Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress

BSIH ((E)-N′-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) is a prodrug version of the metal chelator SIH ((E)-N′-(2-hydroxybenzylidene)isonicotinohydrazide) in which a boronate group prevents metal chelation until reaction with hydrogen peroxide releases SIH, which is then available for sequestering iron(III) and inhibiting iron-catalyzed oxidative damage. While BSIH has shown promise for conditionally targeting iron sequestration in cells under oxidative stress, the yield of SIH is limited by the fact that BSIH exists in cell culture media as an equilibrium mixture with its hydrolysis products isoniazid and 2-formylphenyl boronic acid. In the current study, several BSIH analogs were evaluated for their hydrolytic stability, reaction outcomes with H₂O₂, and prochelator-to-chelator conversion efficiency. Notably, the para-methoxy derivative (p-OMe)BSIH ((E)-N′-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) and the meta-, para-double substituted (MD)BSIH ((E)-N′-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d][1,3]dioxol-5-yl)methylene)isonicotinohydrazide) showed 1.3- and 1.9-fold improved hydrolytic stability compared to BSIH, respectively, leading to a 22 and 50% increase in chelator released. Moreover, both prochelators were found to protect retinal pigment epithelial cells stressed with either H₂O₂ or paraquat insult.     

The hydrolytic susceptibility of prochelator BSIH in aqueous solutions

The prochelator BSIH ((E)-N′-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) contains a boronate group that prevents metal coordination until reaction with peroxide releases the iron chelator SIH ((E)-N′-(2-hydroxybenzylidene)isonicotinohydrazide). BSIH exists in aqueous buffer and cell culture media in equilibrium with its hydrolysis products isoniazid and (2-formylphenyl)boronic acid (FBA). The relative concentrations of these species limit the yield of intact SIH available for targeted iron chelation. While the hydrolysis fragments are nontoxic to retinal pigment epithelial cells, these results suggest that modifications to BSIH that improve its hydrolytic stability yet maintain its low inherent cytotoxicity are desirable for creating more efficient prochelators for protection against cellular oxidative damage.     

Prochelator BHAPI protects cells against paraquat-induced damage by ROS-triggered iron chelation

A prochelator named BHAPI (N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide) based on the structure of experimental metal chelator HAPI (N'-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide) has been synthesized. The prochelator, which shows limited affinity for metal ions, is converted efficiently upon reaction with hydrogen peroxide into its chelator form, which binds di- and trivalent metal ions, including Zn(2+), Cu(2+) and Fe(3+). This work shows that the prochelator has a protective effect on cells under oxidative stress induced by either hydrogen peroxide or the cytotoxic herbicide paraquat. The effect of BHAPI and HAPI on cellular iron status was assessed by monitoring the mRNA level of the transferrin receptor. Whereas the chelator HAPI induces iron deficiency in cultured retinal pigment epithelial cells, the prochelator does not, providing evidence that the differential metal-binding capacity of these compounds observed in vitro is replicated in the cellular context.     

Novel Iron Complexes Behave Like Superoxide Dismutase In Vivo

Novel iron and copper complexes having tris[N-(5-methyl-2-pyridylmethyl)-2-aminoethyl]amine (5MeT-PAA), tris[N-(3-methyl-2-pyridylmethyl)-2-aminoethyl]amine(3MeTPAA),rris[N-(5-methoxycarbonyl-2-pyridylmethyl)-2-aminoethyl]amine (TNAA), tris[(2-thienylmethyI)-2-aminoethyl]amine (TTAA), tris[(2-furylniethyl)-2-aminoethyl]amine (TFAA) or tris[(2-imidazolyl)-2-aminoethyl]amine (TIAA) as ligand. were synthesized to examine the superoxide dismutase (SOD) activity. The concentrations of Fe-3MeTPAA and Fe-TIAA equivalent to 1 unit of SOD (IC₅₀) were 0.5 μM and I.O μM. respectively. Fe-3MeTPAA and Fe-TIAA had higher SOD activity than other Fe and Cu complexes and protected Escherichiu coli cells from paraquat toxicity. In case of using tris[N-(Cmethyl-2-pyridylrnethyl)-2-aminoethyl]amine (6MeTPAA) as ligand, the Fe complex could not be obtained, which may be due to the steric hindrance of Cmethyl substituent. Generally, Cu complexes had low SOD activity, compared with Fe complexes, and could not suppress paraquat toxicity.     

