Evaluation of 99mTc-sulfonamide and sulfocoumarin derivatives for imaging carbonic anhydrase IX expression.

With the aim to prepare hypoxia tumor imaging agents, technetium(I) and rhenium(I) tricarbonyl complexes with dipyridylamine (L1 = N-{[1-(2,2-dioxido-1,2-benzoxathiin-6-yl)-1H-1,2,3-triazol-4-yl]methyl}-N-(2-pyridinylmethyl)-2-pyridinemethanamine; L3 = N-{[1-[N-(4-aminosulfonylphenyl)]-1H-1,2,3-triazol-4-yl]methyl}-N-(2-pyridinyl-methyl)-2-pyridinemethanamine), and iminodiacetate (H2L2 = N-{[1-(2,2-dioxido-1,2-benzoxathiin-6-yl)-1H-1,2,3-triazole-4-yl]methyl}-N-(carboxy-methyl)-glycine; H2L4 = N-{[1-[N-(4-aminosulfonylphenyl)]-1H-1,2,3-triazole-4-yl]methyl}-N-(carboxymethyl)-glycine) ligands appended to sulfonamide or sulfocoumarin carbonic anhydrase inhibitors were synthesized. The Re(I) complexes were characterized using 1H/13C NMR, MS, EA, and in one case the X-ray structure of [Et3NH][Re(CO)3(L2)] was obtained. As expected, the Re coordination geometry is distorted octahedral, with a tridentate iminodiacetate ligand in a fac arrangement dictated by the three strong-field CO ligands. Inhibition studies of human carbonic anhydrases (hCAs) showed that the Re sulfocoumarin derivatives were inactive against hCA-I, -II and -IV, but had moderate affinity for hCA-IX. The Re sulfonamides showed improved affinity against all tested hCAs, with [Re(CO)3(L4)]- being the most active and selective for the hCA-IX isoform. The corresponding 99mTc complexes were synthesized from fac-[99mTc(CO)3(H2O)3]+, purified by HPLC, and obtained with average 41-76% decay-corrected radiochemical yields and with >99% radiochemical purity. Uptake in HT-29 tumors at 1 h post-injection was highest for [99mTc(CO)3(L4)]- (0.14 ±â€¯0.10%ID/g) in comparison to [99mTc(CO)3(L1)]+ (0.06 ±â€¯0.01%ID/g), [99mTc(CO)3(L2)]- (0.03 ±â€¯0.00%ID/g), and [99mTc(CO)3(L3)]+ (0.07 ±â€¯0.03%ID/g). The uptake in tumors was further reduced at 4 h post-injection. For potential imaging application with single photon emission computed tomography, further optimization is needed to improve the affinity to hCA-IX and uptake in hCA-IX expressing tumors.

DNA Interaction and Cytotoxicity of Cyclometalated Ruthenium(II) Complexes as Potential Anticancer Drugs.

To evaluate the anticancer activity of the cyclometalated ruthenium(II) complexes [Ru(bpy)2(C^N)]Cl, we have studied the interaction of these complexes using calf thymus DNA (CT-DNA) and cytotoxicity assays with two tumor (L1210 and HeLa) and a non-tumor (BALB/3T3 clone A31) cell lines. It is suggested that the complexes act as intercalators and/or DNA minor groove binders. Moreover, the complexes display favorable cytotoxicity activities with L1210 and HeLa, which in all cases were significantly more favorable than cisplatin. In contrast, the complexes exhibit appreciably lower cytotoxicity toward BALB/3T3 clone A31.

Syntheses, characterization, and antitumor activities of platinum(II) and palladium(II) complexes with sugar-conjugated triazole ligands.

Four platinum(II) and palladium(II) complexes with sugar-conjugated bipyridine-type triazole ligands, [Pt(II)Cl(2)(AcGlc-pyta)] (3), [Pd(II)Cl(2)(AcGlc-pyta)] (4), [Pt(II)Cl(2)(Glc-pyta)] (5), and [Pd(II)Cl(2)(Glc-pyta)] (6), were prepared and characterized by mass spectrometry, elemental analysis, (1)H- and (13)C-NMR, IR as well as UV/VIS spectroscopy, where AcGlc-pyta and Glc-pyta denote 2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethyl 2,3,4,6-tetra-O-acetyl-ß-D-glucopyranoside (1) and 2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethyl ß-D-glucopyranoside (2), respectively. The solid-state structure of complex 6 was determined by single-crystal X-ray-diffraction analysis. These complexes exhibited in vitro cytotoxicity against human cervix tumor cells (HeLa) though weaker than that of cisplatin.

Synthesis of glucopyranosyl Schiff base zinc(II) complexes capable of interacting with mononucleotides, and their DNA-cleavage activities.

