Shape and Size Tuning of BiIII-Centered Polyoxopalladates: High Resolution 209Bi NMR and 205/206Bi Radiolabeling for Potential Pharmaceutical Applications.

We have discovered five bismuth(III)-containing polyoxopalladates (POPs) which were fully characterized by solution and solid-state physicochemical techniques: the cube-shaped [BiPd12O32(AsPh)8]5- (BiPd12AsL), [BiPd12O32(AsC6H4N3)8]5- (BiPd12AsLN), and [BiPd12O32(AsC6H4COO)8]13- (BiPd12AsLC) as well as the star-shaped [BiPd15O40(PO)10H6]11- (BiPd15P) and [BiPd15O40(PPh)10]7- (BiPd15PL), respectively. The organically modified capping groups phenylarsonate, p-azidophenylarsonate, and p-carboxyphenylarsonate were chosen as the azido (-N3) and carboxyl (-COOH) groups open up opportunities to covalently conjugate (via click reaction, amide coupling, etc.) with targeting vectors. The synthesis of p-azidophenylarsonate is reported here for the first time. The effects of the BiIII template and the organoarsonate vs -posphonate capping groups on the resulting POP shape (cube vs star) are discussed. The 209Bi NMR (I = 9/2) spectra of BiPd12AsL, BiPd12AsLN, and BiPd12AsLC revealed narrow peaks (ν1/2 ∼ 200 Hz) at 5470 ppm with a longitudinal relaxation time in the millisecond range (at 8.46 T). The absence of a quadrupolar relaxation contribution could be attributed to the allocation of BiIII in the highly symmetrical cuboid POP host cage. Similar peaks were absent in the 209Bi-NMR spectra of the star-shaped POPs BiPd15P and BiPd15PL due to the less symmetric coordination environment around the central BiIII ion. Further, 205/206Bi-radiolabeled POPs have been synthesized by incorporating a 205/206BiIII ion in the center of the POP structures. Carrier-free 205/206Bi radioisotopes (as surrogates of α-emitting 213Bi) were incorporated into the POP host-cage for the preparation of 205/206BiPd12AsL, 205/206BiPd12AsLN, 205/206BiPd12AsLC, and 205/206BiPd15PL, respectively. The radiometal incorporation was complete (>99% radiochemical yield) in 10 min according to radio-thin-layer chromatography. The 205/206BiPd12AsL polyanion was purified by solid-phase extraction. The incubation in rat serum showed the formation of a 205/206BiPd12AsL-protein aggregate.

High-Affinity Binding of Metallacarborane Cobalt Bis(dicarbollide) Anions to Cyclodextrins and Application to Membrane Translocation.

Metallacarboranes are a class of inorganic boron clusters that have recently been recognized as biologically active compounds. Herein, we report on the host-guest complexation of several cobalt bis(1,2-dicarbollide) anions (COSANs) with cyclodextrins (CDs) in aqueous solution. The binding affinities reach micromolar values, which are among the highest known values for native CDs, and exceed those for neutral hydrophobic organic guest molecules. The entrapment of the COSANs inside the cavity of CDs was confirmed using NMR and UV-visible spectroscopy, mass spectrometry, cyclic voltammetry, and isothermal titration calorimetry. Complexation by CDs greatly influences the photophysical and electrochemical properties of COSANs. In combination with indicator displacement assays, a label-free fluorescence-based method was developed to allow real-time monitoring of the translocation of COSANs through lipid bilayer membranes.

Tetravalent Metal Ion Guests in Polyoxopalladate Chemistry: Synthesis and Anticancer Activity of [MO8Pd12(PO4)8]12- (M = SnIV, PbIV).

The first two examples of polyoxopalladates(II) (POPs) containing tetravalent metal ion guests, [MO8Pd12(PO4)8]12- (M = SnIV, PbIV), have been prepared and structurally characterized in the solid state, solution, and gas phase. The interactions of the metal ion guests and the palladium-oxo shell were studied by theoretical calculations. The POPs were shown to possess anticancer activity by causing oxidative stress inducing caspase activation and consecutive apoptosis of leukemic cells.

Toxicity evaluation of two polyoxotungstates with anti-acetylcholinesterase activity.

