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An environmentally benign new synthetic method of zinc(II) complexes without the use of organic solvents and alkali was developed, and several types of zinc(II) complexes in high yields were prepared by mixing solid ligands with solid Zn(OH)(2) or ZnO.
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Recent studies have shown that semiempirical methods (e.g., PM3 and AM1) for zinc-containing compounds are unreliable for modeling structures containing zinc ions with ligand environments similar to those observed in zinc metalloenzymes. To correct these deficiencies a reparameterization of zinc at the PM3 level was undertaken. In this effort we included frequency corrected B3LYP/6-311G* zinc metalloenzyme ligand environments along with previously utilized experimental data. Average errors for the heats of formation have been reduced from 46.9 kcal/mol (PM3) to 14.2 kcal/mol for this new parameter set, termed ZnB for "Zinc, Biological." In addition, the new parameter sets predict geometries for the Bacillus fragilis active site model and other zinc metalloenzyme mimics that are qualitatively in agreement with high-level ab initio results, something existing parameter sets failed to do.
Although a large number of transition metals and cations remarkably induce oxidative deterioration of biological macromolecules including lipids, proteins and DNA, the trace element zinc acts as a novel dietary supplement and an essential micronutrient, and serves a wide range of biological functions in human and animal health. Zinc promotes antioxidant and immune functions, stabilizes and maintains the structural integrity of biological membranes, and plays a pivotal role in skin and connective tissue metabolism and repair. Zinc is an integral constituent of a large number of enzymes including antioxidant enzymes, and hormones including glucagon, insulin, growth hormone, and sex hormones. High concentrations of zinc are found in the prostate gland and choroids of the eye. Zinc deficiency leads to biochemical abnormalities including the impairments of growth, dermal, gastrointestinal, neurologic and immunologic systems. Given its superior bioavailability, antioxidant and immune-enhancing properties, zinc methionine may serve as a novel dietary supplement to promote health benefits in humans and animals.
Changes in the concentration of free Zn2+ were monitored in isolated rat hepatocytes using the fluorescent indicator zinquin (ethyl[2-methyl-8-p-toluenesulphonamido-6-quinolyloxy]acetat e). The concentration of Zn2+ in freshly isolated hepatocytes was 1.3 x 10(-6) M (range 0.61-2.7 x 10[-6] M). This value decreased by about 10%-15% during incubation in the absence of zinc and increased in a time- and concentration-dependent manner in the presence of exogenous zinc (Km approximately 10 microM). IIb group metal ions led to a concentration-dependent increase in zinquin fluorescence. The rank of efficacy was Hg approximately Cd > Pb (IVa) >> Cu (Ib) >>> Ni (VIII). This rank resembles their ability to mobilize zinc from metallothioneins. 8-Br-3',5'-cAMP (10[-4]M) caused a rapid decrease in Zn2+ epifluorescence which was apparent within 10 min and was sustained throughout the experiment. This effect was gradually obliterated in the presence of external ZnCl2. The effect was specific for cAMP (or cAMP generating hormones) as the calcium-dependent hormone [arg8]vasopressin (5 x 10[-8] M) did not affect intracellular Zn2+. An integrated role of zinc as a possible mediator in signal transduction is discussed.
Oral administration of high dosages of the dithiocarbamate pesticides maneb and mancozeb was teratogenic in rats but not in mice. The malformations, severe limb and craniofacial defects, were pronounced after maneb treatment but less so after mancozeb and propineb, zinc-containing compounds. The teratogenic effect of maneb was progressively reduced by simultaneously administering increasing amounts of zinc acetate. The mechanism of the teratogenic effect may involve the compounds being chelating agents, trapping zinc required for many important enzyme systems.
An outbreak of hand dermatitis is reported amongst employees working on a new assembly line of an electronics factory. 24 out of 41 employees had signs of irritant contact dermatitis. The fingertips and the dorsal parts of the hands were especially affected. Mechanical factors in combination with zinc-chromium compounds from galvanised steel seemed to be responsible for the dermatitis and the dry skin. The use of an emollient solved the problem.
