Physico-Chemical Characterization of a Highly Rigid Gd(III) Complex Formed with a Phenanthroline Derivative Ligand.

The discovery of the nephrogenic systemic fibrosis (NSF) and its link with the in vivo dissociation of certain Gd(III)-based contrast agents (CAs) applied in the magnetic resonance imaging (MRI) induced a still growing research to replace the compromised agents with safer alternatives. In recent years, several ligands were designed to exploit the luminescence properties of the lanthanides, containing structurally constrained aromatic moieties, which may form rigid Gd(III) complexes. One of these ligands is (1,10-phenanthroline-2,9-diyl)bis(methyliminodiacetic acid) (H4FENTA) designed and synthesized to sensitize Eu(III) and Tb(III) luminescence. Our results show that the conditional stability of the [Gd(FENTA)]- chelate calculated for physiological pH (pGd = 19.7) is similar to those determined for [Gd(DTPA)]2- (pGd = 19.4) and [Gd(DOTA)]- (pGd = 20.1), routinely used in the clinical practice. The [Gd(FENTA)]- complex is remarkably inert with respect to its dissociation (t1/2 = 872 days at pH = 7 and 25 °C); furthermore, its relaxivity values determined at different field strengths and temperatures (e.g., r1p = 4.3 mM-1s-1at 60 MHz and 37 °C) are ca. one unit higher than those of [Gd(DTPA)]2- (r1p = 3.4 mM-1 s-1) and [Gd(DOTA)]- (r1p = 3.1 mM-1 s-1) under the same conditions. Moreover, significant improvement on the relaxivity was observed in the presence of serum proteins (r1p = 6.9 mM-1 s-1 at 60 MHz and 37 °C). The luminescence lifetimes recorded in H2O and D2O solutions indicate the presence of a water molecule (q = 1) in the inner sphere of the complex directly coordinated to the metal ion, possessing a relatively high water exchange rate (kex298 = 29(2) × 106 s-1). The acceleration of the water exchange can be explained by the steric compression around the water binding site due to the rigid structure of the complex, which was supported by DFT calculations. On the basis of these results, ligands containing a phenanthroline platform have great potential in the design of safer Gd(III) agents for MRI.

Copper(II) Complexes of Sulfonated Salan Ligands: Thermodynamic and Spectroscopic Features and Applications for Catalysis of the Henry Reaction.

Copper(II) complexes formed with sulfonated salan ligands (HSS) have been synthesized, and their coordination chemistry has been characterized using pH-potentiometry and spectroscopic methods [UV-vis, electron paramagnetic resonance (EPR), and electron-electron double resonance (ELDOR)-detected NMR (EDNMR)] in aqueous solution. Several bridging moieties between the two salicylamine functions were introduced, e.g., ethyl (HSS), propyl (PrHSS), butyl (BuHSS), cyclohexyl (cis-CyHSS, trans-CyHSS), and diphenyl (dPhHSS). All of the investigated ligands feature excellent copper(II) binding ability via the formation of a (O-,N,N,O-) chelate system. The results indicated that the cyclohexyl moiety significantly enhances the stability of the copper(II) complexes. EPR studies revealed that the arrangement of the coordinated donor atoms is more symmetrical around the copper(II) center and similar for HSS, BuHSS, CyHSS, and dPhHSS, respectively, and a higher rhombicity of the g tensor was detected for PrHSS. The copper(II) complexes of the sulfosalan ligands were isolated in solid form also and showed moderate catalytic activity in the Henry (nitroaldol) reaction of aldehydes and nitromethane. The best yield for nitroaldol production was obtained for copper(II) complexes of PrHSS and BuHSS, although their metal binding ability is moderate compared to that of the cyclohexyl counterparts. However, these complexes possess larger spin density on the nitrogen nuclei than that for the other cases, which alters their catalytic activity.

Palladium (II)-Salan Complexes as Catalysts for Suzuki-Miyaura C-C Cross-Coupling in Water and Air. Effect of the Various Bridging Units within the Diamine Moieties on the Catalytic Performance.

