In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.

Objective: Polycystic ovary syndrome (PCOS) is a frequent reproductive and metabolic disorder associated with insulin resistance (IR). Berberine (BBR) is an isoquinoline derivative alkaloid extracted from Chinese medicinal herbs that has been used as an insulin sensitizer. BBR may have a potential therapeutic value for PCOS. The aim of this study was to evaluate the effects of BBR in comparison to metformin (MET) on the metabolic features of women with PCOS. Design and methods: Eighty-nine subjects with PCOS and IR subjects were randomized into one of three treatment groups: BBRCcompound cyproterone acetate (CPA; nZ31), METCCPA (nZ30), and placeboCCPA (nZ28) for 3 months. Clinical characteristics of the women and metabolic and hormonal parameters were assessed before and after the period of treatment. Results: Treatment with BBR in comparison to MET showed decrease in waist circumference and waistto-hip ratio (WHR; P!0.01), total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDLC; P!0.05) as well as increase in high-density lipoprotein cholesterol (HDLC) and sex hormone-binding globulin (SHBG; P!0.05). Similarly, treatment with BBR in comparison to placebo showed decrease in WHR, fasting plasma glucose, fasting insulin, homeostasis model assessment for IR, area under the curve of insulin, TC, LDLC, and TG (P!0.05) as well as increase in HDLC and SHBG (P!0.01). Conclusions: Intake of BBR improved some of the metabolic and hormonal derangements in a group of treated Chinese women with PCOS. Main effects could be related to the changes in body composition in obesity and dyslipidemia. Further controlled studies are needed for the assessment of the potential favorable metabolic effects of BBR in women with PCOS.

A convergent diastereo- and enantioselective total synthesis of anti-HIV agent chloropeptin I is reported. Important features of the total synthesis include: (1) the use of Ti-catalyzed cyanide addition to imines to prepare a requisite amino acid moiety, (2) the discovery of the positive effect of MeOH in the Cu-mediated biaryl ether formation to afford one of the two macrocyclic peptide moieties, and (3) the discovery of the positive influence of collidine in the diastereoselective Pd-mediated cross-coupling to result in efficient formation of another macrocycle within this medicinally important molecule. This key step is performed in the presence of four unprotected phenols, two of which reside on dichlorophenylglycines.

Objective. Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity.Methods. Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors.Results. A number of non-hydroxamic acidcontaining compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompeti-

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A Pd-mediated method for preparation of the strained macrocyclic moiety of complestatins is disclosed. Through stereoselective synthesis of model macrocycles and the S atropisomer of complestatin, the stereochemical identity of the anti-HIV agent complestatin is established. Investigations described herein illustrate that the compound previously reported as isocomplestatin is the same as complestatin. Thus, the S atropisomer of complestatin is the true isocomplestatin and has not been isolated as a natural product.

Three in one: Copper-catalyzed three-component reactions, involving 2-iodoanilines, aldehydes, and sulfur powder, afford 2-phenylbenzothiazoles in water. A variety of 2-substituted benzothiazoles can be obtained in good to excellent yields of up to 96 % (see scheme).

Easily prepared peptide‐based ligands efficiently promote the Al‐catalyzed enantioselective addition of trimethylsilyl cyanide (TMSCN) to aromatic, aliphatic, cyclic, and acyclic ketones (see scheme for an example). The chiral ligands can be readily recovered and reused without loss of activity or selectivity.