Log βML Research Articles

Silver(I) pyrrole- and furan-2-carboxylate complexes – From their design and characterization to antimicrobial, anticancer activity, lipophilicity and SAR

Two silver(I) complexes with biologically relevant heterocyclic ligands, pyrrole and furan-2- carboxylic acid, were synthesized and their composition was confirmed using elemental, spectral, thermal and structural analyses. The {[Ag(Py2c)]}n (AgPy2c, Py2c = pyrrole-2-carboxylate) and {[Ag(Fu2c)]}n (AgFu2c, Fu2c = furan-2-carboxylate) solubility and stability in biological test stock solution were confirmed by 1H NMR spectroscopy. The X-ray analysis has enabled us to determine typical argentophilic interactions and bridging carboxylate coordination mode of both ligands. Potentiometric data analysis by BSTAC program resulted in the determination of the stability constant of only one species, i.e., the ML (M = Ag+, L = Fu2c−), log βML = 0.59 ± 0.04. Antimicrobial and anticancer tests were performed against selected microorganisms and cell lines with new silver(I) complexes and compared with AgSD (silver(I) sulfadiazine) and cisplatin. From their microbial toxicity point of view, selectivity was determined against lactobacilli (AgPy2c is 8× more effective against S. aureus and E. coli and AgFu2c is 8× more effective against E. coli and 4× against S. aureus). AgFu2c significant anticancer activity was determined against Jurkat cell lines (IC50 = 8.00 μM) and was similar to cisPt (IC50 = 6.3 μM) similarly to its selectivity (SI (AgFu2c) = 7.3, SI (cisPt) = 6.4, SI = selectivity index). In addition, cell cycle arrest was observed already in the Sub-G0 phase during a flow cytometry experiment. To evaluate the AgPy2c and AgFu2c bioavailability we also discuss their Lipinski's Rule of Five.

Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for 230U Targeted α-Therapy.

Uranium-230 is an α-emitting radionuclide with favorable properties for use in targeted α-therapy (TAT), a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To successfully implement this radionuclide for TAT, a bifunctional chelator that can stably bind uranium in vivo is required. To address this need, we investigated the acyclic ligands H2dedpa, H2CHXdedpa, H2hox, and H2CHXhox as uranium chelators. The stability constants of these ligands with UO22+ were measured via spectrophotometric titrations, revealing log βML values that are greater than 18 and 26 for the "pa" and "hox" chelators, respectively, signifying that the resulting complexes are exceedingly stable. In addition, the UO22+ complexes were structurally characterized by NMR spectroscopy and X-ray crystallography. Crystallographic studies reveal that all six donor atoms of the four ligands span the equatorial plane of the UO22+ ion, giving rise to coordinatively saturated complexes that exclude solvent molecules. To further understand the enhanced thermodynamic stabilities of the "hox" chelators over the "pa" chelators, density functional theory (DFT) calculations were employed. The use of the quantum theory of atoms in molecules revealed that the extent of covalency between all four ligands and UO22+ was similar. Analysis of the DFT-computed ligand strain energy suggested that this factor was the major driving force for the higher thermodynamic stability of the "hox" ligands. To assess the suitability of these ligands for use with 230U TAT in vivo, their kinetic stabilities were probed by challenging the UO22+ complexes with the bone model hydroxyapatite (HAP) and human plasma. All four complexes were >95% stable in human plasma for 14 days, whereas in the presence of HAP, only the complexes of H2CHXdedpa and H2hox remained >80% intact over the same period. As a final validation of the suitability of these ligands for radiotherapy applications, the in vivo biodistribution of their UO22+ complexes was determined in mice in comparison to unchelated [UO2(NO3)2]. In contrast to [UO2(NO3)2], which displays significant bone uptake, all four ligand complexes do not accumulate in the skeletal system, indicating that they remain stable in vivo. Collectively, these studies suggest that the equatorial-spanning ligands H2dedpa, H2CHXdedpa, H2hox, and H2CHXhox are highly promising candidates for use in 230U TAT.