New glucopyranosyl Schiff base zinc complexes, [Zn(GlcSal)(2) ] (1; GlcSalH=N-(2-deoxy-ß-D-glucopyranos-2-yl-salicylaldimine) and [Zn(AcOGlcSal)(2) ] (2; AcOGlcSalH=N-(2-deoxy-ß-D-1,3,4,6-tetraacetylglucopyranos-2-yl-salicylaldimine) were synthesized, and characterized by spectral and analytical methods. The interaction between the Zn complexes and mononucleotides was investigated by (1)H-NMR, (31)P-NMR and UV/VIS spectroscopies. Mononucleotides, cytidine 5'-monophosphate (CMP) and uridyl 5'-monophosphate (UMP), interacted with these complexes to form a 1:1 complex with 1 and a 1:2 complex with 2, depending on the presence of the OH group of glucopyranosyl substituents. The DNA-cleavage activities of 1 and 2 were studied using plasmid DNA (pBR322) in a medium of 5 mM Tris·HCl/50 mM NaCl buffer in the presence of H(2)O(2). The DNA-cleavage activity decreased in the order of 2>1>Zn(OAc)(2), indicating the significant promoting effect of the glucopyranosyl Schiff base ligand and the participation of the glucopyranosyl OH groups in the cleavage mechanism. The mechanism of the DNA cleavage by 1 and 2 was investigated by evaluation of the effect of a HO· radical scavenger and a singlet-oxygen ((1)O(2)) quencher under aerobic conditions. The former exhibited little effect, excluding the HO· radical as an active species and supporting the hydrolysis mechanism for the main process of the DNA cleavage. The latter quencher somewhat hindered the cleavage, indicating the partial participation of a (1)O(2) as a competitive active species in the present system.

Integrated palladium-catalyzed arylation of heavier Group 14 hydrides.

A convenient procedure has been developed for the preparation of Group 14 compounds by integrated palladium-catalyzed cross-coupling of aromatic iodides with the corresponding Group 14 hydrides in the presence of a base. The reaction conditions can be applied to the cross-coupling of tertiary, secondary, and primary Group 14 compounds. In most cases, the desired arylated products were obtained in synthetically useful yields. Even in the case of aryl iodides containing OH, NH(2), CN, or CO(2)R groups, the reactions proceeded with good to high yields with tolerance of these reactive functional groups. A possible application of this method is the unique synthesis of a fungicidal diarylmethyl(1H-1,2,4-triazol-1-ylmethyl)silane derivative.

Structure and photochemical properties of (mu-alkoxo)bis(mu-carboxylato)diruthenium complexes with naphthylacetate ligands.

Two new dinuclear Ru(III) complexes containing naphthalene moieties, K[Ru2(dhpta)(mu-O2CCH2-1-naph)2] (1) and K[Ru2(dhpta)(mu-O2CCH2-2-naph)2] (2) (H5dhpta = 1,3-diamino-2-hydroxypropane-N,N,N',N'-tetraacetic acid, naph-1-CH2CO2H = 1-naphthylacetic acid, naph-2-CH2CO2H = 2-naphthylacetic acid), were synthesized. Complex 2 crystallized as an orthorhombic system having a space group of Pbca with unit cell parameters a = 10.6200(5) A, b = 20.270(1) A, c = 35.530(2) A, and Z = 8. EXAFS analysis of 1 and 2 in the solid states and in solution clarified that the dinuclear structures of 1 and 2 were kept in DMSO solutions. Variable-temperature magnetic susceptibility data indicated that the two Ru(III) centers are strongly antiferromagnetically coupled as shown by the large coupling constants, J = -581 cm(-1) (1) and -378 cm(-1) (2). In the cyclic voltammograms of 1 and 2, one oxidation peak and two reduction peaks which were assigned to the redox reaction of the ruthenium moieties were observed in DMF. The large conproportionation constants estimated from the reduction potentials of Ru(III)Ru(III) and Ru(III)Ru(II) indicated the great stability of the mixed-valent state. The mixed-valent species [Ru(III)Ru(II)(dhpta)(mu-O2CCH2-R)2](2-) (R = 1-naph (6) and R = 2-naph (7)) were prepared by controlled potential electrolysis of 1 and 2 in DMF. The electronic absorption spectra of 6 and 7 were similar to that of [Ru(III)Ru(II) (dhpta)(mu-O2CCH3)2](2-) which is a typical Class II type mixed-valent complex. The fluorescence decay of 1 and 2 indicated that there are two quenching processes which come from the excimer and monomer states. The short excimer lifetimes of 1 and 2 were ascribed to the energy transfer from the naphthyl moieties to the Ru centers. The different excimer ratio between 1 and 2 suggested that the excimer formation is affected by the conformation of the naphthyl moieties in the diruthenium(III) complexes.

Synthesis and insulin-mimetic activities of metal complexes with 3-hydroxypyridine-2-carboxylic acid.

