Thomas G. Gray

Neuraminidase Is Important for the Initiation of Influenza Virus Infection in Human Airway Epithelium

ABSTRACT Influenza virus neuraminidase (NA) plays an essential role in release and spread of progeny virions, following the intracellular viral replication cycle. To test whether NA could also facilitate virus entry into cell, we infected cultures of human airway epithelium with human and avian influenza viruses in the presence of the NA inhibitor oseltamivir carboxylate. Twenty- to 500-fold less cells became infected in drug-treated versus nontreated cultures (P < 0.0001) 7 h after virus application, indicating that the drug suppressed the initiation of infection. These data demonstrate that viral NA plays a role early in infection, and they provide further rationale for the prophylactic use of NA inhibitors.

Hexanuclear and higher nuclearity clusters of the Groups 4–7 metals with stabilizing π-donor ligands

Abstract The chemistry of early transition element clusters with π-donor ligands is growing rapidly. We review the syntheses of these compounds, with an emphasis on progress in the last 6 years. The predominant synthetic routes to such clusters are spontaneous self-assembly, apparent fragment condensation, excision from solids, and global ligand substitution. Mechanistic conclusions about cluster-forming reactions are discussed where possible. We conclude with prospects for future research.

Homoleptic, Four-Coordinate Azadipyrromethene Complexes of d10 Zinc and Mercury

Tetraarylazadipyrromethenes, and especially their boron chelates, are a growing class of chromophores that are photoactive toward red light. The coordination chemistry of these ligands remains to be explored. Reported here are four-coordinate zinc(II) and mercury(II) complexes of tetraarylazadipyrromethene ligands. The new complexes contain two azadipyrromethenes bound per d(10) metal center and are characterized by (1)H NMR, optical absorption spectroscopy, X-ray diffraction crystallography, and elemental analysis. Solid-state structures show that these bis-chelate complexes distort significantly from idealized D2d symmetry. AM1 geometry optimizations indicate relaxation energies in the range of 6.8-15.2 kcal mol(-1); interligand pi-stacking provides an added energetic impetus for distortion. The absorption spectra show a marked increase in the absorption intensity in the red region and, in the case of the zinc(II) complexes, the development of a second distinct absorption band in this region, which is red-shifted by ca. 40-50 nm relative to the free ligand. Semiempirical INDO/S computations indicate that these low-energy optical absorptions derive from allowed excitations among ligand-based orbitals that derive from the highest occupied molecular orbital and lowest unoccupied molecular orbital of the free azadipyrromethene.

Bonding and Reactivity of a μ‐Hydrido Dicopper Cation

A bent dicopper-hydride cation that has an N-heterocyclic carbene supporting ligand has a Cu-H-Cu angle of 122° in the solid state. Density functional theory suggests an open three-centered metal-hydrogen interaction. The hydride reacts readily with methanol and with carbon dioxide; insertion of phenylacetylene affords a gem-dicopper vinyl complex.

Subpicosecond intersystem crossing in mono- and di(organophosphine)gold(I) naphthalene derivatives in solution.