Sensitive detection of acetylcholine based on a novel boronate intramolecular charge transfer fluorescence probe

A highly sensitive and selective fluorescence method for the detection of acetylcholine (ACh) based on enzyme-generated hydrogen peroxide (H₂O₂) and a new boronate intramolecular charge transfer (ICT) fluorescence probe, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-butyl-1,8-naphthalimide (BN), was developed. This strategy involves the reaction of ACh with acetylcholinesterase (AChE) to produce choline, which is further oxidized by choline oxidase (ChOx) to obtain betaine and H₂O₂. The enzyme-generated H₂O₂ reacts with BN and results in hydrolytic deprotection of BN to generate fluorescent product (4-hydroxyl-N-butyl-1,8-naphthalimide, ON). Two consecutive linear response ranges allow determining ACh in a wide concentration range with a low detection limit of 2.7 nM (signal/noise = 3). Compared with other fluorescent probes based on the mechanism of nonspecific oxidation, this reported boronate probe has the advantage of no interference from other biologically relevant reactive oxygen species (ROS) on the detection of ACh. This study provides a new method for the detection of ACh with high selectivity and sensitivity.     

Iron prochelator BSIH protects retinal pigment epithelial cells against cell death induced by hydrogen peroxide

Dysregulation of localized iron homeostasis is implicated in several degenerative diseases, including Parkinson’s, Alzheimer’s, and age-related macular degeneration, wherein iron-mediated oxidative stress is hypothesized to contribute to cell death. Inhibiting toxic iron without altering normal metal-dependent processes presents significant challenges for standard small molecule chelating agents. We previously introduced BSIH (isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide) prochelators that are converted by hydrogen peroxide into SIH (salicylaldehyde isonicotinoyl hydrazone) chelating agents that inhibit iron-catalyzed hydroxyl radical generation. Here, we show that BSIH protects a cultured cell model for retinal pigment epithelium against cell death induced by hydrogen peroxide. BSIH is more stable than SIH in cell culture medium and is more protective during long-term experiments. Repetitive exposure of cells to BSIH is nontoxic, whereas SIH and desferrioxamine induce cell death after repeated exposure. Combined, our results indicate that cell protection by BSIH involves iron sequestration that occurs only when the cells are stressed by hydrogen peroxide. These findings suggest that prochelators discriminate toxic iron from healthy iron and are promising candidates for neuro- and retinal protection.     

Carbonic anhydrase inhibitors: Crystallographic and solution binding studies for the interaction of a boron-containing aromatic sulfamide with mammalian isoforms I–XV

We investigated the inhibition of carbonic anhydrase (CA, EC 4.2.1.1) isoforms I–XV with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfamide and other simple or sugar sulfamides, a class of less investigated CA inhibitors (CAIs). The crystal structure of the adduct of hCA II with the boron-substituted sulfamide shows the organic scaffold of this compound bound in the hydrophilic half of the active site where it makes a large number of van der Waals contacts with Ile91, Gln92, Val121, Phe131, Leu198, and Thr200. The data here reported provide further insights into sulfamide binding mechanism confirming that this zinc-binding group could be usefully exploited for obtaining new potent and selective CAIs.     

Synthesis and photoluminescence properties of asymmetrical europium(III) complexes involving carbazole, phenanthroline and bathophenanthroline units

Three novel europium complexes, Eu(CCHPD)₃Phen = Tris[1-(9H-carbazol-9-yl)-3-[(6-(9H- carbazol-9-yl)hexoxy)-phenyl]-1,3-dione](1,10-phenanthroline) europium(III), Eu(CCHPD)₃Bath = Tris[1-(9H-carbazol-9-yl)-3-[(6-(9H-carbazol-9-yl)hexoxy)-phenyl]-1,3-dione](bathophenanthroline) europium(III) and Eu(CPD)₃Phen = Tris[1-(9H-carbazol-9-yl)-3-phenylpropane]-1,3-dione](1,10-phenanthroline) europium(III), have been synthesized and characterized (Scheme 1). Involved ligands consist of different chelating and non-chelating units: appended carbazole (Br-Carb), phenanthroline (Phen), bathophenanthroline (Bath) and 1-(9H-carbazol-9-yl)-3-phenylpropane]-1,3-dione (CPD). The luminescence properties show that the carbazole moiety is a better sensitizer for the metal centred (MC) emitting states relative to Phen and Bath. Moreover, its charge-transporting properties make such complexes appealing for their application in electroluminescent devices.     

