Biodistribution and photodynamic efficacy of a water-soluble, stable, halogenated bacteriochlorin against melanoma

The in vitro phototoxicity of a photostable, synthetic, water‐soluble, halogenated bacteriochlorin, 5,10,15,20‐tetrakis(2‐chloro‐5‐sulfophenyl)bacteriochlorin (TCPBSO₃H), toward mouse melanoma (S91) cells is ～60‐fold higher than that of the analogous porphyrin, and is associated with very weak toxicity in the dark; 90 % of S91 cells were killed in response to a light dose of 0.26 J cm^?2 in the presence of [TCPBSO₃H]=5 μM . In vivo toxicity toward DBA mice is very low, even at doses of 20 mg kg^?1. In vivo pharmacokinetics and biodistribution of TCPBSO₃H were studied in DBA mice with S91 tumors; 24 h after intraperitoneal injection of 10 mg kg^?1, TCPBSO₃H demonstrated preferential accumulation in S91 mouse melanoma, with tumor‐to‐normal tissue ratios of 3 and 5 for muscle and skin, respectively. Photodynamic therapy (PDT) performed under these conditions, with 90 mW cm^?2 diode laser irradiation at λ 750 nm for 20 min (total light dose of 108 J cm^?2), resulted in tumor regression. Tumor recurrence was observed only approximately two months after treatment, confirming the efficacy of this PDT against melanoma.     

2,3-Dihydro-1H-cyclopenta[b]quinoline Derivatives as Acetylcholinesterase Inhibitors-Synthesis, Radiolabeling and Biodistribution

In the present study we describe the synthesis and biological assessment of new tacrine analogs in the course of inhibition of acetylcholinesterase. The obtained molecules were synthesized in a condensation reaction between activated 6-BOC-hydrazinopyridine-3-carboxylic acid and 8-aminoalkyl derivatives of 2,3-dihydro-1H-cyclopenta[b]quinoline. Activities of the newly synthesized compounds were estimated by means of Ellman's method. Compound 6h (IC(50) = 3.65 nM) was found to be most active. All obtained novel compounds present comparable activity to that of tacrine towards acetylcholinesterase (AChE) and, simultaneously, lower activity towards butyrylcholinesterase (BChE). Apart from 6a, all synthesized compounds are characterized by a higher affinity for AChE and a lower affinity for BChE in comparison with tacrine. Among all obtained molecules, compound 6h presented the highest selectivity towards inhibition of acetylcholinesterase. Molecular modeling showed that all compounds demonstrated a similar binding mode with AChE and interacted with catalytic and peripheral sites of AChE. Also, a biodistribution study of compound 6a radiolabeled with (99m)Tc was performed.     

Alkyne Metatheses in Transition Metal Coordination Spheres: Convenient Tungsten‐ and Molybdenum‐Catalyzed Syntheses of Novel Metallamacrocycles

