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The design and preliminary SAR of a new series of 1H-quinazolin-4-one (QAZ) allosteric HCV NS5B thumb pocket 2 (TP-2) inhibitors was recently reported. To support optimization efforts, a molecular dynamics (MD) based modeling work...
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The design and preliminary SAR of a new series of 1H-quinazolin-4-one (QAZ) allosteric HCV NS5B thumb pocket 2 (TP-2) inhibitors was recently reported. To support optimization efforts, a molecular dynamics (MD) based modeling workflow was implemented, providing information on QAZ binding interactions with NS5B. This approach predicted a small but critical ligand-binding induced movement of a protein backbone region which increases the pocket size and improves access to the backbone carbonyl groups of Val 494 and Pro 495. This localized backbone shift was consistent with key SAR results and was subsequently confirmed by X-ray crystallography. The MD protocol guided the design of inhibitors, exploiting novel H-bond interactions with the two backbone carbonyl groups, leading to the first thumb pocket 2 NS5B inhibitor with picomolar antiviral potency in genotype (gt) 1a and 1b replicons (EC_(50) = 120 and 110 pM, respectively) and with EC_(50) ≤ 80 nM against gt 2?6.
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All key biological macromolecules are susceptible to carbonylation - an irreparable oxidative damage with deleterious biological consequences. Carbonyls in proteins, lipids and DNA from cell extracts have been used as a biomarker ...
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All key biological macromolecules are susceptible to carbonylation - an irreparable oxidative damage with deleterious biological consequences. Carbonyls in proteins, lipids and DNA from cell extracts have been used as a biomarker of oxidative stress and aging, but formation of insoluble aggregates by carbonylated proteins precludes quantification. Since carbonylated proteins correlate with and become a suspected cause of morbidity and mortality in some organisms, there is a need for their accurate quantification and localization. Using appropriate fluorescent probes, we have developed an in situ detection of total proteins, DNA, RNA, lipids and carbonyl groups at the level of the whole organism. In C. elegans, we found that after UV irradiation carbonylation co-localizes mainly with proteins and, to a lesser degree, with DNA, RNA and lipids. The method efficiency was illustrated by carbonylation induction assessment over 5 different UV doses. The procedure enables the monitoring of carbonylation in the nematode C. elegans during stress, aging and disease along its life cycle including the egg stage.
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Still going strong in his seventies, Professor Howard Alper continues to make an impact on chemistry internationally. This Account highlights some of his key scientific achievements in catalysis. What began as a fundamental intere...
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Still going strong in his seventies, Professor Howard Alper continues to make an impact on chemistry internationally. This Account highlights some of his key scientific achievements in catalysis. What began as a fundamental interest in the chemistry of metal carbonyls and their activity modes, evolved into a versatile program addressing some of the most significant and challenging issues in catalysis. Using well-defined metal carbonyl complexes, he and his lab were able to make fundamental insights into diverse transformations involving the catalytic properties of metal carbonyls, including carbonylative ring expansions. His creative and truly interdisciplinary research in catalysis has also resulted in notable contributions to carbonylation, hydrofunctionalization, and cycloaddition chemistry.
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Intermediates of the cobalt carbonyl-catalysed carbonylation of ortho-substituted benzyl haides were identified by IR,~1H-and ~13C-NMR spectra.The molecular structures of the acyl-type derivatives 2-MeC_6H-4CH_2C(O)Co(CO)_3PPh_3 a...
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Intermediates of the cobalt carbonyl-catalysed carbonylation of ortho-substituted benzyl haides were identified by IR,~1H-and ~13C-NMR spectra.The molecular structures of the acyl-type derivatives 2-MeC_6H-4CH_2C(O)Co(CO)_3PPh_3 and 2-PhC_6H_4CH_2C(O)Co(CO)_3PPh_3 were determined by X-ray crystallography.Structural features of these complexes are discussed.
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Dimethyl formamide (DMF) can be a convenient source of the carbonyl ligand in the coordination chemistry of rhodium, ruthenium, iridium, and platinum. We have undertaken a thorough study concerning the course of this reaction. In ...