Boronated phosphonium salts containing arylboronic acid, closo-carborane, or nido-carborane: synthesis, X-ray diffraction, in vitro cytotoxicity, and cellular uptake

The preparation of boronated triaryl and tetraaryl phosphonium salts of the type [PPh₃CH₂R]Br [R is 4-boronophenyl (1), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (2), 3-boronophenyl (3), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (4), 2-boronophenyl (5), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (6), and closo-1,2-carboran-1-yl (7)] is described. These compounds were prepared by the reaction of triphenylphosphine with benzylic bromides or 1-bromomethyl-closo-1,2-carborane in acetonitrile solution at 85 °C. The zwitterionic nido-7,8-carborane derivative PPh₃CH₂C₂B₉H₁₁ (8) was prepared by treatment of 7 with cesium fluoride in refluxing ethanol. All compounds were fully characterized by multinuclear (¹H, ¹¹B, ¹³C, and ³¹P) 1D- and 2D-NMR spectroscopy, electrospray ionization mass spectrometry, and elemental analysis, and single-crystal X-ray structures were determined for compounds 1, 3, 7, and 8. The cytotoxicities and boron uptake of selected derivatives were investigated in vitro using human glioblastoma (T98G) and canine kidney tubule (MDCK II) cells. The zwitterionic species 8 was found to be the least cytotoxic agent while also delivering the greatest amount of boron to the T98G cells, peaking at 9.15 ± 2.65 μg B/mg protein.     

Study on nucleic acid (CT-DNA and yeast tRNA) binding behaviors and cytotoxic properties of a heterodinuclear Ru(II)-Co(III) polypyridyl complex

A heterodinuclear (Ru(II), Co(III)) metal polypyridyl complex [(phen)₂Ru(bpibH₂)Co(phen)₂]⁵⁺ {phen = 1,10-phenanthroline, bpibH₂ = 1,4-bis([1,10]phebanthroline-[5,6-d]imidazol-2-yl)-benzene} has been designed and synthesized. The comparative study on the interactions of the Ru(II)-Co(III) complex with calf thymus DNA (CT-DNA) and yeast tRNA has been investigated by UV-visible spectroscopy, fluorescence spectroscopy, viscosity, as well as equilibrium dialysis and circular dichroism (CD). The antitumor activities of the complex have been evaluated by MTT {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide} method and Giemsa staining experiment. These results indicate that the structures of nucleic acids have significant effects on the binding behaviors of metal complexes. Furthermore, the complex demonstrates different antitumor activity against selected tumor cell lines in vitro, and can make the cell apoptosis.     

Nickel(II) and copper(II) complexes of Schiff base ligands containing N4O2 and N4S2 donors with pyrrole terminal binding groups: Synthesis, characterization, X-ray structures, DFT and electrochemical studies

A series of hexadentate ligands, H₂L^m (m = 1−4), [1H-pyrrol-2-ylmethylene]{2-[2-(2-{[1H-pyrrol-2-ylmethylene]amino}phenoxy)ethoxy]phenyl}amine (H₂L¹), [1H-pyrrol-2-ylmethylene]{2-[4-(2-{[1H-pyrrol-2-ylmethylene]amino}phenoxy)butoxy]phenyl}amine (H₂L²), [1H-pyrrol-2-ylmethylene][2-({2-[(2-{[1H-pyrrol-2-ylmethylene]amino}phenyl)thio]ethyl}thio)phenyl]amine (H₂L³) and [1H-pyrrol-2-ylmethylene][2-({4-[(2-{[1H-pyrrol-2-lmethylene]amino}phenyl)thio]butyl}thio) phenyl]amine (H₂L⁴) were prepared by condensation reaction of pyrrol-2-carboxaldehyde with {2-[2-(2-aminophenoxy)ethoxy]phenyl}amine, {2-[4-(2-aminophenoxy)butoxy]phenyl}amine, [2-({2-[(2-aminophenyl)thio]ethyl}thio)phenyl]amine and [2-({4-[(2-aminophenyl)thio]butyl}thio)phenyl]amine respectively. Reaction of these ligands with nickel(II) and copper(II) acetate gave complexes of the form ML^m (m = 1−4), and the synthesized ligands and their complexes have been characterized by a variety of physico-chemical techniques. The solid and solution states investigations show that the complexes are neutral. The molecular structures of NiL³ and CuL², which have been determined by single crystal X-ray diffraction, indicate that the NiL³ complex has a distorted octahedral coordination environment around the metal while the CuL² complex has a seesaw coordination geometry. DFT calculations were used to analyse the electronic structure and simulation of the electronic absorption spectrum of the CuL² complex using TDDFT gives results that are consistent with the measured spectroscopic behavior of the complex. Cyclic voltammetry indicates that all copper complexes are electrochemically inactive but the nickel complexes with softer thioethers are more easily oxidized than their oxygen analogs.     