Highly Efficient Extraction of Trivalent f‐Cations Using Several N‐Pivot Tripodal Diglycolamide Ligands in an Ionic Liquid: The Role of Ligand Structure on Metal Ion Complexation

Complexation of trivalent lanthanides and actinides was studied in a room temperature ionic liquid (RTIL) using five N‐pivot tripodal diglycolamide ligands (LI–LV) having different structural features, viz. spacer lengths and substituents. The nature of the metal/Ligand complex changed with the substitution of N atom near the tripodal platform from ML with LIII and LIV to ML2 with LI, LII and LV (where M = Eu3+/Nd3+/Am3+). With 0.2 mmol/L ligands, the distribution ratio of Am3+ at 1 m HNO3 followed the order: LI (210) > LII (42) > LIII (2.1) > LV (0.7) > LIV (0.2). The formation constants between Nd3+ and the ligands (log βML,ML2) followed an identical order, viz. LI > LII > LIII > LV > LIV. The extraction of Am3+ or Eu3+ with all the ligands followed a cation‐exchange extraction mechanism, which is in sharp contrast to the results obtained in a molecular solvent (n‐dodecane), where a solvation extraction mechanism prevalied. Luminescence studies on the Eu3+ extract in RTIL confimed the absence of water molecules in the inner coordination sphere of the complex. EXAFS studies indicated that all three DGA arms were binding to the Eu3+ cation.

Evaluation of the Tetrakis(3-Hydroxy-4-Pyridinone) Ligand THPN with Zirconium(IV): Thermodynamic Solution Studies, Bifunctionalization, and in Vivo Assessment of Macromolecular 89Zr-THPN-Conjugates.

Zirconium-89 (89Zr) is a suitable radionuclide for positron-emission tomography (PET) of long-circulating targeting vectors such as monoclonal antibodies (mAbs). Due to stability concerns for the most widely used 89Zr-chelating agent desferrioxamine B (DFO) in preclinical studies, alternative 89Zr-chelators are currently being developed. We recently reported on the first tetrakis(3-hydroxy-4-pyridinone) (3,4-HOPO) ligand THPN, which was identified as a promising 89Zr-chelator. In this study, we aimed to further explore this octadentate chelate in vitro and in vivo. The [ZrIV(THPN)] thermodynamic stability was quantified in solution titration studies, which revealed one of the highest formation constants reported for a zirconium chelate (log βML 50.3(1), pM = 42.8). Solution stabilities with iron(III) were also exceptionally high and can compete with some of the strongest FeIII-chelates. A first bifunctional derivative of the octadentate ligand, p-SCN-Bn-THPN, was then produced in a multistep synthesis. To assess and compare the long-term 89Zr complex stability, bifunctional THPN, as well as the literature chelators p-SCN-Phe-DFO and p-SCN-Phe-DFO*, were conjugated to the high-molecular weight (800 kDa) polymeric carrier hyperbranched polyglycerol (HPG). The functionalized HPGs were radiolabeled with 89ZrIV, and the integrity of the radioconjugates was assessed over several days in vitro and in vivo. While all three radioconjugates remained >95% intact over 5 days in human plasma, the in vivo study in healthy mice revealed higher physiologic stability of the DFO and DFO* radiochelates over bifunctional THPN conjugates. This was evidenced by increased bone uptake of osteophilic 89ZrIV for THPN. This finding contrasts with the exceptionally high thermodynamic stability of the chelate and suggests either a kinetic or metabolic lability, or may stem from coordinative changes due to the covalent conjugation of the 89Zr-THPN radiochelate as suggested by density functional theory (DFT) calculations. These important findings inform the design of next generation 3,4-HOPO chelates with the aim of improving the physiologic stability. This study furthermore demonstrates how HPG can be used as a robust carrier tool to assess and compare the long-term in vivo stability of radiochelates.

Gold Plate Electrodes Functionalized by Multiwall Carbon Nanotube Film for Potentiometric Thallium(I) Detection.

Solid-contact potentiometric ion-selective electrodes (SC-ISEs) for thallium determination have been designed using multiwall carbon nanotubes (MWCNTs) as the ion-to-electron transducer. Dispersed MWCNTs were drop-casted over a gold plate electrode. Two different crown ethers were used in the sensing membrane for the recognition of thallium (I). Sensorsbased on dibenzo-18-crown-6 (DB18C6) as a neutral carrier and NaTPB as an anionic additive exhibited a near Nernstian response of 57.3 mV/decade towards Tl+ ions over the activity range 4.5 × 10−6–7.0 × 10−4 M, with a limit of detection of 3.2 × 10−7 M. The time required to achieve 95% of the steadyequilibrium potential was <10 s. The complex formation constant (log βML) between dibenzo-18-crown-6 and thallium (I) (i.e., 5.99) was measured using the sandwich membrane technique. The potential response was pH independent over the range 3.0–9.5. The introduction of MWCNTs as an electron-ion-transducer layer between gold plate and the sensing membrane lead to a smaller membrane resistance and a large double layer capacitance, which was proven using impedance spectra and chronopotentiometry (i.e., 114.9 ± 12 kΩ, 52.1 ± 3.3 pF, 200 ± 13.2 kΩ, and 50 ± 4.2 µF). Additionally, reduction ofthe water layer between the sensing membrane and the underlying conductor wastested. Thus, it is clear that MWCNTs can be used as a transducing layer in SC-ISEs. The proposed sensor was introduced as an indicator electrode for potentiometric titration of single and ternary mixtures of I−, Br−, and S2− anions.

