Bispidine Complexes Research Articles

64Cu tumor labeling with hexadentate picolinic acid-based bispidine immunoconjugates.

Discussed are two picolinate appended bispidine ligands (3,7-diazabicyclo[3.3.1]nonane derivatives) in comparison with an earlier described bis-pyridine derivative, which are all known to strongly bind CuII. The radiopharmacological characterization of the two isomeric bispidine complexes includes quantitative labeling with 64CuII at ambient conditions with high radiochemical purities and yields (molar activities >200 MBq/nmol). Challenge experiments in presence of EDTA, cyclam, human serum and SOD demonstrate high stability and inertness of the 64Cu-bispidine complexes. Biodistribution studies performed in Wistar rats indicate a rapid renal elimination for both 64Cu-labeled chelates. The bispidine ligand with the picolinate group in N7 position was selected for further biological experiments, and its backbone was therefore substituted with a benzyl-NCS group at C9. Two tumor target modules (TMs), targeting prostate stem cell antigen (PSCA), overexpressed in prostate cancer, and the fibroblast activation protein (FAP) in fibrosarcoma, were selected for thiourea coupling with the NCS-functionalized ligand and lysine residues of TMs. Small animal PET experiments on tumor-bearing mice showed specific accumulation of the 64Cu-labeled TMs in PSCA- and FAP-overexpressing tumors (standardized uptake value (SUV) for PC3: 2.7±0.6 and HT1080: 7.2±1.25) with almost no uptake in wild type tumors.

Oxidation of Cobalt(II) Bispidine Complexes with Dioxygen

Bispidine (3,7-diazabicyclo[3.3.1]nonane) ligands, derivatives of diazaadamantane, possess a very rigid backbone and have a high degree of pre-organization for cis-octahedral coordination geometries. Despite their rigidity, they exert a flexible coordination sphere, resulting in stable complexes with a variety of metal ions in various oxidation states. Due to the known high III/II redox potentials of their cobalt complexes, the CoII bispidine complexes are generally resistant to oxidation by dioxygen. Discussed in the present study are various CoII bispidine complexes with tetra- and pentadentate bispidines, with one of these complexes shown to be unstable under aerobic conditions. The decay process has been identified as an oxidative elimination of the 2-methylene pyridine substituent at one of the tertiary amine donors, resulting in picolinate, which is found coordinated to a CoIII product, where the dealkylated N-donor remains unprotonated. The mechanism of this interesting reaction has been studied, and details of the resulting structure of the product complex are discussed.

Copper-Bispidine Complexes: Synthesis and Complex Stability Study.

A new series of dicarboxylic derivatives of bispidines have been synthesized to develop novel copper(II) complexes suitable as imaging agents for positron emission tomography. For characterization purposes, copper complexes of bispidines were synthesized in the pure form and in quantitative yields by neutralization of ligands with malachite. The formation of complexes and their stoichiometries were studied by potentiometric titration, cyclic voltammetry, and spectroscopic methods. The stability constants were found to be fairly suitable for copper cation fixation inside dianionic chelate molecules.

Bispidin-9,9-diol Analogues of Cisplatin, Carboplatin, and Oxaliplatin: Synthesis, Structures, and Cytotoxicity

3,7-Diallyl-bispidin-9-one (6) (bispidin-9-one = 3,7-diazabicyclo[3.3.1]nonan-9-one) is converted to N-unsubstituted spiro[bispidin-9,2'-[1,3]dioxolane] (12; 35%). The ketal crystallizes in the forms of anhydrous 12a and the dihydrate 12b. The molecules in anhydrous 12a are linked to each other, forming N1-H1···N2-H2···N1* hydrogen-bond chiral helices of alternating chirality. In the dihydrate 12b, the ketal molecules are connected to a central string of water molecules by O3-H···O1 and O4-H···N1 hydrogen bonds, but not to themselves. Reaction of 12 with (1,5-hexadiene)PtCl2 affords almost quantitatively spiro[bispidin-9,2'-[1,3]dioxolane]PtCl2 (13). Cleavage of the ketal to retrieve the ketone produces the geminal diol (bispidin-9,9-diol)PtCl2 (14; 85%). Compound 14 reacts with Ag2cbdca (cbdca = 1,1-cyclobutanedicarboxylate) to give the dihydrate (bispidin-9,9-diol)Pt(cbdca)·2H2O (15b), which can be dehydrated to obtain anhydrous (bispidin-9,9-diol)Pt(cbdca) (15a). Similarly, anhydrous (bispidin-9,9-diol)Pt(oxalate) (16) is obtained. Crystal structures of 14 and 15b reveal association by various forms of O-H···O, O-H···Cl, N-H···Cl, and N-H···O hydrogen bonds. Biological studies showed a moderate cytotoxic activity of the bispidin-9,9-diol complexes 14-16, compared to the 9,9-unsubstituted bispidine complexes. No unspecific cytotoxicity of 14-16 up to 316 μM was found against the noncancer cell line HEK293.

