Chutes and Ladders is an exciting up-and-down-again game in which players race to be the first to the top of the board. Along the way, they will find ladders to help them advance, and chutes that will cause them to move backwards. The development of nucleoside analogs for clinical treatment of hepatitis C presents a similar scenario in which taking shortcuts may help quickly advance a program, but there is always a tremendous risk of being sent backwards as one competes for the finish line. In recent years the treatment options for chronic hepatitis C virus (HCV) infection have expand due to the development of a replicon based in vitro evaluation system, allowing for the identification of multiple drugable viral targets along with a concerted and substantial drug discovery effort. Three major drug targets have reached clinical study for chronic HCV infection: the NS3/4A serine protease, the large phosphoprotein NS5A, and the NS5B RNA-dependent RNA polymerase. Recently, two oral HCV protease inhibitors were approved by the FDA and were the first direct acting anti-HCV agents to result from the substantial research in this area. There are currently many new chemical entities from several different target classes that are being evaluated worldwide in clinical trials for their effectiveness at achieving a sustained virologic response (SVR) (Pham et al., 2004; Radkowski et al., 2005). Clearly the goal is to develop therapies leading to a cure that are safe, widely accessible and available, and effective against all HCV genotypes (GT), and all stages of the disease. Nucleoside analogs that target the HCV NS5B polymerase that have reached human clinical trials is the focus of this review as they have demonstrated significant advantages in the clinic with broader activity against the various HCV GT and a higher barrier to the development of resistant viruses when compared to all other classes of HCV inhibitors.
Abstractα-Amino acid thiol esters derived from N-protected mono-, di-, and tripeptides couple with aryl, π-electron-rich heteroaryl, or alkenyl boronic acids in the presence of stoichiometric Cu(I) thiophene-2-carboxylate (CuTC) and catalytic Pd 2 (dba) 3 /triethylphosphite to generate the corresponding Nprotected peptidyl ketones in good to excellent yields and in high enantiopurity. Triethylphosphite plays a key role as a supporting ligand by mitigating an undesired palladium-catalyzed decarbonylation-β-elimination of the α-amino thiol esters. The peptidyl ketone synthesis proceeds at room temperature under non-basic conditions and demonstrates a high tolerance to functionality.
The electronic and magnetic properties of the newly synthesized single-layer (1 L) transition-metal dichalcogenide (TMD) PtSe2 are studied by first-principles calculations. We find the strain or selenium vacancy (VSe) alone cannot induce the magnetism. However, an interplay between strain and VSe leads to the magnetism due to the breaking of Pt-Pt metallic bonds. Different from the case of 1 L-MoS2 with VS, the defective 1 L-PtSe2 has the spatially extended spin density, which is responsible for the obtained long range ferromagnetic coupling. Moreover, the 1 L-PtSe2 with VSe undergoes a spin reorientation transition from out-of-plane to in-plane magnetization, accompanying a maximum magnetocrystalline anisotropy energy of ∼9–10.6 meV/VSe. These results indicate the strain not only can effectively tune the magnetism but also can manipulate the magnetization direction of 1 L-TMDs.
Among the reported two-dimension macrocycles, bi- and tetra-nuclear macrocyclic metallasupramolecules are designed to have novel specific cavities with different shapes and dimensions, and demonstrate good selectivity and binding for planar aromatic guests and small organic molecules. This feature article focus on the progress in the development of host-guest behavior of bi- and tetra-nuclear macrocyclic metallasupramolecules. Examples in which X-ray structural determination is essential for establishing the real composition and geometry of the host-guest systems are highlighted.
Described herein is a Cu-catalyzed transformation of peptidic thiol esters and boronic acids into peptidyl ketones that takes place at room temperature in DMF or in DMF/H 2 O open to air and uses only catalytic quantities of a Cu carboxylate to mediate the reaction. This aerobic transformation occurs only at a thiol ester capable of coordinating to Cu through its S-appendage and is hampered neither by racemization of the reactants or products, nor by the presence of disulfides or of unprotected phenols, alcohols, or indoles. KeywordsC-C coupling; Cross-coupling; Synthetic methods; Copper; Peptidomimetics; Protein modifications In recent decades great strides have been made in uncovering novel methods for the metalcatalyzed construction of C-C and C-X bonds from organic halides/sulfonates/ phosphonates [1][2][3][4][5][6][7][8][9][10][11] and through C-H functionalization. [12][13][14][15][16][17][18][19][20][21][22][23][24] The great majority of these metal-catalyzed couplings are now carried out using mild organic transfer agents such as boronic acids, organostannanes, and organosilanes. The synthetic power and breadth of impact of these modern methods for the efficient and selective generation of a variety of bond types in a vast array of target molecules is unquestioned. And, yet, significant unmet challenges remain for the synthetic scientist to address. One holy grail is the highly chemoselective, nonenzymatic formation of a C-C or C-X bond at a specific site on a functionally complex biomolecule under biologically relevant conditions (i.e., minimal or no protecting groups, ambient temperatures, neutral pH reaction conditions, aerobic or anaerobic conditions, compatibility with protic solvents). [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] NIH Public Access In probing the value of Cu-catalyzed, aerobic, desulfitative coupling for the construction of peptidyl ketones, a control experiment using tryptophan-derived thiol esters validated the importance of the nature of the thiol ester S-pendant on the substrate reactivity (Scheme 1): at 50 °C in DMF with 5 mol % Cu I 3-methylsalicylate (CuMeSal) the reaction occurred only with the tryptophan derived thiophenyl ester bearing an ortho CONHt-Bu group and not with the simple thiophenyl ester.This result clearly confirmed that a coordinating moiety on the pendant group of the thiol ester is a requisite condition for this Cu-catalyzed, aerobic reaction. As described in the initial manuscript disclosing the "second generation" desulfitative coupling,[73] the reaction is rendered catalytic in Cu under aerobic conditions through "scavenging" of the thiolate residue with a second sacrificial equivalent of the boronic acid. A Cu-centered transmetalation/ reductive elimination sequence generates a thioether thus removing thiolate from the reaction system and regenerating Cu I for subsequent reaction with O 2 and continuation of the catalytic cycle.A brief study of the influence of the nature of the ortho-positioned amide group on the obs...
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