The human immunodeficiency virus type 1 (HIV-1) nucleocapsid p7 protein contains two retrovirus-type zinc finger domains that are required for multiple phases of viral replication. Chelating residues (three Cys residues and one His residue) of the domains are absolutely conserved among all strains of HIV-1 and other retroviruses, and mutations in these residues in noninfectious virions. These properties establish the zinc finger domains as logical targets for antiviral chemotherapy. Selected dithiobis benzamide (R-SS-R) compounds were previously found to inhibit HIV-1 replication by mediating an electrophilic attack on the zinc fingers. Unfortunately, reaction of these disulfide-based benzamides with reducing agents yields two monomeric structures (two R-SH structures) that can dissociated and no longer react with the zinc fingers, suggesting that in vivo reduction would inactivate the compounds. Through an extensive drug discovery program of the National Cancer Institute, a nondissociable tethered dithiane compound (1,2-dithiane-4,5-diol, 1,1-dioxide, cis; NSC 624151) has been identified. This compound specifically attacks the retroviral zinc fingers, but not other antiviral targets. The lead compound demonstrated broad antiretroviral activity, ranging from field isolates and drug-resistant strains of HIV-1 to HIV-2 and simian immunodeficiency virus. The compound directly inactivated HIV-1 virions and blocked production of infectious virus from cells harboring integrated proviral DNA. NSC 624151 provides a scaffold from which medicinal chemists can develop novel compounds for the therapeutic treatment of HIV infection.
Solutions of the zinc hydroxide complex [Tp(Bu(t),Me)]ZnOH in alcohols (ROH; R = Me, Et, Pr(i)) achieve hydride transfer to the NAD(+) model, 10-methylacridinium perchlorate. Deuterium labeling studies, however, demonstrate that the source of the hydride is not the alcohol but, rather, the B [bond] H group of the [Tp(Bu(t),Me)] ligand. A further example in which a [Tp(Bu(t),Me)] ligand acts as a hydride donor is provided by the reaction of the aqua complex [[Tp(Bu(t),Me)]Zn(OH(2))][HOB(C(6)F(5))(3)] with MeOH to generate the zinc hydride complex [Tp(Bu(t),Me)]ZnH. The present study therefore provides a caveat for the often assumed inertness of the B [bond] H group in tris(pyrazolyl)hydroborato ligands, especially in the presence of reactive cationic species.
AIM: The beneficial effect of zinc supplementation on the efficacy of interferon as a treatment for chronic hepatitis C had been demonstrated in hepatitis virus genotype 1b of high viral load. This study focused on patients with genotype 2, which is more sensitive to interferon than genotype 1b, and used consensus interferon (CIFN) with or without zinc. METHODS: We randomized 83 patients with chronic hepatitis C to CIFN at 18 MIU six times/wk for 4 wk, followed by CIFN at 18 MIU six times/wk for another 20 wk, in combination with polaprezinc 300 mg (regimen A, n=41) or as monotherapy (regimen B, n=42). Thirty-one patients in regimen A and 33 patients in regimen B completed the clinical trial; the remaining patients withdrew because of side effects or a transfer to another hospital. RESULTS: Sustained biochemical response, defined as a normal aminotransferase level at the end of the 6-mo post-treatment observation, was 68% and 69%, and sustained virological response, defined as undetectable HCV-RNA at the end of the 6-mo post-treatment observation, was 54% and 67% for regimens A and B, respectively. CONCLUSION: CIFN treatment combined with zinc did not enhance the effect of CIFN as shown by biochemical, virological criteria. No side effects related to polaprezinc were noted.
It has been suggested that ZIP7 (Ke4, Slc39a7) belongs to the ZIP family of zinc transporters. Transient expression of the V5-tagged human ZIP7 fusion protein in CHO cells led to elevation of the cytoplasmic zinc level. However, the precise function of ZIP7 in cellular zinc homeostasis is not clear. Here we report that the ZIP7 gene is ubiquitously expressed in human and mouse tissues. The endogenous ZIP7 was associated with the Golgi apparatus and was capable of transporting zinc from the Golgi apparatus into the cytoplasm of the cell. Moreover, by using the yeast mutant strain Deltazrt3 that was defective in release of stored zinc from vacuoles, we found that ZIP7 was able to decrease the level of accumulated zinc and in the meantime to increase the nuclear/cytoplasmic labile zinc level in the ZIP7-expressing zrt3 mutant. We showed that the protein expression of ZIP7 was repressed under zinc-rich condition, whereas there were no effects of zinc on ZIP7 gene expression and intracellular localization. Neither did zinc deficiency affect the intracellular distribution of ZIP7 in mammalian cells. Our study demonstrates that ZIP7 is a functional zinc transporter that acts by transporting zinc from the Golgi apparatus to the cytoplasm of the cell.