Catalytic oxidation of alkanes by iron bispidine complexes and dioxygen: oxygen activation versus autoxidation

Organic substrates (specifically cis-1,2-dimethylcyclohexane, DMCH) are oxidized by O2 in the presence of iron(II)-bispidine complexes. It is shown that this oxidation reaction is not based on O2 activation by the nonheme iron catalysts as in Nature but due to a radical-based initiation, followed by a radical- and ferryl-based catalytic reaction.

Tuning of the Properties of Transition-Metal Bispidine Complexes by Variation of the Basicity of the Aromatic Donor Groups

Bispidines (3,7-diazabicyclo[3.3.1]nonanes) as very rigid and highly preorganized ligands find broad application in the field of coordination chemistry, and the redox potentials of their transition-metal complexes are of importance in oxidation reactions by high-valent iron complexes, aziridination catalyzed by copper complexes, and imaging by (64)Cu positron emission tomography tracers. Here, we show that the redox potentials and stability constants of the copper(II) complexes of 15 tetradentate bispidines can be varied by substitution of the pyridine rings (variation of the redox potential over ca. 450 mV and of the complex stability over approximately 10 log units). It is also shown that these variations are predictable by the pKa values of the pyridine groups as well as by the Hammett parameters of the substituents, and the density functional theory based energy decomposition analysis also allows one to accurately predict the redox potentials and concomitant complex stability. It is shown that the main contribution emerges from the electrostatic interaction energy, and the partial charges of the pyridine donor groups therefore also correlate with the redox potentials.

Zero-Field Splitting in a Series of Structurally Related Mononuclear NiII–Bispidine Complexes

The synthesis, single-crystal X-ray structures, electronic absorption spectra, and magnetic properties of six Ni(II) complexes with a tetradentate (L(1)) and three pentadentate (L(2), L(3), L(4)) bispidine ligands (3,7-diazabicyclo[3.3.1]nonane derivatives), Ni(L(1)·H2O)(OH2)2](PF6)2, [Ni(L(1)·H2O)(O2NO)]NO3, [Ni(L(1)·H2O)(OOCCH3)]PF6, [Ni(L(2)·H2O)NCMe](PF6)2, [Ni(L(3)·H2O)OH2](PF6)2, and [Ni(L(4)·H2O)NCMe](PF6)2 are reported. The Ni-donor bonding to pyridine and tertiary amine groups and oxygen- or nitrogen-bound coligands, completing the octahedral coordination sphere of Ni(II), is analyzed using a combination of ab initio electronic structure calculations (complete active space self-consistent field, CASSCF, followed by N-electron valence perturbation theory, NEVPT2) and angular overlap ligand field analysis. Magnetic properties are rationalized with an analysis of the magnetic anisotropy in terms of zero-field splitting and g-tensor parameters, obtained from first principles, and their correlation with the Ni(II)-donor bonding parameters from the ligand field analysis of the ab initio results. A two-dimensional spectrochemical series of the ligands considered, according to their σ and π bonding to Ni(II), is also derived.

Structure, Bonding, and Catecholase Mechanism of Copper Bispidine Complexes

Oxygen activation by copper(I) complexes with tetra- or pentadentate mono- or dinucleating bispidine ligands is known to lead to unusually stable end-on-[{(bispidine)Cu}(2)(O(2))](2+) complexes (bispidines are methyl-2,4-bis(2-pyridin-yl)-3,7-diazabicyclo-[3.3.1]-nonane-9-diol-1,5-dicarboxylates); catecholase activity of these dinuclear Cu(II/I) systems has been demonstrated experimentally, and the mechanism has been thoroughly analyzed. The present density functional theory (DFT) based study provides an analysis of the electronic structure and catalytic activity of [{(bispidine)Cu}(2)(O(2))](2+). As a result of the unique square pyramidal coordination geometry, the d(x(2)-y(2)) ground state leads to an unusual σ/π bonding pattern, responsible for the stability of the peroxo complex and the observed catecholase activity with a unique mechanistic pathway. The oxidation of catechol to ortho-quinone (one molecule per catalytic cycle and concomitant formation of one equivalent of H(2)O(2)) is shown to occur via an associative, stepwise pathway. The unusual stability of the end-on-peroxo-dicopper(II) complex and isomerization to copper(II) complexes with chelating catecholate ligands, which inhibit the catalytic cycle, are shown to be responsible for an only moderate catalytic activity.