A toxicity evaluation of two Keggin-type heteropolytungstates, K7[Ti2PW10O40]·6H2O and K6H[SiV3W9O40]·3H2O, with different inhibitory potencies toward acetylcholinesterase activity (IC50 values of 1.04×10-6 and 4.80×10-4mol/L, respectively) was performed. Wistar albino rats were orally treated with single doses (5 and 50mg/kg) of both investigated compounds. The biochemical parameters of renal (serum urea and creatinine) and liver function (direct and total bilirubin, alanine transaminase, and aspartate aminotransferase) were determined after 24h and 14days. A histopathological analysis of liver tissue was carried out 14days after the polyoxotungstate administration. Both applied doses of the investigated compounds did not induce statistically significant alterations of the renal function markers. However, the polyoxotungstate treatment caused an increase in the activities of serum alanine transaminase and aspartate aminotransferase in a time- and concentration-dependent manner, although statistically significant changes in bilirubin concentrations were not observed. Furthermore, the detected hepatotoxic effect was confirmed by histhopathological analysis that suggested some reversible liver tissue damage two weeks after the treatment, especially in the case of K6H[SiV3W9O40]·3H2O. Accordingly, the toxicity of these two polyoxotungstates with anti-acetylcholinesterase effect cannot be considered as a severe one, but their potential clinical application would require a more complex toxicological study.

Gallium(III)-Containing, Sandwich-Type Heteropolytungstates: Synthesis, Solution Characterization, and Hydrolytic Studies toward Phosphoester and Phosphoanhydride Bond Cleavage.

The gallium(III)-containing heteropolytungstates [Ga4(H2O)10(ß-XW9O33)2](6-) (X = As(III), 1; Sb(III), 2) were synthesized in aqueous acidic medium by reaction of Ga(3+) ions with the trilacunary, lone-pair-containing [XW9O33](9-). Polyanions 1 and 2 are isostructural and crystallized as the hydrated sodium salts Na6[Ga4(H2O)10(ß-AsW9O33)2]·28H2O (Na-1) and Na6[Ga4(H2O)10(ß-SbW9O33)2]·30H2O (Na-2) in the monoclinic space group P21/c, with unit cell parameters a = 16.0218(12) Å, b = 15.2044(10) Å, c = 20.0821(12) Å, and ß = 95.82(0)°, as well as a = 16.0912(5) Å, b = 15.2178(5) Å, c = 20.1047(5) Å, and ß = 96.2(0)°, respectively. The corresponding tellurium(IV) derivative [Ga4(H2O)10(ß-TeW9O33)2](4-) (3) was also prepared, by direct reaction of sodium tungstate, tellurium(IV) oxide, and gallium nitrate. Polyanion 3 crystallized as the mixed rubidium/sodium salt Rb2Na2[Ga4(H2O)10(ß-TeW9O33)2]·28H2O (RbNa-3) in the triclinic space group P1̅ with unit cell parameters a = 12.5629(15) Å, b = 13.2208(18) Å, c = 15.474(2) Å, α = 80.52(1)°, ß = 84.37(1)°, and γ = 65.83(1)°. All polyanions 1-3 were characterized in the solid state by single-crystal XRD, FT-IR, TGA, and elemental analysis, and polyanion 2 was also characterized in solution by (183)W NMR and UV-vis spectroscopy. Polyanion 2 was used as a homogeneous catalyst toward adenosine triphosphate (ATP) and the DNA model substrate 4-nitrophenylphosphate, monitored by (1)H and (31)P NMR spectroscopy. The encapsulated gallium(III) centers in 2 promote the Lewis acidic synergistic activation of the hydrolysis of ATP and DNA model substrates at a higher rate in near-physiological conditions. A strong interaction of 2 with the P-O bond of ATP was evidenced by changes in chemical shift values and line broadening of the (31)P nucleus in ATP upon addition of the polyanion.

Organoantimony(III)-Containing Tungstoarsenates(III): From Controlled Assembly to Biological Activity.