Reactions of (CO)₅Re(Br), (η⁵‐C₅H₅)Ru(Cl)(PPh₃)₂, and [Pt(μ‐Cl)(C₆F₅)(S(CH₂CH₂‐)₂)]₂ with the alkyne‐containing phosphine Ph₂P(CH₂)₆C≡CCH₃ give the bis(phosphine) complexes fac‐(CO)₃Re(Br)(Ph₂P(CH₂)₆C≡CCH₃)₂ ( 5 ), (η⁵‐C₅H₅)Ru(Cl)(Ph₂P(CH₂)₆C≡CCH₃)₂ ( 6 ), and trans‐(Cl)(C₆F₅)Pt(Ph₂P(CH₂)₆C≡CCH₃)₂ ( 7 ). Alkyne metatheses with the catalyst (t‐BuO)₃W(≡C‐t‐Bu) (10–15 mol %, chlorobenzene, 80 °C) give the seventeen‐membered metallamacrocycles fac‐(CO)₃Re(Br)(Ph₂P(CH₂)₆CC(CH₂)₆P Ph₂) ( 8 ), (η⁵‐C₅H₅)Ru(Cl)(Ph₂P(CH₂)₆CC(CH₂)₆P Ph₂) ( 9 ), and trans‐(Cl)(C₆F₅)Pt(PPh₂(CH₂)₆CC(CH₂)₆P Ph₂) ( 10 ). ³¹P NMR analyses show 90–75% conversions to 8 – 10 (59–47% isolated after chromatography). The identity of 8 was confirmed by a crystal structure, and 10 was hydrogenated over Pd/C to fac‐(CO)₃Re(Br)(Ph₂P(CH₂)₆CC(CH₂)₆P Ph₂) ( 12 , 87%), which was crystallographically characterized earlier. A catalyst derived from Mo(CO)₆/4‐chlorophenol effects a slower conversion of 7 to 10 at 140 °C. In the case of 5 , a mer, trans isomer of 8 is isolated ( 11 , 44%), as established by NMR and IR data. In 10 – 12 , the diphosphines span trans positions. These results, together with previous examples involving group VIII metallocenes, establish the wide viability of the title reaction.     

3D Ln–Ag (Ln = Nd; Eu) coordination polymers based on N- and O-donor ligands: Synthesis, crystal structures and luminescence

The self-assembly of isonicotinic acid with metal salts under hydrothermal conditions gave two isostructural 3D 4d–4f coordination polymers, Ln₂Ag₄(OX)(IN)₆(H₂O)_1.5 · 2(ClO₄) [Ln = Nd (1); Eu (2), OX = oxalic acid, IN = isonicotinic acid]. Compounds 1 and 2 are 3D coordination frameworks via 2D layers built by carboxylate groups of isonicotinic acid and oxalate ligands coordinating to metal centers and completing the linear linker by silver ions. Furthermore, the luminescent properties of complex 2 have also been investigated.     

3D Ln–Ag (Ln = Nd; Eu) coordination polymers based on isonicotinate and oxalate ligands: Synthesis, crystal structures and luminescence

The self-assembly of isonicotinic acid with metal salts under hydrothermal conditions obtained two new 4d–4f coordination polymers, LnAg(OX)(IN)₂·H₂O (Ln = Nd (1); Eu (2), OX = oxalic acid, IN = isonicotinic acid). The 3D isostructural complexes 1 and 2 are constructed by the assembly of 2D layers, which are built by carboxylate groups of isonicotinic acid and oxalate ligands coordinating to metal centers, with 1D linear linkers completed by silver ions. Furthermore, the luminescent property of complex 2 was investigated.     

DNA-lipid complexes carrying azobenzene moieties: Preparation, characterization, and photoisomerization

Novel DNA-lipid complexes carrying azobenzene moieties were prepared by substituting sodium counter cations with cationic amphiphilic lipids, namely lipid(AZO) and lipid(diAZO), in which the actual molar ratios of phosphate to lipid were 1:1.05 and 1:1.02, respectively. DNA-lipid(AZO) and DNA-lipid(diAZO) complexes were soluble in common organic solvents including CHCl₃, CH₂Cl₂, methanol, and ethanol, while insoluble in THF, toluene, and water. CD spectroscopy revealed that DNA-lipid(AZO) and DNA-lipid(diAZO) complexes took a predominantly double helical structure in methanol and CHCl₃ and that the helical structure was fairly stable against heating. The trans-azobenzene of the DNA-lipid complexes in the side chain isomerized into cis upon UV irradiation, while the helical conformation of DNA backbone hardly changed. The cis-azobenzene moiety reisomerized into trans upon visible-light irradiation, but they did not recover completely the original geometry of azobenzene moieties in the side chain. Both DNA-lipid(AZO) and DNA-lipid(diAZO) exhibited lyotropic LC properties. The onset temperatures of weight loss of DNA-lipid(AZO) and DNA-lipid(diAZO) were both 226 °C according to TGA in air.     

