prepared and structurally characterized. The internuclear separation in these Ni II M 0 species is highly sensitive to diphosphine basicity and is smallest in the dppe complexes wherein the planar Ni [a] IBS Center for Multidimensional Carbon Materials,

For the first time, two organometallic triphenylethylene compounds (Fc-diOH and DFO), with strong antiproliferative activity in breast cancer cells, but insoluble in biological fluids, were incorporated in two types of stealth nanoparticles (NP): PEG/PLA nanospheres (NS) and nanocapsules (NC). Their physicochemical parameters were measured (size, zeta potential, encapsulation and loading efficiency), and their biological activity was assessed. In vitro drug release after high dilution of loaded NPs was measured by estradiol binding competition in MELN cells. The influence of the encapsulated drugs on the cell cycle and apoptosis was studied by flow cytometry analyses. Notwithstanding potential drug adsorption at the NP surface, Fc-diOH and DFO were incorporated efficiently in NC and NS, which slowly released both compounds. They arrested the cell cycle in the S-phase and induced apoptosis, whose activity is increased by loaded NS. A decrease in their antiproliferative activity by th...

Organoiridium complexes … … are noteworthy scaffolds for the design of enzyme inhibitors. As described by E. Meggers and co-workers in their Communication on page 3839 ff., a nanomolar and selective iridium-based inhibitor for the receptor protein kinase VEGFR3 (Flt4) has been discovered. This nontoxic octahedral iridium(III) complex, which is synthesized through stereoselective oxidative addition starting from a suitable square-planar iridium(I) precursor, is revealed to interfere with the development of blood vessels in vivo in two different zebrafish angiogenesis models.

Organoiridium complexes … … are noteworthy scaffolds for the design of enzyme inhibitors. As described by E. Meggers and co-workers in their Communication on page 3839 ff., a nanomolar and selective iridium-based inhibitor for the receptor protein kinase VEGFR3 (Flt4) has been discovered. This nontoxic octahedral iridium(III) complex, which is synthesized through stereoselective oxidative addition starting from a suitable square-planar iridium(I) precursor, is revealed to interfere with the development of blood vessels in vivo in two different zebrafish angiogenesis models.

All reactions were conducted using 5.0 mmol of antimony(V) dibromide precursor and 10.0 mmol of potassium or sodium salt of carboxylic acid. Aryl substituted antimony(V) dibromide was ground together with the chosen carboxylic acid salt and dried in vacuo prior to use. The mixture of reagents were placed in a Schlenk flask with dried toluene (ca 100 mL) and stirred for 12 hours. The salt(s) formed were filtered off and the resulting clear solution was removed under reduced pressure to yield a solid residue. Synthesis of bis-(2-thiophenecarboxylato)triphenylantimony(V), [SbPh 3 (C 4 H 3 SCO 2) 2 ], 12 Reaction of triphenylantimony(V) dibromide (2.56 g, 5 mmol) with the potassium salt of 2-thiophenecarboxylic acid (1.66 g, 10 mmol) was performed and purified according to GP, producing a colourless solid. This was identified as 12.

Au(III) chloride compounds with 7,8-benzoquinoline (bqn)-[Au(bqn)Cl 3 ] and [Au(bqn*)Cl 2 ] (bqn* being deprotonated, at the C(10) carbon, monoanionic form of bqn) were studied by 1 H-13 C, 1 H-15 N HMQC and HMBC-NMR. 1 H, 13 C and 15 N coordination shifts were discussed in relation to the molecular structures, revealing characteristic variability patterns. Analogous NMR measurements were performed for the new (bqnH +) 2 (AuCl 4-)Clsalt, studied also by single crystal X-ray diffraction. All compounds exhibited fluorescence.