Water-soluble salan ligands were synthesized by hydrogenation and subsequent sulfonation of salens (N,N'-bis(slicylidene)ethylenediamine and analogues) with various bridging units (linkers) connecting the nitrogen atoms. Pd (II) complexes were obtained in reactions of sulfosalans and [PdCl4]2-. Characterization of the ligands and complexes included extensive X-ray diffraction studies, too. The Pd (II) complexes proved highly active catalysts of the Suzuki-Miyaura reaction of aryl halides and arylboronic acid derivatives at 80 °C in water and air. A comparative study of the Pd (II)-sulfosalan catalysts showed that the catalytic activity largely increased with increasing linker length and with increasing steric congestion around the N donor atoms of the ligands; the highest specific activity was 40,000 (mol substrate) (mol catalyst × h)-1. The substrate scope was explored with the use of the two most active catalysts, containing 1,4-butylene and 1,2-diphenylethylene linkers, respectively.

Organic Solvent-Free, Pd(II)-Salan Complex-Catalyzed Synthesis of Biaryls via Suzuki-Miyaura Cross-Coupling in Water and Air.

With use of a Pd(II)-sulfosalan complex as a water-soluble catalyst, we have developed an efficient synthesis of biaryls via Suzuki-Miyaura cross-coupling in water under aerobic conditions. The water-insoluble target molecules were isolated by simple filtration in analytical purity after washing with 0.01 M aqueous HCl (20 examples). In most cases, palladium contamination was below 5 ppm considered acceptable for active pharmaceutical ingredients. The established method is scalable, reproducible, and provides biaryl products in isolated yields up to 91%.

Diagnosis of Melanoma with 61Cu-Labeled PET Tracer.

Until the recent years, substances containing radioactive 61Cu were strongly considered as potential positron-emitting radiopharmaceuticals for use in positron emission tomography (PET) applications; however, due to their suitably long half-life, and generator-independent and cost-effective production, they seem to be economically viable for human imaging. Since malignant melanoma (MM) is a major public health problem, its early diagnosis is a crucial contributor to long-term survival, which can be achieved using radiolabeled α-melanocyte-stimulating hormone analog NAPamide derivatives. Here, we report on the physicochemical features of a new CB-15aneN5-based Cu(II) complex ([Cu(KFTGdiac)]-) and the ex vivo and in vivo characterization of its NAPamide conjugate. The rigid chelate possesses prompt complex formation and suitable inertness (t1/2 = 18.4 min in 5.0 M HCl at 50 °C), as well as excellent features in the diagnosis of B16-F10 melanoma tumors (T/M(SUVs) (in vivo): 12.7, %ID/g: 6.6 ± 0.3, T/M (ex vivo): 22).

Bipyridil-based chelators for Gd(III) complexation: kinetic, structural and relaxation properties.

In the last 20 years, research in the field of MRI (magnetic resonance imaging) contrast agents (CAs) has been intensified due to the emergence of a disease called nephrogenic systemic fibrosis (NSF). NSF has been linked to the in vivo dissociation of certain Gd(III)-based compounds applied in MRI as CAs. To prevent the dechelation of the probes after intravenous injection, the improvement of their in vivo stability is highly desired. The inertness of the Gd(III) chelates can be increased through the rigidification of the ligand structure. One of the potential ligands is (2,2',2'',2'''-(([2,2'-bipyridine]-6,6'-diylbis(methylene))bis(azanetriyl))tetraacetic acid) (H4DIPTA), which has been successfully used as a fluorescent probe for lanthanides; however, it has never been considered as a potential chelator for Gd(III) ions. In this paper, we report the thermodynamic, kinetic and structural features of the complex formed between Gd(III) and DIPTA. Since the solubility of the [Gd(DIPTA)]- chelate is very low under acidic conditions, hampering its thermodynamic characterization, we can only assume that its stability is close to that determined for the structural analogue [Gd(FENTA)]- (H4FENTA: (1,10-phenanthroline-2,9-diyl)bis(methyliminodiacetic acid)), which is similar to that determined for the agent [Gd(DTPA)]2- routinely used in clinical practice. Unfortunately, the inertness of [Gd(DIPTA)]- is significantly lower (t1/2 = 1.34 h) than that observed for [Gd(EGTA)]- and [Gd(DTPA)]2- as a result of its spontaneous dissociation pathway during dechelation. The relaxivity values of [Gd(DIPTA)]- are comparable with those of [Gd(FENTA)]- and somewhat higher than the values characterizing [Gd(DTPA)]2-. Luminescence lifetime measurements indicate the presence of one water molecule (q = 1) in the inner sphere of the complex with a relatively high water exchange rate (k298ex = 43(5) × 106 s-1). DFT calculations suggest a rigid distorted tricapped trigonal prismatic polyhedron for the Gd(III) complex. On the basis of these results, we can conclude that the bipyridine backbone is not favourable with respect to the inertness of the chelate.

