Metabolism during pregnancy is a dynamic and precisely programmed process, the failure of which can bring devastating consequences to the mother and fetus. To define a high-resolution temporal profile of metabolites during healthy pregnancy, we analyzed the untargeted metabolome of 784 weekly blood samples from 30 pregnant women. Broad changes and a highly choreographed profile were revealed: 4,995 metabolic features (of 9,651 total), 460 annotated compounds (of 687 total), and 34 human metabolic pathways (of 48 total) were significantly changed during pregnancy. Using linear models, we built a metabolic clock with five metabolites that time gestational age in high accordance with ultrasound (R = 0.92). Furthermore, two to three metabolites can identify when labor occurs (time to delivery within two, four, and eight weeks, AUROC R 0.85). Our study represents a weekly characterization of the human pregnancy metabolome, providing a high-resolution landscape for understanding pregnancy with potential clinical utilities. ll

Two new diketopiperazine dimers, WIN 64821 (la) and WIN 64745 (2), were isolated from an Aspergillus culture originally isolated from soil and their structures established on the basis of chemical and spectroscopic evidence. The dimer la has Cl symmetry with each of two equivalent

In search for new biologically active molecules, diversity-oriented synthetic (DOS) strategies break through the limitation of traditional library synthesis by sampling new chemical space. Many natural products can be regarded as intriguing starting points for DOS, wherein stereochemically rich core structures may be reorganized into chemotypes which are distinctly different from the parent structure. Ideally such transformations should be general and involve few steps in order to be suited for library applications. With this objective in mind, the highly oxygenated natural product fumagillol has been successfully remodeled in several ways utilizing a reaction discovery-based approach. In reactions with amines, excellent regiocontrol in a bis-epoxide opening/cyclization sequence can be obtained by size-dependent interaction of an appropriate catalyst with the parent molecule, forming either perhydroisoindole or perhydroisoquinoline products. Perhydroisoindoles can be further remodeled by cascade processes to afford either morpholinone or bridged 4,1-benzoxazepine-containing structures.

[reaction: see text] Microwave-promoted, cobalt-catalyzed intramolecular [2 + 2 + 2] cyclizations of dialkynylnitriles successfully gave 5,6,7,8-tetrahydro-1,6-naphthyridines. The efficient synthesis of these relatively simple, yet rarely addressed heterocycles enabled the preparation of a collection of these compounds.

ABBREVIATIONS: ALPHA screen, amplifi ed luminescent proximity homogeneous assay; CMLD-BU, Center for Chemical Methodology and Library Development at Boston University; Core106, N-terminal 106-residue portion of core protein; CRC, control response curve; EC 50 , median effective concentration (required to induce a 50% effect); Eu, europium cryptate; FC, fl ag-core106; GC, GST-core106; GSH, glutathione; GST, glutathione-S-transferase; HBV, hepatitis B virus; HCV, hepatitis C virus; HPE, hundred percent effect; HRP, horseradish peroxidase; HTS, high-throughput screening; IC 50 , median inhibition concentration (concentration that reduces the effect by 50%); LOPAC, Library of Pharmacologically Active Compounds; SD, standard deviation; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TMB, 3,3′,5,5′-Tetramethylbenzidine; TR-FRET, time-resolved fl uorescence-resonance energy transfer; XL-665, allophycocyanin; ZPE, zero percent effect. ABSTRACT Binding of hepatitis C virus (HCV) RNA to core, the capsid protein, results in the formation of the nucleocapsid, the fi rst step in the assembly of the viral particle. A novel assay was developed to discover small molecule inhibitors of core dimerization. This assay is based on time-resolved fl uorescence resonance energy transfer (TR-FRET) between anti-tag antibodies labeled with either europium cryptate (Eu) or allophycocyanin (XL-665