Femtosecond-to-microsecond broadband transient absorption experiments are reported for Cy(3)PAu(2-naphthyl) (1), (Cy(3)PAu)(2)(2,6-naphthalenediyl) (2), and (Cy(3)PAu)(2)(2,7-naphthalenediyl) (3), where Cy = cyclohexyl. Global and target analyses of the data, based on a sequential kinetic model, reveal four spectral components. These components are assigned to (1) excited state absorption (ESA) of the ligand-centered S(1) state; (2) ESA of a receiver ligand-to-metal or metal-to-ligand charge transfer triplet state (τ(1) ≤ 300 fs); (3) ESA of the vibrationally excited, ligand-centered T(1) state (τ(3) = 7-10 ps); and (4) ESA of the relaxed T(1) state. Intersystem crossing (ISC) occurs in hundreds of femtoseconds, while internal conversion (IC) in the triplet manifold is slow (τ(2) ≈ 2 ps). The relaxed T(1) state shows biphasic decay kinetics in 2 and 3 with lifetimes of hundreds of picoseconds and hundreds of nanoseconds in air-saturated conditions, while only monophasic decay is observed in 1 under identical conditions. The primary decay pathway of the T(1) state is assigned to quenching by O(2), while the secondary channel is tentatively assigned to self-quenching or triplet-triplet annihilation. The ISC rate in 1 is not modulated significantly by the incorporation of a second heavy-atom group effecter. Instead, the position at which the second Au(I)-phosphine group is attached plays a noticeable role in the ISC rate, showing a 3-fold decrease in that of 2 compared to that of 3. The results challenge the conventional view that the rate of IC is larger than that of ISC, lending further support to the emerging kinetic model proposed for other transition-metal complexes. Gold(I) now joins the exclusive group of transition metals known to form organometallic complexes exhibiting excited-state nonequilibrium dynamics.

Catalytic Aerobic Oxidation by a Trianionic Pincer CrIII/CrV Couple

Aerobic oxidation that incorporates both O atoms into a substrate (PPh(3)) is achieved by employing a Cr(III)/Cr(V)[triple bond]O catalytic couple. A terphenyl trianionic pincer ligand stabilizes a high oxidation state Cr(V)[triple bond]O complex, and both the reduced (Cr(III), IR/X-ray) and oxidized (Cr(V)[triple bond]O, electron paramagnetic resonance/IR/X-ray) participants in the catalytic cycle are characterized.

Room-temperature synthesis of cyclometalated iridium(III) complexes: kinetic isomers and reactive functionalities

Cyclometalated iridium(III) complexes have been prepared in high yields from base-assisted transmetalation reactions of cis-bis(aquo)iridium(III) complexes with boronated aromatic proligands. Reactions proceed at room temperature. Potassium hydroxide and potassium phosphate are effective supporting bases. Kinetic, meridional isomers are isolated because of the mildness of the new technique. Syntheses are faster with KOH, but the gentler base K3PO4 broadens the reactions scope. Complexes of chelated ketone, aldehyde, and alcohol complexes are reported that bind iridium through formally neutral oxygen and formally anionic carbon. The new complexes luminesce with microsecond-scale lifetimes at 77 K and nanosecond-scale lifetimes at room temperature; emission quenches in air. Two complexes, an aldehyde and its reduced (alcohol) derivative, are crystallographically characterized. Their bonding is examined with density-functional theory calculations. Time-dependent computations suggest that the Franck–Condon triplet states of these complexes have mixed orbital parentage, arising from one-particle transitions that mingle through configuration interaction.

Constrained Digold(I) Diaryls: Syntheses, Crystal Structures, and Photophysics

A series of di(gold(I) aryls), L(AuR)(2) (L = DPEphos, DBFphos, or Xantphos; R = 1-naphthyl, 2-naphthyl, 9-phenanthryl, or 1-pyrenyl), have been prepared. The complexes were characterized by multinuclear NMR spectroscopy, static and time-dependent optical spectroscopy, mass spectrometry, microanalysis, and X-ray crystallography. In addition, DFT calculations on model dinuclear gold complexes have been used to examine the electronic structures. Photophysical properties of the dinuclear complexes have been compared to mononuclear analogues. Low-temperature excited-state lifetimes for both the mononuclear and dinuclear complexes in toluene indicate triplet-state emission. Time-resolved DFT calculations suggest that emission originates from aryl-ligand transitions, even if the LUMO resides elsewhere.

Gold-containing indoles as anticancer agents that potentiate the cytotoxic effects of ionizing radiation.