Synthesis, Spectral and Antibacterial Studies of Copper(II) Tetraaza Macrocyclic Complexes

A novel family of tetraaza macrocyclic Cu(II) complexes [CuLX(2)] (where L = N(4) donor macrocyclic ligands) and (X = Cl(-), NO(3) (-)) have been synthesized and characterized by elemental analysis, magnetic moments, IR, EPR, mass, electronic spectra and thermal studies. The magnetic moments and electronic spectral studies suggest square planar geometry for [Cu(DBACDT)]Cl(2) and [Cu(DBACDT)](NO(3))(2) complexes and distorted octahedral geometry to the rest of the ten complexes. The biological activity of all these complexes against gram-positive and gram-negative bacteria was compared with the activity of existing commercial antibacterial compounds like Linezolid and Cefaclor. Six complexes out of twelve were found to be most potent against both gram-positive as well as gram-negative bacteria due to the presence of thio group in the coordinated ligands.     

Novel NK1R-Targeted 68Ga-/177Lu-Radioconjugates with Potential Application against Glioblastoma Multiforme: Preliminary Exploration of Structure–Activity Relationships

Locoregionally administered, NK1 receptor (NK1R) targeted radionuclide therapy is a promising strategy for the treatment of glioblastoma multiforme. So far, the radiopharmaceuticals used in this approach have been based on the endogenous agonist of NK1R, Substance P or on its close analogues. Herein, we used a well-known, small molecular NK1R antagonist, L732,138, as the basis for the radiopharmaceutical vector. First, 14 analogues of this compound were evaluated to check whether extending the parent structure with linkers of different lengths would not deteriorate the NK1R binding. The tested analogues had affinity similar to or better than the parent compound, and none of the linkers had a negative impact on the binding. Next, five DOTA conjugates were synthesized and used for labelling with ⁶⁸Ga and ¹⁷⁷Lu. The obtained radioconjugates turned out to be fairly lipophilic but showed rather limited stability in human plasma. Evaluation of the receptor affinity of the (radio)conjugates showed that neither the chelator nor the metal negatively impacts the NK1R binding. The ¹⁷⁷Lu-radioconjugates exhibited the binding characteristics towards NK1R similar or better than that of the ¹⁷⁷Lu-labelled derivative of Substance P, which is in current clinical use. The experimental results presented herein, along with their structural rationalization provided by modelling, give insight for the further molecular design of small molecular NK1R-targeting vectors.     

Nanocobaltite: Preparation,Characterization, and their Catalytic Activity

Mixed transition metal oxides (MTMO) nanoparticles of 3rd‐series (NiCo₂O₄, CuCo₂O₄, and ZnCo₂O₄) were prepared by a co‐precipitation method. These were characterized by X‐ray diffraction (XRD) and transmission electron microscopy (TEM). The particle size was found to be in the order of 53.0, 43.4, and 21.2 nm, respectively. The thermolysis of ammonium perchlorate (AP), AP‐HTPB (hydroxyterminated polybutadiene) composite solid propellants (CSPs), and HTPB was found to be catalyzed with MTMOs and the burning rate of CSPs was also enhanced. TG and ignition delay study demonstrated that the higher temperature decomposition (HTD) of AP is catalyzed enormously by these catalysts and CuCo₂O₄ is the best candidate.     

Pillarquinones and Pillararenequinones

Pillar[n]quinones and pillar[n-m]arene[m]quinones are oxidation products of pillar[n]arenes. Their molecular structure resembles the parent compounds. However, their map of electron density is different. Each 1,4-benzoquinone ring, which replaces a 1,4-dialkoxy-substituted benzene ring decreases the electron density in the interior cavity and increases the electron density on the upper and lower rim of the pillar. The electron donor character is stepwise transformed to an electron acceptor status. This effect alters the complexation tendencies, which are the most interesting properties of these macrocyclic host systems.     