INTRODUCTION 2-Butyl-5-chloro-1H-imidazole-4-carbaldehyde (1) and its chemistry is considered to be an important class of Nheterocyclic compounds with various active sites serving as synthons for the synthesis of several new compounds with useful biological properties. Weinstock et al. 1 reported the use of 1 and its derivatives to exhibit potent and selective angiotension II receptor antagonists, Kantevari et al. 2 reported that, N-alkyl chalcone derivatives can be used as angiotension converting enzyme (ACE) inhibitors, Salimbeni et al. 3 reported the N-alkyl derivatives can act as nonpeptide angiotension II receptor antagonists and several reports reveal the use of 1 with various biological activities 4-7. Although there are numerous reports on N-alkylations of various compounds using various solvents but most of them suffer due to hazardous use of solvents, harsh reaction conditions, use of external phase transfer catalysts and longer reaction times. Hence, there is a need for the development of new techniques which are environmentally benign in nature. Use of polyethylene glycol as solvent has attracted the attention of many researchers in the present context of green synthesis. PEG has been considered as green and efficient solvent for carrying various organic reactions. In present work, choose of PEG-600 as solvent provoked by being thermally labile, availability, inexpensive, easy workup and recyclability. PEG-600 has unique solvent property which has excellent cataionic coordination capability which render it a perfect proton abstracter facilitating N-alkylations. Conventional N-alkylations mostly requires base like K2CO3 which neutralize the acid liberated from the reaction PEG-600 Mediated Phase Transfer Catalyst Free N-Alkylations of 2-Butyl-5-chloro-1H-imidazole-4-carbaldehyde

The ferrocenyl compound 2-ferrocenyl-1,1-bis(4-hydroxyphenyl)-but-1-ene (3), is very cytotoxic against breast cancer cells (IC 50 = 0.44 µM against MDA-MB-231). We now report the synthesis of a new series of para-and meta-substituted mono-and di-ferrocenyl phenols [2-ferrocenyl-1-(3-hydroxyphenyl)-1-phenyl-but-1-ene (6), 2-ferrocenyl-1-(3hydroxyphenyl)-1-(4-hydroxyphenyl)-but-1-ene (7), 1,2-di-ferrocenyl-1-(4-hydroxyphenyl)but-1-ene (8), and 1,2-di-ferrocenyl-1-(3-hydroxyphenyl)-but-1-ene (9)] and their electrochemical and biochemical properties, especially in comparison to the previously reported "standard" compounds [2-ferrocenyl-1-(4-hydroxyphenyl)-1-phenyl-but-1-ene (2) and (3)]. We also report the synthesis and characterization of the diphenyl analogue, 2ferrocenyl-1,1-diphenyl-but-1-ene (5). This structure-activity relationship study was motivated by our hypothesis that the cytotoxicity of 3 is related to its ability to form a quinone methide structure after two in situ 1-electron oxidations, a process which requires the presence of at least one p-phenol. The mono-ferrocenyl compounds (including those previously reported) are reasonably well recognized by the oestrogen receptors α (RBAs = 0.9-9.6%) and β (RBAs = 0.28-16.3%), although the bulkier di-ferrocenyl compounds show very little affinity. In vitro, the cytotoxic effects of the phenolic complexes are related to the positioning of the hydroxyl group (para-superior to meta-), and to the number of ferrocenyl groups (one superior to two), with IC 50 values against the MDA-MB-231 cell line ranging from 0.44-3.5 µM. On the hormone-dependent breast cancer cell line MCF-7, the observed effect seems to be the result of two components, one cytotoxic (antiproliferative) and one estrogenic (proliferative). Electrochemical studies show that only the compounds with a pphenol engage in proton-coupled intramolecular electron transfer.

For the first time, two organometallic triphenylethylene compounds (Fc-diOH and DFO), with strong antiproliferative activity in breast cancer cells, but insoluble in biological fluids, were incorporated in two types of stealth nanoparticles (NP): PEG/PLA nanospheres (NS) and nanocapsules (NC). Their physicochemical parameters were measured (size, zeta potential, encapsulation and loading efficiency), and their biological activity was assessed. In vitro drug release after high dilution of loaded NPs was measured by estradiol binding competition in MELN cells. The influence of the encapsulated drugs on the cell cycle and apoptosis was studied by flow cytometry analyses. Notwithstanding potential drug adsorption at the NP surface, Fc-diOH and DFO were incorporated efficiently in NC and NS, which slowly released both compounds. They arrested the cell cycle in the S-phase and induced apoptosis, whose activity is increased by loaded NS. A decrease in their antiproliferative activity by th...