This report describes the design and application of several distinct gold-containing indoles as anticancer agents. When used individually, all gold-bearing compounds display cytostatic effects against leukemia and adherent cancer cell lines. However, two gold-bearing indoles show unique behavior by increasing the cytotoxic effects of clinically relevant levels of ionizing radiation. Quantifying the amount of DNA damage demonstrates that each gold-indole enhances apoptosis by inhibiting DNA repair. Both Au(I)-indoles were tested for inhibitory effects against various cellular targets including thioredoxin reductase, a known target of several gold compounds, and various ATP-dependent kinases. While neither compound significantly inhibits the activity of thioreoxin reductase, both showed inhibitory effects against several kinases associated with cancer initiation and progression. The inhibition of these kinases provides a possible mechanism for the ability of these Au(I)-indoles to potentiate the cytotoxic effects of ionizing radiation. Clinical applications of combining Au(I)-indoles with ionizing radiation are discussed as a new strategy to achieve chemosensitization of cancer cells.

Synthesis, Structures, and Properties of 1,2,4,5-Benzenetetrathiolate Linked Group 10 Metal Complexes

Dimetallic compounds [(P-P)M(S(2)C(6)H(2)S(2))M(P-P)] (M = Ni, Pd; P-P = chelating bis(phosphine), 3a-3f) are prepared from O=CS(2)C(6)H(2)S(2)C=O or (n)Bu(2)SnS(2)C(6)H(2)S(2)Sn(n)Bu(2), which are protected forms of 1,2,4,5-benzenetetrathiolate. Selective monodeprotections of O=CS(2)C(6)H(2)S(2)C=O or (n)Bu(2)SnS(2)C(6)H(2)S(2)Sn(n)Bu(2) lead to [(P-P)Ni(S(2)C(6)H(2)S(2)C=O)] or [(P-P)Ni(S(2)C(6)H(2)S(2)Sn(n)Bu(2))]; the former is used to prepare trimetallic compounds [(dcpe)Ni(S(2)C(6)H(2)S(2))M(S(2)C(6)H(2)S(2))Ni(dcpe)] (M = Ni (6a) or Pt (6b); dcpe = 1,2-bis(dicyclohexylphosphino)ethane). Compounds 3a-3f are redox active and display two oxidation processes, of which the first is generally reversible. Dinickel compound [(dcpe)Ni(S(2)C(6)H(2)S(2))Ni(dcpe)] (3d) reveals two reversible oxidation waves with DeltaE(1/2) = 0.66 V, corresponding to K(c) of 1.6 x 10(11) for the mixed valence species. Electrochemical behavior is unstable to repeated scanning in the presence of [Bu(4)N][PF(6)] electrolyte but indefinitely stable with Na[BArF(24)] (BArF(24) = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate), suggesting that the radical cation generated by oxidation is vulnerable to reaction with PF(6)(-). Chemical oxidation of 3d with [Cp(2)Fe][BArF(24)] leads to formation of [3d][BArF(24)]. Structural identification of [3d][BArF(24)] reveals appreciable shortening and lengthening of C-S and C-C bond distances, respectively, within the tetrathioarene fragment compared to charge-neutral 3d, indicating this to be the redox active moiety. Attempted oxidation of [(dppb)Ni(S(2)C(6)H(2)S(2))Ni(dppb)] (3c) (dppb = 1,2-bis(diphenylphosphino)benzene) with AgBArF(24) produces [[(dppb)Ni(S(2)C(6)H(2)S(2))Ni(dppb)](2)(mu-Ag(2))][BArF(24)](2), [4c][BArF(24)](2), in which no redox chemistry has occurred. Crystal structures of bis(disulfide)-linked compounds [(P-P)Ni(S(2)C(6)H(2)(mu-S(2))(2)C(6)H(2)S(2))Ni(P-P)] are reported. Near IR spectroscopy upon cationic [3d](+) and neutral 6a reveals multiple intense absorptions in the 950-1400 nm region. Time-dependent density functional theory (DFT) calculations on a 6a model compound indicate that these absorptions are transitions between ligand-based pi-type orbitals that have significant contributions from the sulfur p orbitals.