[SmNi(pic)3(H2O)5]n(ClO4)2n · 3nH2O, the first Sm–Ni heterometallic complex of picolinic acid ligand showing novel basket weave topology: Synthesis, structure and magnetics

The first basket weave framework topology of Sm–Ni heterometallic complex with picolinic acid as bridging ligand showing two different coordination modes of picolinic acid has been characterized; The studies on temperature-dependent magnetization indicate the title complex follows the Curie–Wiess paramagnetic behavior down to 5 K.     

Cytotoxic Activity and Structure–Activity Relationship of Triazole‐Containing Bis(Aryl Ether) Macrocycles

Cancer continues to be a worldwide health problem. Certain macrocyclic molecules have become attractive therapeutic alternatives for this disease because of their efficacy and, frequently, their novel mechanisms of action. Herein, we report the synthesis of a series of 20‐, 21‐, and 22‐membered macrocycles containing triazole and bis(aryl ether) moieties. The compounds were prepared by a multicomponent approach from readily available commercial substrates. Notably, some of the compounds displayed interesting cytotoxicity against cancer (PC‐3) and breast (MCF‐7) cell lines, especially those bearing an aliphatic or a trifluoromethyl substituent on the N‐phenyl moiety (IC₅₀<13 μm ). Additionally, some of the compounds were able to induce apoptosis relative to the solvent control; in particular, (Z)‐N‐cyclohexyl‐7‐oxo‐6‐[4‐(trifluoromethyl)phenyl]‐1¹H‐3,10‐dioxa‐6‐aza‐1(4,1)‐triazola‐4(1,3),9(1,4)‐dibenzenacyclotridecaphane‐5‐carboxamide ( 12 f ) was the most potent in this regard (22.7 % of apoptosis).     

Electrochemistry of transition metal complex catalysts. Part 9. One- and two-electron oxidation of iridium complexes with cyclohexane-derived tripod phosphine ligands

The redox chemistry of Ir tripod-type tri-phosphine complexes in dichloromethane is investigated by cyclic voltammetry, hold-ramp experiments, and preparative electrolysis at Pt electrodes. Products are identified by spectroscopic data, as well as EDX and EXAFS results. Complexes with the Ir central atom in the oxidation states +I, +II and +III are detected and several follow-up reactions are possible from those. Most of the intermediates and products are characterized. In particular, experiments in the presence of CO contribute to the assignment of peaks in the cyclic voltammograms. The experimental results for the individual steps are summarized in a comprehensive redox reaction mechanism (mesh scheme) for which most steps are characterized by redox potentials.     

Spectroscopic Analyses and Antimicrobial Activity of Novel Ciprofloxacin and 7-Hydroxy-4-methylcoumarin,the Plant-Based Natural Benzopyrone Derivative

Coumarin is highly distributed in nature, notably in higher plants. The biological features of coumarin include antibacterial, anticancer and antioxidant effects. It is well known that metal ions present in complexes accelerate the drug action and the efficacy of organic therapeutic agents. The main aim of the current study is the synthesis of different complexes of the interaction between ciprofloxacin hydrochloride (CIP) and coumarin derivative 7-hydroxy-4-methylcoumarin (HMC) with Zr(IV). The chelates of CIP with Zr(IV) were prepared and characterized by elemental analysis, melting point, conductance measurements, spectroscopic techniques involving IR, UV-Vis, ¹H NMR, and thermal behavior (TG-DTG) in the presence of HMC, dimethylformamide (DMF), pyridine (Py), and triethylamine (Et₃N). Results of molar conductivity tests showed that the new synthesized complexes are electrolytes with a 1:1 or 1:2 electrolyte ratio, with the chloride ions functioning as counter ions. According to IR spectra, CIP acts as a neutral bidentate ligand with Zr(IV) through one carboxylato oxygen and the carbonyl group, HMC as a monodentate through the carbonyl group, and DMF through the oxygen atom of the carbonyl group and the N atom of Py and Et₃N. The thermal behavior of the complexes was carefully investigated using TG and DTG techniques. TG findings signal that water molecules are found as hydrated and coordinated. The thermal decomposition mechanisms proposed for CIP, HMC, and Zr(IV) complexes are discussed and the activation energies (E_a), Gibbs free energies (∆G*), entropies (∆S*), and enthalpies (∆H*) of thermal decomposition reactions have been calculated using Coats–Redfern (CR) and Horowitz–Metzeger (HM) methods. The studied complexes were tested against some human pathogens and phytopathogens, including three Gram-positive bacteria (Bacillus subtilis, B. cereus, Brevibacterium otitidis) and three Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae), and compared to the free CIP and HMC parent compounds.     