A series of Pt(II) complexes with 3-ethyl-5-methyl-5-(4-pyridyl)hydantoin, 3-propyl-5-methyl-5-(4-pyridyl)hydantoin and 3-benzyl-5-methyl-5-(4-pyridyl)hydantoin with general formulae cis-[Pt(L) 2 Cl 2 ], cis-[Pt(NH 3)LCl 2 ] and trans-[Pt(NH 3)LCl 2 ] were synthesized. The new compounds were characterized by means of elemental analysis, IR, 1 H and 13 C NMR spectroscopy. The studies showed that the ligands coordinate to the platinum ions in a monodentate manner through the nitrogen atom from the pyridine ring. The cytotoxic activity in vitro of the complexes as well as of their previously prepared Pt(II) analogues with other derivatives of 5-methyl-5-(4-pyridyl)hydantoin was screened against a panel of human tumor cell lines. Cytotoxicity was strongly dependent on their lipophilicity, while the most lipophilic Pt(II) complex, carrying 3-benzyl-5-methyl-5-(4-pyridyl)hydantoin as carrier ligand inhibited the viability of tested cells at low micromolar concentrations with IC 50 values comparable to that of cisplatin. A preliminary pharmacodynamic investigation showed that its cytotoxicity is mediated through induction of apoptosis. The cis-and trans-analogues consisting one ammine group in the molecules exhibited far less cytotoxicity in corroboration to the well established structure-activity rules for dia(m)mine platinum(II) complexes.

Five novel ruthenium(II)-arene complexes with polycyclic aromatic ligands were synthesized, comprising three compounds of the formula [RuCl(η 6-p-cym)(L)][PF 6 ], where p-cym = 1-isopropyl-4-methylbenzene and L are the bidentate aromatic ligands 1,10-phenanthroline-5,6-dione, 1, 5-amine-1,10-phenanthroline, 4, or 5,6epoxy-5,6-dihydro-phenanthroline, 5. In the other two complexes [RuCl 2 (η 6-p-cym)(L′)], the metal is coordinated to a monodentate ligand L′, where L′ is phenanthridine, 2, or 9-carbonylanthracene, 3. All compounds were fully characterized by mass spectrometry and elemental analysis, as well as NMR and IR spectroscopic techniques. Obtained ruthenium compounds as well as their respective ligands were tested for their antiparasitic and antitumoral activities. Even though all compounds showed lower Trypanosoma brucei activity than the free ligands, they also resulted less toxic on mammalian cells. Cytotoxicity assays on HL60 cells showed a moderate antitumoral activity for all ruthenium compounds. Compound 1 was the most potent antitumoral (IC 50 = 1.26 ± 0.78 μM) and antiparasitic (IC 50 = 0.19 ± 0.05 μM) agent, showing high selectivity towards the parasites (selectivity index N100). As complex 1 was the most promising antitumoral compound, its interaction with ubiquitin as potential target was also studied. In addition, obtained ruthenium compounds were found to bind DNA, and they are thought to interact with this macromolecule mainly through intercalation of the aromatic ligand.

Eight new phenylisoxazole isoniazid derivatives, 3-(2′-fluorophenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (1), 3-(2′-methoxyphenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (2), 3-(2′-chlorophenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (3), 3-(3′-clorophenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (4), 3-(4′-bromophenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (5), 5-(4′-methoxiphenyl)isoxazole-3-carbaldehyde isonicotinylhydrazone (6), 5-(4′-methylphenyl)isoxazole-3-carbaldehyde isonicotinylhydrazone (7), and 5-(4′-clorophenyl)isoxazole-3-carbaldehyde isonicotinylhydrazone (8), have been synthesized and characterized by FT-IR, 1H-NMR, 13C-NMR, and mass spectral data. The 2D NMR (1H-1H NOESY) analysis of 1 and 2 confirmed that these compounds in acetone-d6 are in the trans(E) isomeric form. This evidence is supported by computational calculations which were performed for compounds 1–8, using DFT/B3LYP level with the 6-311++G(d,p) basis set. The in v...