The XPS of solid complexes of ZnCl2/ZnSO4/ZnOAc2 with alpha-Met/His have been investigated. The results indicate that Zn2+ coordinate with O atom of carboxyl group and N atom of alpha-amino. The N atom of imidazolyl also participates the coordination. While the S atom of methylthio does not coordinate with Zn2+. This results are consistent with IR analyses. The structures of those complexes are presumed.
The complete array of those hydrotris(pyrazolyl/thioimidazolyl)borate ligands that were developed and used in the author's laboratories, with N3, N2S, NS2, and S3 donor sets, was scanned for their ability to form Zn-OH2 and Zn-OH complexes. The coordination motifs found were Zn-OH2, Zn-OH, Zn-OH-Zn, and Zn-O2H3-Zn. Of these, the well-established Zn-OH motif was complemented with novel species bearing N3, NS2, and S3 tripods. The Zn-OH2 motif was observed only with pyrazolylborate ligands and only in unusual situations with coordination numbers higher than 4 for zinc. The new Zn-OH-Zn motif was realized for three different pyrazolylborates, for one NS2 tripod, and for two S3 tripods. Finally, it was verified that the Zn-O2H3-Zn motif again occurs only with pyrazolylborate ligands. The new complexes were identified by a total of 11 structure determinations.
Our originally designed dansylamidoethylcyclen 4 as a biomimetic Zn(2+)-selective fluorophore has been demonstrated to be a good detector of the apoptosis (induced by an anticancer agent, etoposide, and H(2)O(2)) in cancer cells such as HeLa and HL60 cells. The macrocyclic Zn(2+) ligand 4 (mostly as a deprotonated form) is cell-permeable to show weak fluorescence (emission at 550 nm), which forms a strong fluorescent 1:1 Zn(2+) complex 5 (emission at 530 nm) when Zn(2+) is incorporated into the cells by a zinc(II) ionophore pyrithione. Thus formed, Zn(2+) complex 5 is cell-impermeable and remains intact over a few hours. When apoptosis in HeLa or HL60 cells is artificially induced, 4 selectively and strongly stains apoptotic cells only at early stages, which was verified by using the conventional apoptosis detection probe annexin V-Cy3. Detection of the apoptotic cells by 4 was perhaps due to significantly increased free Zn(2+) flux at early stages of apoptosis. Apoptotic detection by 4 has been compared with a presently available Zn(2+) fluorophore, Zinquin 1. We present that 4 has advantages in detection of apoptosis over annexin V-Cy3 and Zinquin 1.
The new tripod ligands bis(pyrazolyl)(3-tert-butyl-2-thioimidazol-1-yl)hydroborate (L(1)) and bis(pyrazolyl)(3-isopropyl-2-thioimidazol-1-yl)hydroborate (L(2)), together with zinc nitrate or zinc chloride and the corresponding thiolates, have yielded a total of 17 zinc-thiolate complexes. These comprise aliphatic as well as aromatic thiolates and a cysteine derivative. Structure determinations have confirmed the tetrahedral ZnN(2)S(2) coordination in the complexes. Upon reaction with methyl iodide, the species L(1).Zn-SR are slowly converted to L(1).Zn-I and the free thioethers CH(3)SR. A kinetic analysis has shown these alkylations to be about 1 order of magnitude slower than those of the tris(pyrazolyl)borate complexes Tp(Ph,Me)Zn-SR. Alkylations with trimethyl phosphate were found to proceed very slowly even in DMSO at 80 degrees C.