Synthesis,Spectroscopy, Single-Crystal Structure Analysis and Antibacterial Activity of Two Novel Complexes of Silver(I) with Miconazole Drug

In a previous article, we reported on the higher toxicity of silver(I) complexes of miconazole [Ag(MCZ)₂NO₃ (1)] and [Ag(MCZ)₂ClO₄ (2)] in HepG2 tumor cells compared to the corresponding salts of silver, miconazole and cisplatin. Here, we present the synthesis of two silver(I) complexes of miconazole containing two new counter ions in the form of Ag(MCZ)₂X (MCZ = 1-[2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole]; X = BF₄⁻ (3), SbF₆⁻ (4)). The novel silver(I) complexes were characterized by elemental analysis, ¹H NMR, ¹³C NMR and infrared (IR) spectroscopy, electrospray ionization (ESI)-MS spectrometry and X-ray-crystallography. In the present study, the antimicrobial activity of all obtained silver(I) complexes of miconazole against six strains of Gram-positive bacteria, five strains of Gram-negative bacteria and yeasts was evaluated. The results were compared with those of a silver sulfadiazine drug, the corresponding silver salts and the free ligand. Silver(I) complexes exhibited significant activity against Gram-positive bacteria, which was much better than that of silver sulfadiazine and silver salts. The highest antimicrobial activity was observed for the complex containing the nitrate counter ion. All Ag(I) complexes of miconazole resulted in much better inhibition of yeast growth than silver sulfadiazine, silver salts and miconazole. Moreover, the synthesized silver(I) complexes showed good or moderate activity against Gram-negative bacteria compared to the free ligand.     

Novel bioactive copper and nickel polymeric complexes: Synthesis,characterization, antimicrobial activity,and DFT calculations

Polymeric complexes, especially metal-containing polymers, possess aggregated medical applications, especially as antibacterial and antifungal agents. This work describes a facile procedure for producing a series of novel copper and nickel complexes of poly(2-hydroxyphenyl methacrylamide) and poly(2-carboxyphenyl methacrylamide). The polymeric ligands were synthesized through a multistep procedure. Firstly, 4-formylphenyl methacrylate was constructed by acylating 4-hydroxybenzaldehyde with methacryloyl chloride. Then, polymerization of the as-prepared monomer to obtain poly(4-formylphenyl methacrylate) using benzoyl peroxide as an initiator. Thirdly, the polymeric ligands PL1 and PL2 were achieved via exchange reactions between poly(4-formylphenyl methacrylate) and o-aminophenol and anthranilic acid, respectively. Consequently, the two ligands were reacted with copper and nickel acetates to afford four target complexes (Cu-PL1, Ni-PL1, Cu-PL2, and Ni-PL2). By FT-IR, ¹HNMR, UV-visible, and TGA analyses, the structures of PL1, PL2, and their complexes were investigated. Furthermore, the geometries of PL1, PL2, and their complexes were reported through a molecular modeling to investigate some interesting parameters such as the bond length, bond angle, charge on the atoms, the HOMO and LUMO using the Material Studio program. The calculation results illustrated that octahedral geometries are proposed for the synthesized metal complexes. The reported antimicrobial efficiency showed a strong potency for most synthesized compounds against the selected microbes, especially compounds Cu-PL1 and Cu-PL2 which are more effective than the standard against Candida albicans.     