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Dimethyl formamide (DMF) can be a convenient source of the carbonyl ligand in the coordination chemistry of rhodium, ruthenium, iridium, and platinum. We have undertaken a thorough study concerning the course of this reaction. In a first step, DMF-containing complexes are produced, which is usually accompanied by chloride redistribution. Then, upon refluxing, carbonyl species in the same oxidation state are obtained, presumably as a result of HCl-mediated DMF decomposition. Provided that water levels are kept low,reduction can occur to provide the complexes [NH_2(CH_3)_2]- [RhCl_2(CO)_2], [NH_2(CH_3)_2][RuCl_3(CO)_2(DMF)], [RuCl_2(CO)_2- (DMF)_2], and [NH_2(CH_3)_2][IrCl_2(CO)_2]. In the case of plat- inum, reduction is not effective and [NH_2(CH_3)_2][PtCl_3(CO)] is obtained. No carbonylpalladium species can be synthesized in this way, the reaction producing copious amounts of colloidal metal. Adding phosphanes to these chlorocarbonyl-containing solutions allows easy, one-step syntheses of a variety of complexes.
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Treating the phenylvinyldene manganese complex Cp(CO)_2MnC ~1C~2HPh, 1, with [Fe(CO)_4 yields the binuclear μ-vinylidene complex Cp(CO)_2MnFe(μ-C~1C ~2HPh)(CO)_4, 2, that further isomerizes to the carbonylated product η~4-[Cp(C...
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Treating the phenylvinyldene manganese complex Cp(CO)_2MnC ~1C~2HPh, 1, with [Fe(CO)_4 yields the binuclear μ-vinylidene complex Cp(CO)_2MnFe(μ-C~1C ~2HPh)(CO)_4, 2, that further isomerizes to the carbonylated product η~4-[Cp(CO)_2MnC~1(CO)C ~2HPhFe(CO)_3, 3. In a computational study of the mechanism using a hybrid density functional method, we considered two stereoisomers for species 2 and 3 where the phenyl group at center C~2 is oriented in cis (E form) or trans (Z form) fashion to the Cp(CO)_2Mn unit. Isomers 2E and 2Z were calculated to be degenerate whereas the experimentally detected species 3E is 8 kcal/mol more stable than its isomer 3Z. The two-step pathway 1 ~→ 2Z ~→ 3E was calculated to be the lowest-energy route with the highest activation barrier at 12 kcal/mol. The activation energy of the alternative single-step pathway 1 ~→ 3E is 19 kcal/mol. We rationalized the stabilization of the ground state of 3E and the transition states leading to or starting from isomer 2Z as conjugation effect between the Mn-CC metallaallene fragment and the co-planar phenyl ring.
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[M_3(CO)_(12)], [H_4M_4(CO)_(12)], [H_3M_4(CO)_(12)]~- (M = Ru, Os) and [Ru_6C(CO)_(16)]~(2-) have been synthesized in high yields by one-pot controlled reduction at atmospheric pressure of MCl_3 or [M(CO)_3Cl_2]_2, dissolved in t...
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[M_3(CO)_(12)], [H_4M_4(CO)_(12)], [H_3M_4(CO)_(12)]~- (M = Ru, Os) and [Ru_6C(CO)_(16)]~(2-) have been synthesized in high yields by one-pot controlled reduction at atmospheric pressure of MCl_3 or [M(CO)_3Cl_2]_2, dissolved in t-amyl alcohol or ethylene glycol, working in the presence of alkali carbonates. The selectivity of the reduction is controlled by the: (i) nature and quantity of the alkali carbonate (Na_2CO_3 or K_2CO_3); (ii) nature of the solvent; (iii) gas-phase composition (CO or CO + H_2); (iv) temperature and (v) reaction time. Yields are so high and reaction conditions so mild that, in most cases, these new syntheses are more convenient than those previously reported either in solution or on the silica surface as reaction medium.
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Despite the fact that many transition-metal-catalyzed reactions of organosulfur compounds with internal alkynes are ineffective, cobalt carbonyl (Co_2(CO)_8) is an excellent catalyst for carbonylative cyclization of internal alkyn...