Impact of histidine residue on chelating ability of 2'-deoxyriboadenosine

Copper(II) complexes with a new chelator-type nucleoside-histidine modified 2′-deoxyriboadenosine (N-[(9-β-D-2′-deoxyribofuranosylpurin-6-yl)-carbamoyl]histidine) were studied by potentiometric and spectroscopic (UV-visible, CD, EPR) techniques, in conjunction with computer modeling optimization. The ligand can act as bidentate or tridentate depending on pH range. In acidic pH a very stable dimeric complex Cu₂L₂ predominates with coordination spheres of both metal ions composed of oxygen atoms from carboxylic groups, one oxygen atom from ureido group and two nitrogen atoms derived from purine base and histidine ring. Above pH 5, deprotonation of carbamoyl nitrogens leads to the formation of CuL₂, Cu₂L₂H_− 1 and Cu₂L₂H_− 2 species. The CuL₂H_− 1 and CuL₂H_− 2 complexes with three or four nitrogens in Cu(II) coordination sphere have been detected in alkaline medium.Our findings suggest that N-[(9-beta-D-2′-deoxyribofuranosylpurin-6-yl)-carbamoyl]histidine chelates copper(II) ions very efficiently. The resulting complex might be used as an alternative base-pairing mode in which hydrogen-bonded base pairs present in natural DNA are replaced by metal-mediated ones.     

Cyclic metal-radical complexes based on 2-[4-(1-imidazole)phenyl]-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide: Syntheses, crystal structures and magnetic properties

Using new nitronyl nitroxide radical ligand 2-[4-(1-imidazole)phenyl]-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (NITPhIm), three new complexes [M(hfac)₂(NITPhIm)]₂ (M = Cu(II) 1, Mn(II) 2, Co(II) 3; hfac = hexafluoroacetylacetonate) have been prepared. Three complexes possess cyclic dimer structure in which each NITPhIm radical links two different metal ions through the oxygen of nitroxide group and the nitrogen of imidazole. The magnetic studies show the copper(II) ion interacts ferromagnetically with the directly bonding nitronyl nitroxide while manganese(II) and cobalt(II) ions strong antiferromagnetically interact with the directly coordinated nitroxide groups. There is a weak antiferromagnetic coupling between the metal ion and the nitroxide through phenyl and imidazole rings of the radical ligand, which is agreement with spin polarization mechanism. The results show that the minor changes in the structure of radical ligand can change the magnetic behavior of radical-metal complex.     

Stoichiometry-focused (18)F-labeling of alkyne-substituted oligodeoxynucleotides using azido([(18)F]fluoromethyl)benzenes by Cu-catalyzed Huisgen reaction

A novel method for ¹⁸F-radiolabeling of oligodeoxynucleotides (ODNs) by a Cu-catalyzed Huisgen reaction has been developed by using the lowest possible amount of the precursor biomolecule for the realization of stoichiometry-oriented PET (positron emission tomography) chemistry. Under the optimized cyclization conditions of p- or m-azido([¹⁸F]fluoromethyl)benzene and alkyne-substituted ODN (20 nmol) at 40 °C for 15 min in the presence of CuSO₄, TBTA [tris((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine], and sodium ascorbate (2:1:2), the synthesis of ¹⁸F-labeled ODNs with sufficiently high radioactivities of 2.1-2.5 GBq and specific radioactivities of 1800-2400 GBq/??mol have been accomplished for use in animal and human PET studies.     