Novel conjugated ruthenium(II), rhodium-(III), and iridium(III) organometallic complexes of triazoles 1 and 2 synthesized and evaluated for anticancer activity against cervical (HeLa), kidney (HEK293), nonsmall lung cancer (A549), and leukemia (MT4) cancer cell lines are reported herein. The complexes are κ 2-N,C coordinated and have the formula [ML(Ar)Cl] (where L is 1-benzyl-4-phenyl-1H-1,2,3-triazole for 1 and 1-benzyl-4-hydroxymethyl-1H-1,2,3-triazole for 2, Ar is p-cymene for Ru II and Os II and Cp* for Rh III and Ir III , and M is metal). NMR studies, including HMBC and NOESY, were employed to unambiguously elucidate their structures and provide their conformational information in solution. Single-crystal X-ray diffraction data have been used to establish the solid-state structures of selected complexes, which further confirm the structural elucidation by NMR. Dynamic NMR studies, such as differential transferred NOE, have been employed to distinguish between isomers 1a_I and 1a_II of ruthenium(II) complexes of triazole 1. The rhodium(III) (1b) and iridium(III) (1c) complexes exhibited good cytotoxic activities (CC 50 = 4−6 μM) comparable to that of the drug auranofin against lung cancer A549 cell lines (CC 50 = 4.69 μM). While triazole 1 based ruthenium(II) (1a) and osmium(II) (1d) complexes displayed modest anticancer activities against HeLa and HEK293 cell lines, the analogous rhodium(III) and iridium(III) complexes exhibited good potential (CC 50 = 9−54 μM versus auranofin (3−9 μM)) against these cancer cell lines. Insightful NMR studies on the interaction between the DNA model guanosine 5′-GMP and the complexes 1b,c reveal a possible mode of action of the aquated complexes involving carbenylation with DNA bases or purines through the triazolyl proton H-5. From the findings, these complexes could possibly confer their cytotoxic activities through intercalation with the DNA of pathological cells. Therefore, carbenylation of the triazolylrhodium(III) and iridium(III) complexes by DNA guanosine 5′-GMP is proposed as a novel mode of DNA intercalation of these complexes in cancer cells.

With the utilization of molecular hybridization, a series of novel morpholinopyrimidine based distinctive pyrazole carboxamides were designed and synthesized in an attempt to develop newer antimicrobial agents against the increasing bacterial resistance. Structure of final targeted compounds were confirmed by spectral analysis i. e. 1H‐NMR, 13C‐NMR and Mass spectra. The newly synthesized compounds were screened for their preliminary in‐vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi, antituberculosis activity against Mycobacterium tuberculosis H37Rv and antimalarial activity against Plasmodium falciparum. In addition to this, In‐silico molecular docking study and ADME properties were likewise studied for the targeted compounds. It was inferred that from the series, Fluorinated anilide derivatives of morpholinopyrimidine clubbed with pyrazole carboxylate emerged out as potential antimicrobial candidates from the in‐vitro antimicrobial assay.

Gold(III) compounds have been examined for potential anti-cancer activity. It is proposed that the molecular targets of these compounds are thiol-containing biological molecules such as the cathepsin cysteine proteases. These enzymes have been implicated in many diseases including cancer. The catalytic mechanism of the cathepsin cysteine proteases is dependent upon a cysteine at the active site which is accessible to the interaction of thiophilic metals such as gold. The synthesis and biological activity of square-planar six-membered cycloaurated Au(III) compounds with a pyridinyl-phenyl linked backbone and two monodentate or one bidentate leaving group is described. Gold(III) cycloaurated compounds were able to inhibit both cathepsins B and K. Structure/activity was investigated by modifications to the pyridinyl-phenyl backbone, and leaving groups. Optimal activity was seen with substitution at the 6 position of the pyridine ring. The reversibility of inhibition was tested by reactivation in the presence of cysteine with a bidentate thiosalicylate compound being an irreversible inhibitor. Five compounds were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. The thiosalicylate compound was tested in vivo against the HT29 human colon tumor xenograft model. A modest decrease in tumor growth was observed compared with the untreated control tumor.

The DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, [PtIV(HL)(AL)(OH)2](NO3)2 (where HL is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL is 1S,2S-diaminocyclohexane). The resultant platinum(IV)-chlorambucil prodrugs, PCLB, 5CLB, and 56CLB, were characterized using high-performance liquid chromatography, nuclear magnetic resonance, ultraviolet-visible, circular dichroism spectroscopy, and electrospray ionization mass spectrometry. The prodrugs displayed remarkable antitumor potential across multiple human cancer cell lines compared to chlorambucil, cisplatin, oxaliplatin, and carboplatin, as well as their platinum(II) precursors, PHENSS, 5MESS, and 56MESS. Notably, 56CLB was exceptionally potent in HT29 colon, Du145 prostate, MCF10A breast, MIA pancreas, H460 lung, A2780, and ADDP ovarian cell lines, with GI50 values ra...

Various unsymmetrical 1,n¢-disubstituted ferrocenoyl amino acids were obtained by palladium-catalyzed aminocarbonylation starting from 1,1¢-diiodoferrocene. The reactions were carried out in one-pot, using an equimolar mixture of two amino acid esters as nucleophiles. The structures of the products were determined by 1 H NMR, 13 C NMR, IR and MS analyses. Each was found to adopt an ordered, intramolecularly hydrogen bonded conformation.

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

The Schiff-base 5-methyl-4-{(pyridin-2-ylmethylene)amino}-4H-1,2,4-triazole-3-thiol (L-H) reacts in alcoholic solution (methanol, ethanol, isopropanol) at room temperature with the dinuclear precursor [(η 6-MeC 6 H 4 Pr i)RuCl 2 ] 2 to give a series of neutral complexes of the general formula (η 6-MeC 6 H 4 Pr i)Ru(L-OR) (R = Me, 1; R = Et, 2; R = Pr i , 3). In these complexes, the Schiff-base ligand coordinates to the arene ruthenium unit in a S,N,Ntridentate fashion and concomitantly to the coordination process a nucleophilic addition of the alcohol occurs on the imine carbon of L, thus forming the corresponding L-OR ligand. The molecular structure of 3, solved by single-crystal X-ray analysis, shows a piano-stool arrangement with the p-cymene, the S thiolato , the N imine and N pyridyl surrounding the chiral-atmetal ruthenium center and an OPr i group attached to the imine carbon. The insertion of an alkoxy group on the carbon atom reduces the imine function and introduces chirality on the ligand, thus generating a second chiral center and potentially diastereoisomeric complexes. However, steric hindrance on the ligand forces the formation of only one pair of enantiomers.

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The series of complexes: cis-[Pd(PMSA)2X2], cis-[Pt(PMSA)2X2], trans-[Pt(PMSA)2I2] and [Pt(PMSA)4]Cl2 (PMSA = N-3-pyridinylmethanesulfonamide; X = Cl, Br, I), previously synthesized and characterized by us, as well as the free ligand PMSA, were tested for their cytotoxic activity without electroporation - against murine leukemia F4N and human SKW-3 and MDA-MB-231 tumour cell lines - and with electroporation - against the latter two cell lines. The majority of the complexes exhibited cytotoxic effects (IC50 < 100 μmol/l) under the conditions of electroporation. Both cis- and trans-[Pt(PMSA)2I2] had pronounced cytotoxic effects (29 - 61 μmol/l against MDA-MB-231 cells).

