Pericyclic reactions may be the most important class of organic reactions. Certainly, the mechanisms of these reactions have been the subject of the most heated and interesting controversies. Woodward and Hoffmann defined the concept of a pericyclic reaction: a concerted reaction in which all bonds are made or broken around a circle. Although the Woodward-Hoffmann rules declare what may and may not happen, the rules served not to settle mechanistic questions but to raise the stakes on what were already lively controversies. This Account traces 60 years of

The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led to the discovery of compound 24 (PF-00868554). Compound 24 is a potent and selective HCV polymerase inhibitor with a favorable pharmacokinetic profile and has recently entered a phase II clinical evaluation in patients with genotype 1 HCV.

We have identified a sine oculis gene in the planarian Girardia tigrina (Platyhelminthes; Turbellaria; Tricladida). The planarian sine oculis gene (Gtso) encodes a protein with a sine oculis (Six) domain and a homeodomain that shares significant sequence similarity with so proteins assigned to the Six-2 gene family. Gtso is expressed as a single transcript in both regenerating and fully developed eyes. Whole-mount in situ hybridization studies show exclusive expression in photoreceptor cells. Loss of function of Gtso by RNA interference during planarian regeneration inhibits eye regeneration completely. Gtso is also essential for maintenance of the differentiated state of photoreceptor cells. These results, combined with the previously demonstrated expression of Pax-6 in planarian eyes, suggest that the same basic gene regulatory circuit required for eye development in Drosophila and mouse is used in the prototypic eye spots of platyhelminthes and, therefore, is truly conserved during evolution.homeobox ͉ eye morphogenesis ͉ platyhelmint ͉ eye evolution T he study of the genetic network that regulates the development of the Drosophila visual system has resulted in the identification of several transcription factors and other nuclear proteins that are required for the specification of early eye morphogenesis (1-4). These factors seem to act in a hierarchy in which sine oculis (so) is regulated directly by Pax-6 (5, 6), the master control function. In turn, so requires eyes absent (eya), encoding a nuclear protein (7), to induce ectopic eyes (4). This genetic pathway has been established in Drosophila (8), but homologous proteins also regulate eye development in vertebrates, suggesting that this regulatory network is old, is conserved in evolution, and has been adapted to the control of development of different visual systems found in both clades (9). Both the identification and functional characterization of homologous genes in more primitive organisms, such as the platyhelminthes, will help to clarify the age and extent of conservation of this genetic cascade.Sine oculis is a homeobox-containing gene that is required for the development of the visual system in Drosophila (10, 11). A murine homologue, Six3, is expressed in the developing eye (12). In both of these model systems, so and Six are expressed early in eye development as well as in other structures. Combined overexpression of so and eya in Drosophila induces ectopic eyes (4), whereas, in vertebrates, Six3 overexpression results in ectopic lens formation (13,14). Planarians (Platyhelminthes; Turbellaria; Tricladida) are located at the base of the Lophotrochozoa Protostomia clade (15, 16). The eye spots of planarians are one of the most ancestral and simple types of visual systems, close to the prototypic eye proposed by Charles Darwin (see ref.8). The planarian eye spots consist of two cell types: a bipolar nerve cell with a rhabdomere as a photoreceptive structure and a cup-shaped structure composed of pigment cells (17). During head regeneration, new e...

PF-00868554 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase, which exerts its inhibitory effect by binding to the thumb base domain of the protein. It is a potent and selective inhibitor, with a mean 50% inhibitory concentration of 0.019 M against genotype 1 polymerases and a mean 50% effective concentration (EC 50 ) of 0.075 M against the genotype 1b-Con1 replicon. To determine the in vitro antiviral activity of PF-00868554 against various HCV strains, a panel of chimeric replicons was generated, in which polymerase sequences derived from genotype 1a and 1b clinical isolates were cloned into the 1b-Con1 subgenomic reporter replicon. Our results indicate that PF-00868554 has potent in vitro antiviral activity against a majority (95.8%) of genotype 1a and 1b replicons, with an overall mean EC 50 of 0.059 M. PF-00868554 showed no cytotoxic effect in several human cell lines, up to the highest concentration evaluated (320 M). Furthermore, the antiviral activity of PF-00868554 was retained in the presence of human serum proteins. An in vitro resistance study of PF-00868554 identified M423T as the predominant resistance mutation, resulting in a 761-fold reduction in susceptibility to PF-00868554 but no change in susceptibility to alpha interferon and a polymerase inhibitor that binds to a different region. PF-00868554 also showed good pharmacokinetic properties in preclinical animal species. Our results demonstrate that PF-00868554 has potent and broadspectrum antiviral activity against genotype 1 HCV strains, supporting its use as an oral antiviral agent in HCV-infected patients.

Molecular modeling calculations using high-level ab initio methods (MP2/6-31+G) of a new type of spiro beta-lactams predict that these systems could adopt a beta-turn secondary structure in solution. Strong intramolecular hydrogen bonds stabilize the beta-turn conformation with a geometry that is very close to the ideal type II beta-turns. The synthesis of the spiro beta-lactams is achieved by Staudinger reaction of a cyclic ketene derived from N-bencyloxycarbonyl-L-proline acid chloride with an imine. This reaction allows the formation of the spiranic backbone in a single-step with high diastereoselectivity and good yields. The new spiro beta-lactams obtained are the core for the preparation of different types of peptidomimetics using well-established peptide chemistry. The NMR conformational analysis shows that these compounds adopt beta-turn conformation as predicted by the theoretical studies.

An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.

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A series of 7-azabicyclo[2.2.l]hept-5-ene complexes are prepared from [0s(NH3)5(q2-L)l2+ (L = pyrrole, 1-methylpyrrole, 2,5-dimethylpyrrole, 1,2,5-trimethylpyrrole, or 1-(trimethylsily1)pyrrole) and various dipolarophiles (e.g., acrylonitrile, methyl acrylate, a-methylene-y-butyrolactone, dimethyl maleate, dimethyl fumarate, N-phenyl maleimide, cyclopentene-1,2-dicarboxylic acid anhydride, and (E>-and (a-methyl 3-(3'-pyridyl)acrylate). The cycloaddition is promoted by coordination of the pyrrole with [Os(NH&]*+ across C3 and C4, transforming the uncoordinated portion of the pyrrole nucleus into an azomethine ylide capable of undergoing 1,3-dipolar cycloadditions.The metal serves not only to activate the pyrrole ring but also to stabilize the resulting 7-azabicyclo[2.2.l]heptene ligands. A number of organic 7-azabicyclo[2.2. llheptanes, including analogs of the alkaloid epibatidine, have been synthesized by this methodology. For the cases examined, the cycloaddition favors ex0 stereochemistry of the electronwithdrawing substituent when the pyrrole nitrogen is unsubstituted. Crystal structures have been determined for the complexes obtained from the reactions of pyrrole with N-phenylmaleimide @a), 2,5dimethylpyrrole with dimethyl maleate (13a), and 2,5-dimethylpyrrole with a-methylene-y-butyrolactone (22a).