61Cu-Labelled radiodiagnostics of melanoma with NAPamide-targeted radiopharmaceutical.

Malignant melanoma is a major public health problem with an increasing incidence and mortality in the Caucasian population due to its significant metastatic potential. The early detection of this cancer type by imaging techniques like positron emission tomography acts as an important contributor to the long-term survival. Based on literature data, the radio labelled alpha-MSH analog NAPamide molecule is an appropriate diagnostic tool for the detection of melanoma tumors. Inspired by these facts, a new radiotracer, the [61Cu]Cu-KFTG-NAPamide has been synthesized to exploit the beneficial features of the positron emitter 61Cu and the melanoma specificity of the NAPamide molecule. In this work, we report a new member of the CB-15aneN5 ligand family (KFTG) as the chelator for 61Cu(II) complexation. On the basis of the thorough physico-chemical characterization, the rigid [Cu(KFTG)]+ complex exhibits fast complex formation (t1/2 = 155 s at pH 5.0 and 25 °C) and high inertness (t1/2 = 2.0 h in 5.0 M HCl at 50 °C) as well as moderate superoxide dismutase activity (IC50 = 2.3 µM). Furthermore, the [61Cu]Cu-KFTG-NAPamide possesses outstanding features in the diagnostics of B16-F10 melanoma tumors by PET imaging: (T/M(SUVs) (in vivo): appr. 14, %ID/g: 7 ± 1 and T/M (ex vivo): 315 ± 24 at 180 min).

Coordination chemistry and catalytic applications of Pd(II)-, and Ni(II)-sulfosalan complexes in aqueous media.

With the aim of identifying new types of water-soluble catalyst precursors for modification of biological membranes by homogeneous hydrogenation in aqueous solution and under mild conditions, we have performed detailed equilibrium and spectroscopic characterization of complex formation between nickel(II) or palladium(II) and salan-type ligands sulfonated in their aromatic rings (N,N'-bis(2-hydroxy-5-sulfonatobenzyl)-1,4-diaminoethane (HSS), N,N'-bis(2-hydroxy-5-sulfonatobenzyl)-1,4-diaminopropane (PrHSS) and N,N'-bis(2-hydroxy-5-sulfonatobenzyl)-1,4-diaminobutane (BuHSS)) in the slightly acidic-alkaline pH range. The stability constants of the metal complexes were determined using pH-potentiometry. The catalytic activities of the [Ni(HSS)] and [Pd(HSS)] complexes in hydrogenation and redox isomerization of oct-1-en-3-ol were also studied. The results indicate, that all of the investigated ligands exhibit excellent nickel(II) and palladium(II) binding ability via the formation of (O-,N,N,O-) linked chelate system. Both [Ni(HSS)] and [Pd(HSS)] catalyze the hydrogenation and redox isomerization of oct-1-en-3-ol. [Pd(HSS)] shows excellent activity and the reaction was highly selective to the formation of octan-3-ol. [Ni(HSS)] is also an active and selective catalyst for this hydrogenation reaction and to the best of our knowledge, [Ni(HSS)] is the first nickel(II)-based, hydrolytically stable, water-soluble catalyst bearing sulfonated salan moiety.