Nitro group containing furans such as dantrolene, a muscle relaxant and nitrofurantoin an antibiotic are in clinical use 1 while other derivatives find diverse applications in industry 2-4. Yet other substituted furan-2-carbaldehydes possess a C 2 cabonyl group that may act as a reactive centre for various condensation reactions. Many of the published condensations products are biologically active compounds 5,6 or can be used as intermediates in organic synthesis 7,8. Chalcones, α,β-unsaturated ketones 9-11 display a wide range of pharmaceutical properties, including cytotoxity 12, 13 , antimitotic 14 , antimutagenic 15 antitumor-promoting, antibacterial 16 , antiviral 17 and anti-inflammatory 18 activities. They are also useful in material science fields such as non-linear optics (NLO) 19 , optical limiting 20 , electrochemical sensing 21 , Langmuir films and photo-initiated polymerization 22. Various chalcone derivatives are notable materials for their second harmonic generation (SHG) 23. They are well known intermediates for synthesizing various heterocyclic compounds. Cyclization of chalcones, leading to various heterocycles, such as thiazines, pyrimidines, pyrazoline etc. which have potentials as efficacious antibacterial agents. A survey of literature in the recent past reveals that some pyrazoline derivatives possess antibacterial 24,25 , anti-inflammatory 26,27 and antifungal effects 28. Some 1-aryl-3-[5-(p-nitrophenyl)-2-propen-1-ones were obtained from the corresponding 5-p-nitrophenylfuran-2carbaldehyde are reported and were used for the synthesis of 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines claimed to have antibacterial and antiviral properties 29. We would now like to report

1,2‐Benzothiazine‐3‐carboxamide 1,1‐dioxide derivatives such as meloxicam are known to display numerous pharmacological activities. We prepared a series of 4‐hydroxy‐2‐alkyl‐2H‐benzo[e][1,2]thiazine‐3‐carboxamide 1,1‐dioxide ligands 1a–f and their Ru(η6‐p‐cymene) complexes 2a–f, inspired by synergistic effects observed with other bioactive ligands coordinated to metal centres. The molecular structures of 1a, 2a, and 2b were determined by X‐ray diffraction analyses. The stability of the metal complexes was characterized in DMSO and DMSO/H2O on the basis of 1H NMR spectroscopy and their protein binding capabilities were studied using mass spectrometry. In vitro cytotoxicities of the Ru complexes were determined against human colorectal carcinoma (HCT116), non‐small cell lung carcinoma (NCI‐H460) and cervical carcinoma (SiHa) cell lines. The low levels of biological activity observed for these Ru complexes were put into context by considering their chemical reactivity with proteins. Th...

The ferrocenyl diphenol 1 [1,1‐bis(4‐hydroxyphenyl)‐2‐ferrocenyl‐but‐1‐ene] displays strong cytotoxic effects against a variety of cancer cells. In the present study we have evaluated the immunomodulatory and antiparasitic activities of compound 1 and its protected dipalmitate analogue 2. We have furthermore compared the antiparasitic results of 1 and 2 with the organic analogue, 3 [1,1‐bis(4‐hydroxyphenyl)‐2‐phenyl‐but‐1‐ene], where the ferrocenyl group has been replaced by a phenyl ring. When assayed against normal (noncancerous) splenocytes, all compounds were considered nontoxic. Compound 1 inhibited NO production by macrophages, inhibited concanavalin A‐induced lymphoproliferation, and was active against Leishmania amazonensis and Trypanosoma cruzi. Compound 2 had lower activity in all assays performed. Surprisingly, compounds 1 and 2 exhibited similar and significant activity against Plasmodium falciparum, with IC50 values of 3.50 and 1.33 µM, respectively. Compound 3 showed a...

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Eight new phenylisoxazole isoniazid derivatives, 3-(2′-fluorophenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (1), 3-(2′-methoxyphenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (2), 3-(2′-chlorophenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (3), 3-(3′-clorophenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (4), 3-(4′-bromophenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (5), 5-(4′-methoxiphenyl)isoxazole-3-carbaldehyde isonicotinylhydrazone (6), 5-(4′-methylphenyl)isoxazole-3-carbaldehyde isonicotinylhydrazone (7), and 5-(4′-clorophenyl)isoxazole-3-carbaldehyde isonicotinylhydrazone (8), have been synthesized and characterized by FT-IR, 1H-NMR, 13C-NMR, and mass spectral data. The 2D NMR (1H-1H NOESY) analysis of 1 and 2 confirmed that these compounds in acetone-d6 are in the trans(E) isomeric form. This evidence is supported by computational calculations which were performed for compounds 1–8, using DFT/B3LYP level with the 6-311++G(d,p) basis set. The in v...