Metal complexes of 3-hydroxypyridine-2-carboxylic acid (H(2)hpic), [Co(Hhpic)(2)(H(2)O)(2)] (1), [Fe(Hhpic)(2)(H(2)O)(2)] (2), [Zn(Hhpic)(2)(H(2)O)(2)] (3), [Mn(Hhpic)(2)(H(2)O)(2)] (4), and [Cu(Hhpic)(2)] (5) have been synthesized and characterized by mass spectrometry, elemental analysis, magnetic susceptibility, infrared, electronic absorption and electron paramagnetic resonance (EPR) spectroscopies. The solid-state structure of 1 has been established by X-ray crystallography. The EPR spectra of 4 and 5 displayed six and four-line hyperfine splitting patterns, respectively, due to coupling of the unpaired electron with the (55)Mn (I=5/2) nucleus and the (63)Cu (I=3/2) nucleus. In the EPR spectrum of 5, an additional five-line super-hyperfine splitting pattern was observed at 77 K, caused by additional interaction of the unpaired electron with ligand nitrogen atoms (I=1), indicating that the structure of 5 was retained in dimethyl sulfoxide solution. The insulin-mimetic activity of these complexes was evaluated by means of in vitro measurements of the inhibition of free fatty acid (FFA) release from epinephrine-treated, isolated rat adipocytes. Complex 5 was found to exhibit the most potent insulin-mimetic activity among the complexes examined in this study.

Electro- and photochemical properties of a (mu-alkoxo)bis(mu-carboxylato)diruthenium complex having two tetraphenylporphinato zinc(II) moieties.

The novel (mu-alkoxo)bis(mu-carboxylato)diruthenium complex K[Ru(2)(dhpta)(mu-O(2)C-p-ZnTPP)(2)] 3 was prepared by simple ligand substitution reaction. Strong antiferromagnetic interaction between two Ru(III) ions of 3 was observed with a coupling constant of -425 approximately -404 cm(-1). The cyclic voltammogram of 3 can be explained in terms of superposition of those of ZnTPP-p-CO(2)H and K[Ru(2)(dhpta)(mu-O(2)CPh)(2)] 2, indicating no significant electrochemical interaction. The large conproportionation constant estimated from the reduction potentials for Ru(III)Ru(III) and Ru(II)Ru(III) indicates great stability of the mixed-valence state. The mixed-valence species [Ru(II)Ru(III)(dhpta)(mu-O(2)C-p-ZnTPP)(2)](2-) 4 was prepared by controlled potential electrolysis. The electronic absorption spectrum of 4 was quite similar to that of [Ru(II)Ru(III)(dhpta)(mu-O(2)CCH(3))(2)](2-) which is a typical Class II complex. The fluorescence from the S(2) state of the ZnTPP unit of 3 was significantly (78%) quenched. The electron transfer from the ZnTPP unit to Ru(III) ions in 3 is a plausible mechanism, even though energy transfer could not be ruled out completely. The free energy change for electron transfer, Delta G(CS), was estimated to be ca.-1.1 eV, which is similar to typical values for the reorganization energy lambda in polar solvents. Hence, the electron transfer scheme is situated almost at the top of the Marcus parabola, enabling ultrafast electron transfer.

Synthesis and insulinomimetic activities of novel mono- and tetranuclear oxovanadium(IV) complexes with 3-hydroxypyridine-2-carboxylic acid.

Two chargeless VO(IV) complexes with 3-hydroxypyridine-2-carboxylic acid (H2hpic), [VO(Hhpic-O,O)(Hhpic-O,N)(H2O)].3H2O (1) and the cyclic tetramer [(VO)4(mu-(hpic-O,O',N))4(H2O)4].8H3O (2), have been synthesized and characterized by elemental analysis, mass, infrared, electronic absorption, electron spin resonance (ESR) spectroscopies, and X-ray crystallography. Their coordination structures are similar to each other (and 1 is readily transformed into 2), but are quite different from that of bis(pyridine-2-carboxylato)oxovanadium(IV). The magnetic susceptibility of 2 indicates the presence of a weak ferromagnetic intramolecular interaction between the V atoms at low temperature, in addition to a weak antiferromagnetic intermolecular interaction. The ESR signal of 2 was broad, while 1 showed an eight-line hyperfine splitting pattern due to coupling of the unpaired electron with the 51V nucleus (I=7/2). The ESR spectrum and cyclic voltammogram of 2 clearly show that the cyclic tetramer remains intact in solution. The insulinomimetic activity of 1 and 2 was evaluated by means of in vitro measurements of the inhibition of free fatty acid release from epinephrine-treated isolated rat adipocytes. While 1 exerted higher insulinomimetic activity than VOSO4, the activity of 2 was significantly lower than that of VOSO4. Hence 2 appears to retain its cyclic structure during the in vitro test. These results indicate that the rational ligand design for VO complexes might be a promising approach to obtain superior insulinomimetic activity.