Dipicolinate Complexes of Gallium(III) and Lanthanum(III).

Three dipicolinic acid amine-derived compounds functionalized with a carboxylate (H3dpaa), phosphonate (H4dppa), and bisphosphonate (H7dpbpa), as well as their nonfunctionalized analogue (H2dpa), were successfully synthesized and characterized. The 1:1 lanthanum(III) complexes of H2dpa, H3dpaa, and H4dppa, the 1:2 lanthanum(III) complex of H2dpa, and the 1:1 gallium(III) complex of H3dpaa were characterized, including via X-ray crystallography for [La4(dppa)4(H2O)2] and [Ga(dpaa)(H2O)]. H2dpa, H3dpaa, and H4dppa were evaluated for their thermodynamic stability with lanthanum(III) via potentiometric and either UV-vis spectrophotometric (H3dpaa) or NMR spectrometric (H2dpa and H4dppa) titrations, which showed that the carboxylate (H3dpaa) and phosphonate (H4dppa) containing ligands enhanced the lanthanum(III) complex stability by 3-4 orders of magnitude relative to the unfunctionalized ligand (comparing log βML and pM values) at physiological pH. In addition, potentiometric titrations with H3dpaa and gallium(III) were performed, which gave significantly (8 orders of magnitude) higher thermodynamic stability constants than with lanthanum(III). This was predicted to be a consequence of better size matching between the dipicolinate cavity and gallium(III), which was also evident in the aforementioned crystal structures. Because of a potential link between lanthanum(III) and osteoporosis, the ligands were tested for their bone-directing properties via a hydroxyapatite (HAP) binding assay, which showed that either a phosphonate or bisphosphonate moiety was necessary in order to elicit a chemical binding interaction with HAP. The oral activity of the ligands and their metal complexes was also assessed by experimentally measuring log Po/w values using the shake-flask method, and these were compared to a currently prescribed osteoporosis drug (alendronate). Because of the potential therapeutic applications of the radionuclides 67/68Ga, radiolabeling studies were performed with 67Ga and H3dpaa. Quantitative radiolabeling was achieved at pH 6.5 in 10 min at room temperature with concentrations as low as 10-5 M, and human serum stability studies were undertaken.

Unexpected lanthanide cation selectivity of bis-β-ketovinylated diaza-18-crown-6 and open-chain diamines: cooperative effect of the second keto group

New diaza-18-crown-6 based ligands were prepared by the β-ketovinylation of diaza-18-crown-6 by TMS-protected ynones. The obtained N,N′-bis-(3-oxo-3-arylpropen-1-yl)-7,16-diaza-18-crown-6 ligands (aryl = p-MeOC6H4, p-Me2NC6H4) selectively bind the Ln3+ in preference to main group cations, showing high Ln3+/Zn2+ and Ln3+/Pb2+ selectivities (from 2 to 5.5 in log βML values determined by UV-spectrophotometric titration in CH3OH). The Me2N-derivative is also a holmium-selective fluoro-ionofore, as its intense emission is almost completely quenched by Ho3+ salts at concentrations as low as 10−5 mol l−1. The monoazacrown analogs with only one enaminone group complex less strongly with Ln3+ and are less selective, but bis-β-ketovinylated open-chain diamines (N,N′-dibenzyl-3,6-dioxaoctane-1,8-diamine and N,N′-dibenzyldecane-1,10-diamine) show almost the same binding constants with La3+ (log βML = 3.5–3.7) and Pb2+ (log βML = 1.6) as the corresponding diaza-18-crown-6 derivative. This and the changes observed in the 1H NMR spectra of the azacrown enaminone ligands in the presence of La3+ indicate the exocyclic coordination of Ln3+ with the carbonyl oxygens of the side arms. Rotation around the =C–N bond is restricted in enaminone ligands and especially in their complexes with Ln3+, which allows to explain the observation of two sub-sets of signals in the 1H NMR spectra of bis-β-ketovinylated diaza-18-crown-6 in the presence of La(NO3)3 by the existence of two rotamers of the ligands. Diaza-18-crown-6 and open-chain diamines with two β-ketovinyl side arms selectively bind rare earth group cations in preference to main group cations (Pb2+, Zn2+ and Ba2+) through the exocyclic coordination of Ln3+ with the carbonyl oxygens of the side arms. The presence of the second β-ketovinyl group is essential, as ligands with only one β-ketovinyl group do not show such selectivity.