For the first time, two organometallic triphenylethylene compounds (Fc-diOH and DFO), with strong antiproliferative activity in breast cancer cells, but insoluble in biological fluids, were incorporated in two types of stealth nanoparticles (NP): PEG/PLA nanospheres (NS) and nanocapsules (NC). Their physicochemical parameters were measured (size, zeta potential, encapsulation and loading efficiency), and their biological activity was assessed. In vitro drug release after high dilution of loaded NPs was measured by estradiol binding competition in MELN cells. The influence of the encapsulated drugs on the cell cycle and apoptosis was studied by flow cytometry analyses. Notwithstanding potential drug adsorption at the NP surface, Fc-diOH and DFO were incorporated efficiently in NC and NS, which slowly released both compounds. They arrested the cell cycle in the S-phase and induced apoptosis, whose activity is increased by loaded NS. A decrease in their antiproliferative activity by th...

1,2‐Benzothiazine‐3‐carboxamide 1,1‐dioxide derivatives such as meloxicam are known to display numerous pharmacological activities. We prepared a series of 4‐hydroxy‐2‐alkyl‐2H‐benzo[e][1,2]thiazine‐3‐carboxamide 1,1‐dioxide ligands 1a–f and their Ru(η6‐p‐cymene) complexes 2a–f, inspired by synergistic effects observed with other bioactive ligands coordinated to metal centres. The molecular structures of 1a, 2a, and 2b were determined by X‐ray diffraction analyses. The stability of the metal complexes was characterized in DMSO and DMSO/H2O on the basis of 1H NMR spectroscopy and their protein binding capabilities were studied using mass spectrometry. In vitro cytotoxicities of the Ru complexes were determined against human colorectal carcinoma (HCT116), non‐small cell lung carcinoma (NCI‐H460) and cervical carcinoma (SiHa) cell lines. The low levels of biological activity observed for these Ru complexes were put into context by considering their chemical reactivity with proteins. Th...

Three new ruthenium(II)-arene complexes, namely [(η 6-p-cymene)Ru(Me 2 dppz)Cl]PF 6 (1), [(η 6-benzene)Ru(Me 2 dppz)Cl]PF 6 (2) and [(η 6-p-cymene)Ru(aip)Cl]PF 6 (3) (Me 2 dppz = 11,12-dimethyldipyrido[3,2-a:2',3'-c]phenazine; aip = 2-(9-anthryl)-1H-imidazo[4,5-f][1,10] phenanthroline) have been synthesized and characterized using different spectroscopic techniques including elemental analysis. The complexes were found to be well soluble and stable in DMSO. The biological activity of the three complexes was tested in three different human cancer cell lines (A549, MDA-MB-231 and HeLa) and in one human non-cancerous cell line (MRC-5). Complexes 1 and 3, carrying η 6-p-cymene as the arene ligand, were shown to be toxic in all cell lines in the low micromolar/subnanomolar range, with complex 1 being the most cytotoxic complex of the series. Flow cytometry analysis revealed that complex 1 caused concentration-and time-dependent arrest of the cell cycle in G2-M and S phase in HeLa cells. This event is followed by the accumulation of the sub-G1 DNA content after 48 h, in levels higher than cisplatin and in the absence of phosphatidylserine externalization. Fluorescent microscopy and acridine orange/ethidium bromide staining revealed that complex 1 induced both apoptotic and necrotic cell morphology characteristics. Drug-accumulation and DNA-binding studies performed by inductively coupled plasma mass spectrometry in HeLa cells showed that the total ruthenium uptake increased in a time-and concentration-dependent manner, and that complex 1 accumulated more efficiently than cisplatin at equimolar concentrations. The introduction of a Me 2 dppz ligand into the ruthenium(II)-p-cymene scaffold was found to allow for the discovery of a strongly cytotoxic complex with significantly higher cellular uptake and DNA-binding properties than cisplatin.