Novel sorbents based on silica coated with polyethylenimine and crosslinked with poly(carboxylic acid): Preparation and characterization

Novel sorbents based on silica coated with polyethylenimine (SilPEI) and crosslinked with poly(carboxylic acid) were prepared and characterized. These sorbents are to be used for heavy metal decontamination of aqueous solutions and have to be prepared in easy and ecological ways. A part of the carboxylic moieties [from ethylenediaminetetraacetic acid (EDTA) or citric acid] reacts with some of the amine groups of polyethylenimine, initially coated onto the silica, whereas the other part remains free for further metal complexation. By changing various parameters (temperature, pH, presence or absence of an amide‐forming agent), the conditions to prepare the best sorbent—that is, the sorbent exhibiting both a high capacity for metal complexation and good stability in an acidic medium (conditions for metal desorption or stripping)—were defined. The sorbent was prepared by a reaction of 1 g of SilPEI and 1 g of EDTA in water at 0°C, pH 6, during 10 h, using 0.5 g of 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide hydrochloride as a coupling agent. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 799–805, 2003     

Synthesis and Characterization of N‐Heterocyclic Carbene Substituted Phosphine and Phosphite Rhodium Complexes and their Catalytic Properties in Hydrogenation Reactions

Mixed N‐heterocyclic carbene‐substituted phosphine and phosphite complexes of rhodium were prepared, starting from [Rh(COE)₂Cl]₂ (COE=cyclooctene) by addition of free N‐heterocyclic carbenes (NHC) and PR₃. All new complexes were characterized by spectroscopy. In addition, the structures of trans‐chloro(1,3‐dicyclohexylimidazol‐2‐ylidene)‐bis(triphenylphosphite)rhodium(I) ( 5 ), chloro‐trans‐bis(1,3‐dicyclohexylimidazol‐2‐ylidene) (triphenylphosphine)rhodium(I) ( 6 ), and chloro(η⁴‐1,5‐cyclooctadiene)(1,3‐di‐[(1R,2S,5R)‐2‐isopropyl‐5‐menthylcyclohex‐1‐yl]imidazol‐2‐ylidene)rhodium(I) ( 8 ) were determined by single crystal X‐ray analyses. The hydrogenation of cyclohexene using molecular hydrogen has been optimized for some N‐heterocyclic carbene‐substituted phosphine and phosphite rhodium complexes by variation of the reaction conditions.     

Harmicens,Novel Harmine and Ferrocene Hybrids: Design,Synthesis and Biological Activity

Cancer and malaria are both global health threats. Due to the increase in the resistance to the known drugs, research on new active substances is a priority. Here, we present the design, synthesis, and evaluation of the biological activity of harmicens, hybrids composed of covalently bound harmine/β-carboline and ferrocene scaffolds. Structural diversity was achieved by varying the type and length of the linker between the β-carboline ring and ferrocene, as well as its position on the β-carboline ring. Triazole-type harmicens were prepared using Cu(I)-catalyzed azide-alkyne cycloaddition, while the synthesis of amide-type harmicens was carried out by applying a standard coupling reaction. The results of in vitro biological assays showed that the harmicens exerted moderate antiplasmodial activity against the erythrocytic stage of P. falciparum (IC₅₀ in submicromolar and low micromolar range) and significant and selective antiproliferative activity against the MCF-7 and HCT116 cell lines (IC₅₀ in the single-digit micromolar range, SI > 5.9). Cell localization experiments showed different localizations of nonselective harmicene 36 and HCT116-selective compound 28, which clearly entered the nucleus. A cell cycle analysis revealed that selective harmicene 28 had already induced G1 cell cycle arrest after 24 h, followed by G2/M arrest with a concomitant drastic reduction in the percentage of cells in the S phase, whereas the effect of nonselective compound 36 on the cell cycle was much less pronounced, which agreed with their different localizations within the cell.