A family of three sandwich-type, phenylantimony(III)-containing tungstoarsenates(III), [(PhSb(III) ){Na(H2 O)}As(III) 2 W19 O67 (H2 O)](11-) (1), [(PhSb(III) )2 As(III) 2 W19 O67 (H2 O)](10-) (2), and [(PhSb(III) )3 (B-α-As(III) W9 O33 )2 ](12-) (3), have been synthesized by one-pot procedures and isolated as hydrated alkali metal salts, Cs3 K3.5 Na4.5 [(PhSb(III) ){Na(H2 O)}As(III) 2 W19 O67 (H2 O)]⋅41H2 O (CsKNa-1), Cs4.5 K5.5 [(PhSb(III) )2 As(III) 2 W19 O67 (H2 O)]⋅35H2 O (CsK-2), and Cs4.5 Na7.5 [(PhSb(III) )3 (B-α-As(III) W9 O33 )2 ]⋅42H2 O (CsNa-3). The number of incorporated {PhSb(III) } units could be selectively tuned from one to three by careful control of the reaction parameters. The three compounds were characterized in the solid state by single-crystal XRD, IR spectroscopy, and thermogravimetric analysis. The aqueous solution stability of sandwich polyanions 1-3 was also studied by multinuclear ((1) H, (13) C, (183) W) NMR spectroscopy. Effective inhibitory activity against six different kinds of bacteria was identified for all three polyanions, for which the activity increased with the number of incorporated {PhSb(III) } groups.

Diphosphates and diphosphonates in polyoxometalate chemistry.

In the wide area of polyoxometalate (POM) chemistry, diphosphate/diphosphonate-based POMs represent a more recent area of study. However, in this short time it has emerged to become very dynamic, as shown by the wide variety of compounds reported. Ever since the discovery of the first polyoxotungstate framework constructed from diphosph(on)ate ligands, a widespread investigation on the preparative chemistry and properties of such compounds has followed. The main focus of such a study is based on factors such as the oxidation state of the metal, the effect of pH and temperature during synthesis, and the presence of different functional groups on the diphosphonate. In this review we discuss in detail all diphosphate/diphosphonate-based POMs, beginning with early developments, subsequent growth in interest, and finally focusing on the very latest developments.

Polyoxomolybdodiphosphonates: examples incorporating ethylidenepyridines.

We have synthesized and structurally characterized three pyridylethylidene-functionalized diphosphonate-containing polyoxomolybdates, [{Mo(VI)O(3)}(2){Mo(V)(2)O(4)}{HO(3)PC(O)(CH(2)-3-C(5)NH(4))PO(3)}(2)](6-) (1), [{Mo(VI)(2)O(6)}(2){Mo(V)(2)O(4)}{O(3)PC(O)(CH(2)-3-C(5)NH(4))PO(3)}(2)](8-) (2), and [{Mo(V)(2)O(4)(H(2)O)}(4){O(3)PC(O)(CH(2)-3-C(5)NH(4))PO(3)}(4)](12-) (3). Polyanions 1-3 were prepared in a one-pot reaction of the dinuclear, dicationic {Mo(V)(2)O(4)(H(2)O)(6)}(2+) with 1-hydroxo-2-(3-pyridyl)ethylidenediphosphonate (Risedronic acid) in aqueous solution. Polyanions 1 and 2 are mixed-valent Mo(VI/V) species with open tetranuclear and hexanuclear structures, respectively, containing two diphosphonate groups. Polyanion 3 is a cyclic octanuclear structure based on four {Mo(V)(2)O(4)(H(2)O)} units and four diphosphonates. Polyanions 1 and 2 crystallized as guanidinium salts [C(NH(2))(3)](5)H[{Mo(VI)O(3)}(2){Mo(V)(2)O(4)}{HO(3)PC(O)(CH(2)-3-C(5)NH(4))PO(3)}(2)]·13H(2)O (1a) and [C(NH(2))(3)](6)H(2)[{Mo(VI)(2)O(6)}(2){Mo(V)(2)O(4)}{O(3)PC(O)(CH(2)-3-C(5)NH(4))PO(3)}(2)]·10H(2)O (2a), whereas polyanion 3 crystallized as a mixed sodium-guanidinium salt, Na(8)[C(NH(2))(3)](4)[{Mo(V)(2)O(4)(H(2)O)}(4){O(3)PC(O)(CH(2)-3-C(5)NH(4))PO(3)}(4)]·8H(2)O (3a). The compounds were characterized in the solid state by single-crystal X-ray diffraction, IR spectroscopy, and thermogravimetric and elemental analyses. The formation of polyanions 1 and 3 is very sensitive to the pH value of the reaction solution, with exclusive formation of 1 above pH 7.4 and 3 below pH 6.6. Detailed solution studies by multinuclear NMR spectrometry were performed to study the equilibrium between these two compounds. Polyanion 2 was insoluble in all common solvents. Detailed computational studies on the solution phases of 1 and 3 indicated the stability of these polyanions in solution, in complete agreement with the experimental findings.