A series of 9-(2-(1-arylethylidene)hydrazinyl)acridine and its analogs were designed, synthesized and evaluated for biological activities. Various biochemical assays were performed to determine the free radical scavenging capacity of synthesized compounds (4a-4j). Anticancer activity of these compounds was assessed against two different human cancer cell lines viz cervical cancer cells (HeLa) and liver cancer cells (HepG2) as well as normal human embryonic kidney cell line (HEK 293). Compounds 4b, 4d and 4e showed potential anti-proliferative effects on HeLa cells. Based on results obtained from antioxidant and cytotoxicity studies, 4b, 4d and 4e were further studied in detail for different biological activities. 4b, 4d and 4e reduced the cell growth, inhibited metastatic activity and declined the potential of cell migration in HeLa cell lines. Topoisomerase1 (Top1) treated with compounds 4b, 4d and 4e exhibited inhibition of Top1 and prevented DNA replication. Molecular docking results validate that interaction of compounds 4b, 4d and 4e with Top1-DNA complex, which might be accountable for their inhibitory effects. Further it was concluded that compounds 4b, 4d and 4e arrests the cells at S phase and consequently induces cell death through DNA damage in HeLa cells.

Objective: Current therapies to treat P. falciparum malaria are heavily reliant on artemisinin-based combinations. However, resistance to artemisinin has recently been identified, and resistance to key artemisinin partner drugs is already widespread. Therefore, there is an urgent need for new antimalarial drugs with improved attributes over older therapies. The objective of this research work is to synthesize new antimalarial agents more effective against clinically relevant malarial strains. Methods: In present work, a series of ten 3-phenyl-2-thioxothiazolidin-4-one (MF1-MF10) derivatives, were synthesized by Knoevenagel condensation of N-phenyl rhodanine (I1) with substituted aromatic or hetro aromatic aldehydes using microwave irradiation. N-phenyl rhodanine (I1) was synthesized by a conventional reaction involving methyl-2-mercaptoacetate (1) and phenyl Isothiocyanates in presence of triethylamine. All the synthesized compounds were characterized by various spectroscopic techniques and evaluated for in-vitro antimalarial activity by microdilution technique against resistance strains of Plasmodium falciparum. Results: The antimalarial activity data showed that six compounds (MF1, MF3, MF4, MF5, MF7 and MF8) exhibited IC50 values ranging from 1.0-1.30 µg/ml, three compounds (MF2, MF6 and MF10) displayed IC50 values in the range of 0.9-1.0 µg/ml. Compound MF9 showed most significant result with maximum activity (IC50 = 0.85µg/ml). Conclusion: The antimalarial activity results revealed that compound MF9 possess potent activity and could be identified as a promising lead for further investigation.

A phosphorescent cage of the form [Pd4Ru8]24+ is reported. The cage was formed using the metalloligand [Ru(dtbubpy)2(qpy)]2+, where qpy = 4,4':2',2'':4'',4'''-quaterpyridine and dtbubpy = 4,4'-di-tert-butyl-2,2'-bipyridine. The cage has been characterised by NMR, ESI-MS, TEM and X-ray diffraction analyses and its emission properties elucidated by steady-state and time-resolved emission spectroscopy.

Substitution reactions of square-planar [CuCl 2 (en)] and square-pyramidal [CuCl 2 (terpy)] complexes (where en= 1,2-diaminoethane and terpy= 2,2':6',2''terpyridine) with bio-relevant nucleophiles have been investigated at pH 7.4 in the presence of 0.010 M NaCl. Mechanism of substitution was probed via mole-ratio, kinetic, mass spectroscopy and EPR studies. In the presence of an excess of chloride, the octahedral complex anion [CuCl 4 (en)] 2forms rapidly while equilibrium reaction was observed for [CuCl 2 (terpy)]. Different order of reactivity of selected bio-molecules toward Cu(II) complexes was observed. The nature of the buffer just affects the Cu(II) complexes conformational dynamics. According to EPR data L-Methionine forms a most stable complex with [CuCl 2 (en)] among the bio-ligands considered while [CuCl 2 (terpy)] complex is very stable and there are no significant changes in its square-pyramidal geometry in the presence of buffer or bio-ligands. The obtained results represent progress in investigation of the mechanism of substitution reactions between Cu(II) complexes and biological relevant nuclepohiles. Also, they provide very useful information for the future design of potential copper-based anticancer drugs (Selimović, E., et al.