[Cu(C6H18N4)(C10H10N2)](ClO4)2, (1-benzylimidazole)[N,N-bis(2-aminoethyl)-1,2-ethanediamine]copper(II) diperchlorate (1), M(r) = 566.88, monoclinic, P2(1)/c, a = 10.549 (1), b = 9.2465 (9), c = 25.256 (2) A, beta = 101.42 (1) degrees, V = 2415 (1) A3, Z = 4, Dm = 1.54 (1), Dx = 1.559 Mg m-3, lambda (Mo K alpha) = 0.71073 A, mu = 1.18 mm-1, F(000) = 1172, T = 296 (1) K, R = 0.048, wR = 0.069 for 3063 reflections. [Zn0.99Cu0.01(C6H18N4)(C10H10N2)](ClO4)2, 1% CuII-doped (1-benzylimidazole)[N,N-bis(2-aminoethyl)-1,2-ethanediamine]zinc(II) diperchlorate (2), M(r) = 568.72, monoclinic, P2(1)/c, a = 10.708 (1), b = 9.229 (2), c = 25.205 (2) A, beta = 101.867 (8) degrees, V = 2438 (1) A3, Z = 4, Dm = 1.54 (1), Dx = 1.549, lambda (Mo K alpha) = 0.71073 A, mu = 1.30 mm-1, F(000) = 1176, T = 295 (1) K, R = 0.041, wR = 0.055 for 3282 reflections. The isostructural distorted trigonalbipyramidal MN5 cations are separated by perchlorate anions. Equatorial M--N distances are similar in both cations [range 2.083 (3) to 2.105 (3) A for (1); 2.073 (3) to 2.084 (3) A for (2)]. In contrast, the axial M--N distances differ substantially [2.043 (3) and 1.971 (3) A for (1); 2.255 (4) and 2.054 (3) A for (2)]. Axial contraction in the copper complex (1) is consistent with a dz2 ground state.
The effect of L-carnosine-zinc complex(Car-Zn) on ethanol absorption was investigated after oral administration(adm) to mice. One hour after oral adm of Car-Zn, and 14C-ethanol was given orally or intraperitoneally(i.p.). After passage of time, the blood was drawn from the tail vein, and 14C-radioactivities determined. The Car-Zn showed a dose-dependent inhibition of the appearance of 14C-radioactivities in blood following oral 14C-ethanol loading, while Zn acetate did not induce any alteration as compared with control. Car-Zn pretreatment did not induce any change in the blood 14C-radioactivity when ethanol was given i.p. The 14C-radioactivity and zinc in gastrointestinal tract after oral adm of Car-Zn and 14C-ethanol showed significantly higher levels than those of control for 7 hr. Distribution of 14C-radioactivities in other organs of Car-Zn treated mice were lower than those of control 3 hr after adm, while it was similar or higher than those of control 7 hr after adm. The excretions of 14C-radioactivity through expiration in Car-Zn group was a lower than that of control. Also, the urinary and fecal excretions of 14C-radioactivity were low values at 5.0% and 0.5% of the administered dose 72 hr after adm, respectively. Also, the 14C-radioactivities remaining in the organs did not detect or were very low values. In vitro study, Car-Zn stimulated the metabolism of ethanol to acetaldehyde and acetic acid in 9,000 g supernatant of small intestine. The major route of excretions of 14C-radioactivity may be excreted into the expired air. The results suggest that Car-Zn shows a long-term adhesive and permeable action on gastrointestinal tract in the mouse; as a result, this may inhibited ethanol absorption.
A new 7-azaindole zinc(II) compound, Zn(7-azaindole)2(CH3COO)2 (1), a new ligand N-(2-pyridyl)-7-azaindole (NPA), and two NPA zinc(II) complexes, Zn(NPA)(CH3COO)2 (2) and Zn(NPA)((S)-(+)-CH3CH2CH(CH3)COO)2 (3), have been synthesized and structurally characterized. Compound 1 has a tetrahedral geometry, whereas compounds 2 and 3 have irregular six-coordinate geometry. The NPA ligand in compounds 2 and 3 functions as a bidentate chelate to the zinc center. Compound 1 has a blue luminescence in the solution and the solid state. Compounds 2 and 3 emit a blue color in the solid state. In solution, compounds 2 and 3 are fluxional, as established by 1H NMR experiments. Compound 1 is thermally stable, whereas compounds 2 and 3 undergo decomposition when heated in the solid state. A blue electroluminescent device using compound 1 as the emitting layer has been fabricated. Crystal data: NPA, monoclinic, P2(1)/c, a = 13.993(5) A, b = 8.456(3) A, c = 16.886(5) A, beta = 104.666(12) degrees, V = 1932.9(11) A3; 1, triclinic, P1, a = 9.5114(18) A, b = 10.460(7) A, c = 11.002(3) A, alpha = 117.18(3) degrees, beta = 103.287(18) degrees, gamma = 90.94(2) degrees, V = 938.3(7) A3; 2, monoclinic, C2/c, a = 13.234(6) A, b = 9.373(3) A, c = 13.956(7) A, beta = 113.24(3) degrees, V = 1590.7(12) A3; 3, monoclinic, P2(1), a = 11.047(7) A, b = 15.343(9) A, c = 13.785(8) A, beta = 100.123(9) degrees, V = 2300(2) A3.