Syntheses, structures, and magnetic properties of three Fe(II) complexes with reduced radical ligands

Three new Fe(II) complexes [Fe(HIM2py)₂(SCN)₂] (1), [Fe(HIM2py)₂(H₂O)₂](ClO₄)₂ · 2H₂O (2), and [Fe(HIM2py)₂(4,4-bipy)](ClO₄)₂ · 3CH₃CH₂OH (3) (4,4-bipy = 4,4′-bipyridine, HIM2py = 1-hydroxyl-2(2′-pyridyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole) have been synthesized and characterized structurally as well as magnetically. The X-ray analysis reveals that HIM2py ligands are coordinated to the metal ions as an unusual six-membered didentate chelate with the κ²N(py), O(HIM) mode. Fe(II) ions in complex 3 are bridged by 4,4-bipy, leading to a 1D chain structure. The magnetic behavior of complex 3 is investigated, showing weak antiferromagnetic interactions.     

Synthesis, characterization and X-ray crystal structure of [Re(L4)(CO)3]Br · 2CH3OH (L4 = N,N-bis[(2-diphenylphosphino)ethyl]methoxyethylamine): A model compound for novel cationic Tc(I)-tricarbonyl radiotracers useful for heart imaging

This report describes synthesis and evaluation of cationic complexes, [^99mTc(CO)₃(L)]⁺ (L = N-methoxyethyl-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (L1), N-[(15-crown-5)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (L2) and N-[(18-crown-6)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (L3)) as potential radiotracers for heart imaging. Preliminary results from biodistribution studies in female adult BALB-c mice indicated that the cationic ^99mTc(I)-tricarbonyl complex, [^99mTc(CO)₃(L2)]⁺, has a significant localization in the heart at 60 min post-injection. To understand the coordination chemistry of these bisphosphine ligands with the ^99mTc(I)-tricarbonyl core, we prepared [Re(CO)₃(L4)]Br (L4: N,N-bis[(2-diphenylphosphino)ethyl]methoxyethylamine) as a model compound. [Re(CO)₃(L4)]Br has been characterized by elemental analysis, IR, ESI-MS, NMR (¹H, ¹³C, ¹H-¹H COSY, and ¹H-¹³C HMQC) methods, and X-ray crystallography. In solid state, [Re(CO)₃(L4)]⁺ has a distorted octahedron coordination geometry with PNP occupying one facial plane. The chelator backbone adopts a “chair” conformation with phosphine-P atoms at equatorial positions and the amine-N at the apical site. In solution, [Re(CO)₃(L4)]⁺ is able to maintain its cationic nature with no dissociation of carbonyl ligands or any of the three PNP donors.     

Synthesis and characterization of cobalt(II)-salicylate complexes derived from N4-donor ligands: Stabilization of a hexameric water cluster in the lattice host of a cobalt(III)-salicylate complex

The syntheses and structural characterization of four cobalt(II)-salicylate complexes, [(TPA)Co^II(HSA)](ClO₄) (1), [(isoBPMEN)Co^II(HSA)](BPh₄) (2), [(TPzA)Co^II(HSA)](ClO₄) (3) and [(6Me₃TPA)Co^II(HSA)](BPh₄) (4) [TPA = tris(2-pyridylmethyl)amine, isoBPMEN = N¹,N¹-dimethyl-N²,N²-bis(2-pyridylmethyl)ethane-1,2-diamine, TPzA = tris((3,5-dimethyl-1H-pyrazole-1-yl)methyl)amine and 6Me₃TPA = tris(6-methyl-2-pyridylmethyl)amine] are described. While 2, 3 and 4 are unreactive towards dioxygen, 1 reacts slowly with molecular oxygen to a cobalt(III)-salicylate complex, [(TPA)Co^III(SA)](ClO₄) (1a). Two different crystalline forms, 1a and 1a·4H₂O were isolated depending upon the condition of oxidation and crystallization. The solid-state structures of cobalt(III)-salicylate unit in both 1a and 1a·4H₂O show a six-coordinate distorted octahedral coordination geometry at the cobalt(III) center ligated by the tetradentate ligand (TPA) where the dianionic salicylate (SA) binds in a bidentate fashion through one carboxylate and one phenolate oxygen. The hydrated form 1a·4H₂O reveals a hexameric water cluster formation in the inorganic lattice host. The complex cation and the perchlorate counterion are involved in stabilizing the (H₂O)₆ cluster in a rare ‘pentamer planar+1’ conformation. A one-dimensional water tape consisting of edge-shared water hexamers is observed. The water tape represents a subunit of ice structure.     