A 224Ra-labeled polyoxopalladate as a putative radiopharmaceutical.

Despite their attractive properties, internal targeted alpha therapies using 223/224Ra are limited to bone-seeking applications. As there is no suitable chelator available, the search for new carriers to stably bind Ra2+ and to connect it to biological target molecules is necessary. Polyoxopalladates represent a class of compounds where Ra2+ can be easily introduced into the Pd-POM core during a facile one-pot preparation. Due to the formation of a protein corona, the connection to other targeting (bio)macromolecules is possible.

Novel pH responsive supramolecular hydrogels of chitosan hydrochloride and polyoxometalate: In-vitro, in-vivo and preliminary safety evaluation.

In the current study, electrostatically-driven pH responsive, supramolecular hydrogels of the trilacunary Wells-Dawson-type 15-tungsto-2-phosphate polyanion (P2W15) and chitosan hydrochloride (ChCl) were prepared, using methacrylic acid as pH responsive agent using benzoyl peroxide (BPO) as initiator. The prepared hydrogels were characterized by FT-IR, SEM, XRD and thermal analyses (TGA-DSC). The swelling and pH based P2W15 release profile of the hydrogels showed maximum swellability and release at pH 7.4. Different mathematical models were applied, showing that P2W15 release followed supercase transport-II mechanism and zero-order kinetics. The cytotoxicity results showed that free and embedded P2W15 exhibited dose-dependent cytotoxicity against cancer cell lines (MCF-7; HeLa) with minimal effects on normal cells (Vero). The developed hydrogels were administered to the rabbits for determining the pharmacokinetic behavior of the polyanion. Moreover, the developed hydrogel system as well as polyanion concentration used were also checked for its oral tolerability and safety evaluation in rabbits. The histopathological studies, serum chemistry (except blood glucose level) and hematological investigations exhibited that administered hydrogel suspension at maximal tolerable dose (4000mg/kg body weight) and polyanion concentration used (20mg) were safe from in-vivo point of view. The developed hydrogels exhibited desirable qualities of a drug delivery system that can be used for the delivery of the embedded polyanion.

The polyoxo-22-palladate(ii), [Na2PdO12(As(V)O4)15(As(V)O3OH)](25-) .

The polyoxo-22-palladate [Na2PdO12(As(V)O4)15(As(V)O3OH)](25-) (1), which represents a novel polyoxo-noble-metalate structural type, was synthesized by reaction of Pd(2+) and AsO4(3-) ions in aqueous solution. Polyanion 1 comprises two {NaPd11} units linked by two arsenate bridges, and hence represents the first example of a defect, monolacunary {Pd11} polyoxopalladate nanocube with arsenate capping groups. The title polyanion was characterized in the solid state as well as by theoretical calculations.

Antidiabetic potential of polyoxotungstates: in vitro and in vivo studies.

Diabetes mellitus is a chronic metabolic disorder continuously affecting people all over the world. A common way to treat diabetes mellitus is to limit the conversion of carbohydrates into glucose which is mediated by glucosidase enzymes. Diabetes mellitus is also famous for its life-threatening microvascular (retinopathy, neuropathy and nephropathy) and macrovascular (atherosclerosis) complications. Aldose reductases present in eye lens (ALR1) and kidney (ALR2) are responsible for microvascular complications. The production of advanced glycation end products (AGEs) is involved in the development of atherosclerosis. The present work was aimed at the synthesis and in vitro/in vivo evaluation of different polyoxotungstates against glucosidases (α- and ß), aldose reductases (ALR1 and ALR2) and AGEs to discover a new treatment which may limit the complications associated with diabetes mellitus. The polyanion [P6W18O79](20-) was found to be the most potent inhibitor of α-glucosidase (IC50 = 1.33 ± 0.41 µM), ALR1 (IC50 = 0.4 ± 0.009 µM) and ALR2 (IC50 = 0.38 ± 0.02 µM). Animal studies showed that the polyanion [H2W12O40](6-) was very effective in reducing the blood glucose level to 84.25 ± 5.07 mg dL(-1) when compared with standard antidiabetic drug glibenclamide (150.62 ± 9.35 mg dL(-1)) measured after maximum 8 h of dose administration. The data obtained from in vitro and in vivo experiments confirm that [P6W18O79](20-) and [H2W12O40](6-) could be used as a new treatment of diabetes mellitus.