Optimization of the Efficiency of Oxidation Catalysts Based on Iron Bispidine Complexes

AbstractHigh‐valent bispidine iron‐oxo complexes are among the most efficient nonheme iron oxidation catalysts. Here, we report the synthesis and structural analysis of two derivatives of the known pentadentate bispidine ligand L1 {L1 = 2,4‐pyridyl‐7‐(pyridine‐2‐ylmethyl)‐3,7‐diazabicyclo[3.3.1]nonane}: L2 and L3 {L2 = 2,4‐pyridyl‐7‐[1‐(pyridine‐2‐yl)ethyl]‐3,7‐diazabicyclo[3.3.1]nonane; L3 = 2,4‐pyridyl‐7‐[phenyl(pyridine‐2‐yl)methyl]‐3,7‐diazabicyclo[3.3.1]nonane}, and of their FeII complexes. The yield of the catalytic epoxidation of cyclooctene and styrene with iodosylbenzene as oxidant increases from the L1‐ to the L2‐ to the L3‐based catalyst (e.g., the yield of styrene oxide, with MeCN as solvent, under anaerobic conditions, is 40 %, 90 %, 96 %, respectively), and this is correlated to the FeIII/II reduction potentials {[Fe(L1)(NCMe)]n+ (1.01 V), [Fe(L2)(NCMe)]n+ (1.13 V), and [Fe(L3)(NCMe)]n+ (1.19 V), in MeCN, vs. SCE}. Although this correlation is not unexpected, the interpretation is not entirely trivial, and this is discussed in detail. The rigidity of the bispidine ligands and their preference for relatively large metal ions (low oxidation states, high spin multiplicities) is believed to be responsible for the efficiency of the bispidine‐based catalyst systems, and the present results show possible approaches to further improve the performance of these catalysts.

Structures, spectroscopy and modeling of a rare set of isomeric copper(II) complexes

The structures and spectroscopic properties of various conformations of two diasteromeric pairs of enantiomers of pentacoordinate CuII bispidine complexes with chiral tetradentate ligands are reported. With one of the ligands an interesting type of distortional isomerism was observed experimentally, and this was studied in detail on the basis of the experimental structural and spectroscopic data (UV–Vis–NIR, EPR) and a DFT-, MM- and ligand-field-theory-based analysis.

A combined experimental and computational study on the sulfoxidation by high-valent iron bispidine complexes

Iron-bispidine complexes are efficient catalysts for the oxidation of thioanisole to phenylmethylsulfoxide with iodosylbenzene as oxidant. With the tetradentate bispidine ligand L(1) (L(1) = 2,4-pyridyl-3,7-diazabicyclo[3.3.1]nonane)) the catalytic efficiency is smaller than with the pentadentate bispidine ligand L(2) (L(2) = 2,4-pyridyl-7-(pyridine-2-ylmethyl)-3,7-diazabicyclo[3.3.1]nonane)). Based on the redox potentials (iron complexes with L(1) are stronger oxidants than with L(2)) and known efficiencies in catalytic olefin oxidation and C-H activation reactions, the expectations were different. A DFT-based analysis is used to explain the apparent contradiction, and this is based on differences in the electronic ground states of the ferryl complexes as well as in the oxygen transfer transition states.

Oxidation of Cyclohexane by High-Valent Iron Bispidine Complexes: Tetradentate versus Pentadentate Ligands

The iron-bispidine-catalyzed oxidation of cyclohexane with H(2)O(2), where either a tetradentate or a pentadentate bispidine ligand is coordinated to the iron center, yields up to 35% cyclohexanol and cyclohexanone (alcohol/ketone ratio of up to 4). Product distribution (including (18)O labeling studies), kinetic isotope effects, and the ratio of tertiary/secondary alcohols with adamantane as a substrate (tertiary/secondary) suggest that (i) H abstraction by a ferryl complex is the rate-determining step and that the emerging cyclohexyl radical is short-lived, (ii) there is a parallel reaction involving oxidation by OH radicals, and (iii) there are considerable differences in the reaction pathways between the tetradentate and pentadentate ligand catalyst. These interpretations are fully supported by a DFT-based computational analysis.