CMP(O) tripodands: synthesis, potentiometric studies and extractions

Ligand systems containing three carbamoylmethylphosphonate (CMP) or -phosphine oxide (CMPO) moieties attached to a tripodal platform have been synthesized for metal complexation and subsequent extraction from HNO3 solutions. The incorporation into ion selective electrodes (ISE) and picrate extractions with Na+, K+, Ag+, Ca2+, Cd2+, Hg2+, Pb2+, Cu2+, Eu3+ and Fe3+ shows that CMPO tripodand 3 is very selective for Eu3+ and forms a very stable complex (log βML = 28.3). Liquid–liquid extractions performed with Eu3+ and Am3+ show reasonable extraction properties of the CMP(O) tripodands 3, 11 and 13 in 1,1,2,2-tetrachloroethane, while in 1-octanol for all tripodands studied the distribution coefficients are low. Upon addition of the synergistic agent hexabrominated cobalt bis(dicarbollide) anion (bromo-COSAN) the distribution coefficients for Am3+ and Eu3+ extraction increase considerably for CMP(O) tripodands 3 and 4. Covalently linked COSAN only enhances the extraction of Am3+ and Eu3+ at 0.001–0.01 M HNO3. The functionalization of dendrimer coated magnetic silica particles with CMP(O) tripodands led to very effective particles (31 and 32) for Am3+ and Eu3+ removal from 0.01 M HNO3 solutions.

Coordination properties of tris(2-carboxyethyl)phosphine, a newly introduced thiol reductant, and its oxide.

Acid-base properties and metal-binding abilities of tris(2-carboxyethyl)phosphine (TCEP), a newly introduced thiol group protectant, were studied in solution, using potentiometry, (1)H and (31)P NMR, and UV-vis spectroscopy, and also in the solid state by X-ray diffraction. Stability constants of complexes of the P-oxide of TCEP (TCEPO) were established by potentiometry. The list of metal ions studied included Ni(II), Cu(II), Zn(II), Cd(II), and Pb(II). Cu(II) catalyzed oxidation of TCEP to TCEPO. For all other systems ML complexes were found as major species at neutral pH with TCEP and TCEPO. Monoprotonated MHL species were also detected in weakly acidic conditions for all TCEP complexes and for the Pb(II) complex of TCEPO, while hydrolytic MH(-1)L complexes were found for TCEP at the weakly alkaline pH range. The NiL(4) complex was found to form at excess of TCEP. Overall, the complexes were found to be rather weak, with log beta(ML) values around 3-5 for TCEP and 1.5-2.5 for TCEPO. The phosphorus pK(a) value for TCEP, 7.68, suggests that it can be a good buffer for studies at physiological pH.

Potentiometric determination of the formation constants for complexes of 3,2¢,2¢¢-triaminopropyldiethylamine with cobalt(II), nickel(II), copper(II), zinc(II) and cadmium(II)

The tripodal tetraamine ligand N{(CH2)3NH2}{(CH2)2NH2}2 (pee), has been investigated as an asymmetrical tetraamine chelating agent for CoII, NiII, CuII, ZnII and CdII. The protonation constants for this ligand and the formation constants for its complexes have been determined potentiometrically in 0.1 M KCl at 25 °C. The successive protonation constants (log Kn) are: 10.22, 9.51, 8.78 and 1.60 (n = 1–4). One complex with formula M(pee)2+ (M = Co, Ni, Cu, Zn and Cd) is common to all five metal ions and the formation constant (log βML) is: 12.15, 14.17, 16.55, 13.35 or 9.74, respectively. In addition to the simple complexes, CoII, CuII and ZnII also give hydroxo complexes, and CuII and NiII give complexes with monoprotonated pee. [Zn(pee)](ClO4)2 and [Cd(pee)Cl](ClO4) complexes were isolated and are believed to have tetrahedral and trigonal-bipyramidal structures, respectively.