A Lewis acid catalytic core sandwiched by inorganic polyoxoanion caps: selective H2O2-based oxidations with [Al(III)4(H2O)10(ß-XW9O33H)2](6-) (X = As(III), Sb(III)).

The Al(III)-containing polyanions [Al(III)4(H2O)10(ß-XW9O33H)2](4-) with X = As(III) (1) and Sb(III) (2) feature four aluminum(III) centers sandwiched by two trivacant (ß-XW9O33) Keggin units, and trigger peroxide catalysis as well as substrate coordination via multiple Lewis acid site interactions.

Trilacunary A-beta-Keggin tungstogermanates and -silicates functionalized with phenyltin(IV) electrophiles.

The first organic derivative of a beta-Keggin tungstogermanate, the monomeric Keggin anion [{(C(6)H(5))Sn(OH)}(3)(A-beta-GeW(9)O(34))](4-) (1), was the only species isolated from the reaction of (C(6)H(5))SnCl(3) with Na(10)[A-beta-GeW(9)O(34)] in water, whereas the Si-analogue [{(C(6)H(5))Sn(OH)}(3)(A-beta-SiW(9)O(34))](4-) (2) and two dimeric tungstosilicates, the unprecedented species [{(C(6)H(5))Sn(A-beta-H(3)SiW(9)Sn(2)O(37))}(2)O(2)](8-) (3) and the known sandwich-type polyanion [{(C(6)H(5))Sn(OH)}(3)(A-beta-H(3)SiW(9)O(34))(2)](8-) (4), were isolated starting from [A-beta-SiW(9)O(34)](10-). The novel polyanion 3 can be described as the product of a double Sn-C hydrolysis followed by condensation of two subunits of 2 through double Sn-O-Sn bridge formation. Solid-state characterization has been carried out by infrared spectroscopy, thermogravimetry and single-crystal X-ray diffraction, representing the first structural analysis for 4. A full solution multinuclear NMR ((1)H, (13)C, (117)Sn, and (183)W) and solid-state (117)Sn CP-MAS NMR study enabled full characterization of 1. A weak 1-dimensional polyanion association through (Sn)O-HO(t) hydrogen contacts involving one of the protonated bridging O atoms of the (C(6)H(5))(3)Sn(3)O(12) corner-shared triad is observed for 1 by X-ray diffraction, resulting in a local C(s) pseudosymmetry for the Sn centers detected by solid-state (117)Sn NMR spectroscopy.

The first 3-dimensional assemblies of organotin-functionalized polyanions.

Reaction of the (CH(3))(2)Sn(2+) electrophile toward trilacunary [A-alpha-XW(9)O(34)](n-) Keggin polytungstates (X = P(V), As(V), Si(IV)) with guanidinium as templating-cation resulted in the isostructural compounds Na[C(NH(2))(3)](2)[{(CH(3))(2)Sn(H(2)O)}(3)(A-alpha-PW(9)O(34))] x 9 H(2)O (1), Na[C(NH(2))(3)](2)[{(CH(3))(2)Sn(H(2)O)}(3)(A-alpha-AsW(9)O(34))] x 8 H(2)O (2) and Na(2)[C(NH(2))(3)](2)[{(CH(3))(2)Sn(H(2)O)}(3)(A-alpha-SiW(9)O(34))] x 10 H(2)O (3). Compounds 1-3 constitute the first 3-dimensional assemblies of organotin-functionalized polyanions, as well as the first example of a dimethyltin-containing tungstosilicate in the case of 3, and they show a similar chiral architecture based on tetrahedrally-arranged {(CH(3))(2)Sn}(3)(A-alpha-XW(9)O(34)) monomeric building-blocks connected via intermolecular Sn-O=W bridges regardless of the size and/or charge of the heteroatom.