Tris(trimethylsilyl)stannyl alkali derivatives: Syntheses and NMR spectroscopic properties

Starting from tetrakis(trimethylsilyl)stannane, the tris(trimethylsilyl)stannyl alkali derivatives (Me₃Si)₃SnM, (M = Li, Na, K, Rb, Cs) were prepared in excellent yields. Reaction with MgBr₂ · Et₂O afforded bis[tris(trimethylsilyl)stannyl]magnesium. Reaction products were investigated by means of multinuclear NMR spectroscopy. At low temperatures, coupling of ⁷Li and ¹¹⁹Sn between [(Me₃Si)₃Sn]⁻ and [Li · 3THF]⁺ (337 Hz) or [Li · 12Cr4]⁺ (275 Hz), was observed. NMR chemical shifts and coupling constants of the stannyl anions exhibit a strong dependency on the nature of the cation, solvent system, concentration and temperature. In addition, the molecular structure of tris(trimethylsilyl)stannyl sodium · 15Cr5 was determined by X-ray crystallography. The [Na · 15Cr5]⁺ and [(Me₃Si)₃Sn]⁻ units are joined by a direct Sn-Na contact, 3.0775(18) Å in length.     

Synthesis, anticancer activities, interaction with DNA and mitochondria of manganese complexes

Two new complexes [(Etdpa)MnCl₂] and [(Adpa)Mn(Cl)(H₂O)] (Etdpa = ethyl bis(2-pyridylmethyl)amino-2-propionate; Adpa = bis(2-pyridylmethyl)amino-2-propionic acid) were synthesized and characterized by spectral methods. The crystal structure of [(Etdpa)MnCl₂] shows that the Mn(II) atom is coordinated by three N atoms (N1, N2, N3), one oxygen atom (O1) of the ligand (Etdpa) and two chloride atoms (Cl1, Cl2), forming a distorted octahedral geometry. The binding interaction between ct-DNA and the synthesized complexes was relatively weak, but they can inhibit the induced swelling of Ca²⁺-loaded mitochondria in a dose-dependent manner. The [(Adpa)Mn(Cl)(H₂O)] can cause the obvious decrease of mitochondria membrane potential. The MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenpyltetra-zolium bromide) assay shows that the two Mn(II) complexes are more active against cancer cells. Especially [(Adpa)Mn(Cl)(H₂O)] can inhibit the proliferation of glioma cells with IC₅₀ 9.5 μM. Experimental results indicate that the [(Adpa)Mn(Cl)(H₂O)] could be a new potential antitumor complex to target the mitochondria.     

First-row transition metal complexes of a novel pentadentate amine/imine ligand containing a hexahydropyrimidine core

2-Methyl-2-(pyridin-2-yl)propane-1,3-diamine and formaldehyde are condensed to prepare the hexahydropyrimidine derivative, which is subsequently reacted with two equivalents of 2-vinylpyridine, to produce a novel, potentially pentadentate amine/imine ligand. Full NMR spectroscopic details are reported. The ligand, hexahydro-5-methyl-5-(pyridin-2-yl)-1,3-bis[2-(pyridin-2-yl)ethyl]pyrimidine, acts as a pentadentate in a series of first-row transition metal complexes (M = Ni²⁺, Fe²⁺, Zn²⁺, Cu²⁺) but is tridentate towards Mn²⁺, in the corresponding dibromido complex. Single-crystal X-ray structure analyses reveal the metal ions to be hexacoordinate in the case of M = Ni²⁺, Fe²⁺, with and additional aqua or halido (Br⁻, Cl⁻) ligand, or pentacoordinate (M = Zn²⁺, Cu²⁺, Mn²⁺). Ferric complexes were not obtained, neither from complexation experiments employing iron(III), nor from oxidations using the iron(II) complex, and hydrogen peroxide or iodosylbenzene. In the case of the latter reactions, mass spectrometric data indicate oxidation of the hexahydropyrimidine core, with concomitant decomplexation of the ligand.