A model system using modulation of lanthanide luminescence to signal Zn2+ in competitive aqueous media †

Two pentadentate tribasic ligand systems containing aniline or benzylamine nitrogens covalently linked to a proximate kinetically stable Eu or Tb complex are described. The affinity of these complexes and their non-conjugated analogues for Zn2+, Ca2+ and Mg2+ ions has been measured at ambient pH in a high salt background. Apparent binding constants for the parent ligands (L1: Zn2+ log βML 5.04, Ca2+ 3.91, Mg2+ 2.1, L3: Zn2+ 5.93, Ca2+ 5.00, Mg2+ 3.60) were slightly lowered in the aniline-based terbium conjugate [TbL4], and were the same for the benzylamine-based conjugate [LnL2], except for zinc binding for which a slightly enhanced affinity was observed. Changes in the form of ligand absorption and emission spectra and in the intensity of delayed lanthanide luminescence characterised metal ion binding. With [LnL2], a 42 and 26% increase in emission at 700 nm (Eu) and 545 nm (Tb) accompanied zinc binding in a simulated extracellular background, with an apparent dissociation constant of 0.6 μM (295 K).

Bibracchial diazatetralactams. Side-chain effects on cation binding and ionophoric properties

The formation constants in THF solutions of calcium complexes diazatetralactams bearing two side-chains were found in the range 4.6 < log βML < 8.2 and follow the substituent sequence Boc < Me ∼ CH2CO2Me < CH2CONMe2 < CH2Py. This side-chain effect was again observed in liquid–liquid extraction studies either with calcium or zinc picrates. Efficient zinc extraction constitutes the main difference with the dioxatetralactam series. The metallic ion transport across a chloroformic membrane studied with the pyridine derivative agrees well with extraction data. Specific ionophoric properties were evidenced with ion-selective electrodes.

Solution and Solid State Characterization of a Cadmium Octaazacryptand Complex

The constant for cadmium binding by octaazacryptand L = N(CH2CH2NHCH2CH2NHCH2CH2)3N was determined by potentiometry; log βML =18.3(1). Calculation of pM values (pM = −log [M]) show that L has the highest reported binding affinity for cadmium relative to other [2.2.2] polyoxa−polyaza cryptates. Two cadmium cryptate complexes, [CdL](BF4)2 (1a) and [CdL](OAc)2·2H2O (1b), were synthesized by metalation of the free cryptand. The molecular structures of compounds 1a and 1b were determined by X-ray diffraction. Crystallographic data for 1a: trigonal, P3̄1c, Z = 2, a = 9.581(2) Å, c = 17.003(4) Å, V = 1351.2(5) Å3. Crystallographic data for 1b: monoclinic, C2/c, Z = 4, a = 10.500(2) Å, b = 14.782(3) Å, c = 19.395(4) Å, β = 99.30(2)°, V = 2971(1) Å3. The cadmium ions in both complexes are eight-coordinate and display similar coordination geometries but different ligand conformations, designated as parallel and oblique. The cadmium coordination sphere is best described as a bicapped octahedron. Through 2D NMR experiments we have found that the Cd is in a symmetric environment and the conformation of the ligand in solution is consistent with the parallel conformation observed in one of the solid state structures. The 113Cd NMR shift of this eight-coordinate amine complex is 75 ppm relative to 0.1 M aqueous Cd(ClO4)2, which correlates with shifts observed for other [2.2.2] cadmium polyoxa−polyaza cryptates.

1,3,5‐Trideoxy‐1,3,5‐tris(dimethylamino)‐cis‐inositol, an Efficient Ligand for Hard Trivalent Metal Ions. Determination of the stability constants of the FeIII, AlIII, and CuII complexes in aqueous solution

AbstractThe complexes [Fe(tdci)2]Cl3 and [Al(tdci)2]Cl3 (tdci = 1,3,5‐trideoxy‐1,3,5‐tris(dimethylamino)‐cis‐inositol) were prepared and characterized by mass spectrometry, NMR spectroscopy, and magnetic‐susceptibility measurements. The formation constants were determined in aqueous solution (25°, 0.1M KCl) by potentiometric titration. pK values of H3(tdci)3+: 5.89, 7.62, 9.68; FeIII complexes: log βML = 18.8, log β = 32.6; AlIII complexes: log βML = 14.3, logβ = 26.4. The protonated complex [FeH(tdci)2]4+ has also been identified. In contrast to the high stability of the FeIII and AlIII complexes, only weak interactions of tdci with CuII have been observed in aqueous solution (25°, 0.1M KNO3).