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Despite the fact that many transition-metal-catalyzed reactions of organosulfur compounds with internal alkynes are ineffective, cobalt carbonyl (Co_2(CO)_8) is an excellent catalyst for carbonylative cyclization of internal alkynes with carbon monoxide. When Co_2(CO)_8-catalyzed reactions of internal alkynes with organic thiols are conducted in acetonitrile under 4 MPa pressure of carbon monoxide, thiolative lactonization of internal alkynes successfully takes place with incorporation of two molecules of CO. This carbonylation provides a useful tool to prepare the corresponding α,β-unsaturated γ-thio-γ-lactones (butenolide derivatives) in good yields. In the cases of unsymmetrical alkynes, such as 2-octyne and 6-methyl-2-heptyne, the thiolative lactonization proceeds with moderate regioselectivity to give the butenolide derivatives on which the carbonyl group preferentially bonds to the less hindered acetylenic carbon. Mechanistic pathways about the present thiolative lactonization are also discussed.
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An important recent development in metal disulfide chemistry is the 2001 synthesis by Adams et al. of Mn_2S_2(μ-CO)(CO)_6 containing both a bridging disulfide ligand and a bridging carbonyl group. During the ensuing decade this m...
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An important recent development in metal disulfide chemistry is the 2001 synthesis by Adams et al. of Mn_2S_2(μ-CO)(CO)_6 containing both a bridging disulfide ligand and a bridging carbonyl group. During the ensuing decade this manganese complex has proven to be a key intermediate for the synthesis of diverse manganese carbonyl sulfur derivatives, including heterometallic complexes, phosphine, arsine, and thioether derivatives. The related series of Mn_2S_2(CO)_n complexes (n = 10, 9, 8, 7, 6) has now been studied by density functional theory. The lowest energy Mn_2S_2(CO)_(10) structures have two Mn(CO)_5 units bridged by a symmetrical two-electron donor disulfide ligand without a metal-metal bond. This structure may be derived from dimethyl disulfide by replacement of both methyl groups with isolobal Mn(CO)_5 groups. Decarbonylation of this Mn_2S_2(CO)_(10) structure gives the lowest energy Mn_2S_2(CO)_9 structure containing an unprecedented unsymmetrical four-electron donor bridging disulfide ligand and still no metal-metal ond. However, this Mn_2S_2(CO)_9 structure is predicted to be thermodynamically unstable with respect to disproportionation into Mn_2S_2(CO)_(10)+Mn_2S_2(CO)_8. The lowest energy Mn_2S_2(CO)_8 structure has a sulfurbridging carbonyl group as well as a carbonyl group bridging an Mn-Mn bond. Removal of this sulfurbridging carbonyl group gives the lowest energy Mn_2S_2(CO)_7 structure. This structure corresponds to the experimental Mn_2S_2(μ-CO)(CO)_6 structure synthesized by Adams et al., which has a carbonyl-bridged Mn-Mn single bond. For Mn2S2(CO)6, one of the two low-energy structures can be derived from this Mn_2S_2(μ-CO)(CO)_6 structure by loss of the bridging carbonyl group. The other low-energy Mn_2S_2(CO)_6 structure has two Mn(CO)_3 groups joined by an Mn-Mn bond, which is bridged by two separate sulfide (S) ligands.
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The benzyl-type cobalt carbonyl complexes (para-~tBuC_6H_4Co(CO)_3PPh_3) (4) and [para-ClC_6H_4CH_2C(O)]Co(CO)_3PPh_3 (5) were prepared and characterized by analyses, spectra and X-ray single-crystal diffraction. The overall struc...
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The benzyl-type cobalt carbonyl complexes (para-~tBuC_6H_4Co(CO)_3PPh_3) (4) and [para-ClC_6H_4CH_2C(O)]Co(CO)_3PPh_3 (5) were prepared and characterized by analyses, spectra and X-ray single-crystal diffraction. The overall structures both of the alkylcobalt-type 4 and the acylcobalt-type 5 display trigonal bipyramidal geometry, with the two noncarbonyl ligands in the two axial positions. The relevance of the stereochemistry of complexes 4 and 5 to the supposed mechanism of the CO insertion/deinsertion on cobalt is discussed.
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