Hexadentate Bispidine Derivatives as Versatile Bifunctional Chelate Agents for Copper(II) Radioisotopes

The preparation and use of bispidine derivatives (3,7-diazabicyclo[3.3.1]nonane) as chelate ligands for radioactive copper isotopes for diagnosis (64Cu) or therapy (67Cu) are reported. Starting from the hexadentate bispidine-based bis(amine)tetrakis(pyridine) ligand 1 with a keto and two ester substituents, the corresponding mono-ol 2 and two dicarboxylic acid derivatives 3 and 5 have been synthesized. A range of techniques, including single-crystal X-ray structure analysis, UV/vis spectroscopy, cyclic voltammetry, thin-layer- (TLC), and high-performance liquid chromatography (HPLC), have been used to characterize the structure and stability of the copper(II)-bispidine complexes. A rapid formation (within 1 min) of stable copper(II)-bispidine complexes under mild conditions (ambient temperature, aqueous solution) has been observed. Challenge experiments of these complexes in the presence of a high excess of competing ligands, such as glutathione, cyclam, or superoxide dismutase (SOD), as well as in rat plasma, gave no evidence of demetalation or transchelation. The bifunctional bispidine derivative 5 can be readily functionalized with biologically active molecules at the pendant carboxylate groups. The coupling of a bombesin analogue betahomo-Glu-betaAla-betaAla-[Cha(13),Nle(14)]BBN(7-14), by condensation of a carboxylate of the bispidine backbone with the N-terminus of the peptide produced the bifunctional ligand 6. The radiocopper(II) complex of this bombesin-bispidine conjugate has a considerable hydrophilicity (log D(o/w) < -2.4), and this leads to a very fast blood clearance (blood: 0.28 +/- 0.02 SUV, 1 h p.i.), low liver tissue accumulation (liver: 1.20 +/- 0.27 SUV, 1 h p.i.), and rapid renal-urinary excretion (kidneys: 6.06 +/- 2.96 SUV, 1 h p.i.) as shown by biodistribution studies of 64Cu-6 in Wistar rats. Preliminary in vivo studies of 64Cu-6 in NMRI nu/nu mice, bearing the human prostate tumor PC-3 showed an accumulation of the conjugate in the tumor (2.25 +/- 0.13 SUV, 12.5 min p.i.; 0.94 +/- 0.05 SUV, 55 min p.i.) and allowed a clear visualization of the gastrin-releasing peptide receptor distribution by positron emission tomography (PET).

Catecholase activity of dicopper(II)-bispidine complexes: stabilities and structures of intermediates, kinetics and reaction mechanism

A mechanism for the oxidation of 3,5-di-tert-butylcatechol (dtbc) with dioxygen to the corresponding quinone (dtbq), catalyzed by bispidine-dicopper complexes (bispidines are various mono- and dinucleating derivatives of 3,7-diazabicyclo[3.3.1]nonane with bis-tertiary-amine-bispyridyl or bis-tertiary-amine-trispyridyl donor sets), is proposed on the basis of (1) the stoichiometry of the reaction as well as the stabilities and structures [X-ray, density functional theory (B3LYP, TZV)] of the bispidine-dicopper(II)-3,4,5,6-tetrachlorcatechol intermediates, (2) formation kinetics and structures (molecular mechanics, MOMEC) of the end-on peroxo-dicopper(II) complexes and (3) kinetics of the stoichiometric (anaerobic) and catalytic (aerobic) copper-complex-assisted oxidation of dtbc. This involves (1) the oxidation of the dicopper(I) complexes with dioxygen to the corresponding end-on peroxo-dicopper(II) complexes, (2) coordination of dtbc as a bridging ligand upon liberation of H(2)O(2) and (3) intramolecular electron transfer to produce dtbq, which is liberated, and the dicopper(I) catalyst. Although the bispidine complexes have reactivities comparable to those of recently published catalysts with macrocyclic ligands, which seem to reproduce the enzyme-catalyzed process in various reaction sequences, a strikingly different oxidation mechanism is derived from the bispidine-dicopper-catalyzed reaction.

DFT models for copper(II) bispidine complexes: Structures, stabilities, isomerism, spin distribution, and spectroscopy

Various DFT and ab initio methods, including B3LYP, HF, SORCI, and LF-density functional theory (DFT), are used to compute the structures, relative stabilities, spin density distributions, and spectroscopic properties (electronic and EPR) of the two possible isomers of the copper(II) complexes with derivatives of a rigid tetradentate bispidine ligand with two pyridine and two tertiary amine donors, and a chloride ion. The description of the bonding (covalency of the copper-ligand interactions) and the distribution of the unpaired electron strongly depend on the DFT functional used, specifically on the nonlocal DF correlation and the HF exchange. Various methods may be used to optimize the DFT method. Unfortunately, it appears that there is no general method for the accurate computation of copper(II) complexes, and the choice of method depends on the type of ligands and the structural type of the chromophore. Also, it appears that the choice of method strongly depends on the problem to be solved. LF-DFT and spectroscopically oriented CI methods (SORCI), provided a large enough reference space is chosen, yield accurate spectroscopic parameters; EDA may lead to a good understanding of relative stabilities; accurate spin density distributions are obtained by modification of the nuclear charge on copper; solvation models are needed for the accurate prediction of isomer distributions.