Metabolic Dynamics and Prediction of Gestational Age and Time to Delivery in Pregnant Women.

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 ≥ 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.

Interfacial hydration determines orientational and functional dimorphism of sterol-derived Raman tags in lipid-coated nanoparticles.

Lipid-coated noble metal nanoparticles (L-NPs) combine the biomimetic surface properties of a self-assembled lipid membrane with the plasmonic properties of a nanoparticle (NP) core. In this work, we investigate derivatives of cholesterol, which can be found in high concentrations in biological membranes, and other terpenoids, as tunable, synthetic platforms to functionalize L-NPs. Side chains of different length and polarity, with a terminal alkyne group as Raman label, are introduced into cholesterol and betulin frameworks. The synthesized tags are shown to coexist in two conformations in the lipid layer of the L-NPs, identified as "head-out" and "head-in" orientations, whose relative ratio is determined by their interactions with the lipid-water hydrogen-bonding network. The orientational dimorphism of the tags introduces orthogonal functionalities into the NP surface for selective targeting and plasmon-enhanced Raman sensing, which is utilized for the identification and Raman imaging of epidermal growth factor receptor-overexpressing cancer cells.

Discovery of new antimalarial chemotypes through chemical methodology and library development.

In an effort to expand the stereochemical and structural complexity of chemical libraries used in drug discovery, the Center for Chemical Methodology and Library Development at Boston University has established an infrastructure to translate methodologies accessing diverse chemotypes into arrayed libraries for biological evaluation. In a collaborative effort, the NIH Chemical Genomics Center determined IC(50)'s for Plasmodium falciparum viability for each of 2,070 members of the CMLD-BU compound collection using quantitative high-throughput screening across five parasite lines of distinct geographic origin. Three compound classes displaying either differential or comprehensive antimalarial activity across the lines were identified, and the nascent structure activity relationships (SAR) from this experiment used to initiate optimization of these chemotypes for further development.

An intramolecular inverse electron demand Diels-Alder approach to annulated α-carbolines.

Intramolecular inverse electron demand cycloadditions of isatin-derived 1,2,4-triazines with acetylenic dienophiles tethered by amidations or transesterifications proceed in excellent yields to produce lactam- or lactone-fused α-carbolines. Beginning with various isatins and alkynyl dienophiles, a pilot-scale library of eighty-eight α-carbolines was prepared by using this robust methodology for biological evaluation.

Potent inhibitors of hepatitis C core dimerization as new leads for anti-hepatitis C agents.

New indoline alkaloid-type compounds which inhibit HCV production by infected hepatoma cells have been identified. These compounds, dimeric-type compounds of previously known inhibitors, display double digit nanomolar IC(50) and EC(50) values, with cytotoxicity CC(50) indexes higher than 36 µM, thus providing ample therapeutic windows for further development of HCV drugs.

Enantioselective syntheses of candenatenins B and C using a chiral anthracene auxiliary.

An asymmetric synthesis of two anticancer natural products, candenatenins B and C, is described, leading to a revision of the originally assigned stereochemistry. The synthesis follows a Diels-Alder/retro-Diels Alder strategy using a chiral anthracene auxiliary to access both targets with 90% ee. The inherent structural qualities of the auxiliary allow for both regio- and diastereoselective transformations.

Intramolecular rhodium-catalyzed [2+2+2] cyclizations of diynes with enones.

The Rh(I)-catalyzed inter- and intramolecular [2+2+2] cyclization of diynes with alpha,beta-unsaturated enones proceeds with microwave promotion in good yields. This chemistry was applied to the synthesis of (-)-alcyopterosin I.

New small molecule inhibitors of hepatitis C virus.

New small molecule inhibitors of HCV were discovered by screening a small library of indoline alkaloid-type compounds. An automated assay format was employed which allowed identification of dimerization inhibitors of core, the capsid protein of the virus. These compounds were subsequently shown to block production of infectious virus in hepatoma cells.

Library synthesis using 5,6,7,8-tetrahydro-1,6-naphthyridines as scaffolds.

The chemistry of 5,6,7,8-tetrahydro-1,6-naphthyridine scaffolds, synthesized by intramolecular cobalt-catalyzed [2 + 2 + 2] cyclizations, has been exploited for library synthesis. Urea, amide, and sulfonamide formations were used in the synthesis of a 101-membered library. Screening of the library for antituberculosis activity revealed three lead compounds.

Synthesis of 5,6,7,8-tetrahydro-1,6-naphthyridines and related heterocycles by cobalt-catalyzed [2 + 2 + 2] cyclizations.

[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.

1,2,3,4-Tetrahydro-1,5-naphthyridines and related heterocyclic scaffolds: Exploration of suitable chemistry for library development.

The chemistry of 1,2,3,4-tetrahydro-1,5-naphthyridines and 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepines has been explored with the goal of discovering reactions at N1 suitable for library development. Epoxide openings, palladium-catalyzed N-arylations, DEPBT-promoted acylations, and urea formation through the reaction with isocyanates were all successful. The epoxide opening chemistry using homochiral epichlorohydrin, with epoxide reclosure and a second nucleophilic opening led to the preparation of a small 24-membered library.

Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma.

Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates.

A new chiral anthracene for the asymmetric Diels-Alder/retro-Diels-Alder sequence.

(-)-(R)-9-(1,2-Dimethoxyethyl)anthracene (8) is successfully employed as a chiral template in the Diels-Alder/retro-Diels-Alder sequence for the preparation of alpha,beta-unsaturated lactams. The cycloadditions proceed with complete diastereoselectivity, and regioselectivity in subsequent transformations of the carbonyl groups is also excellent. Flash vacuum pyrolysis accomplishes the cycloreversion.

Convergent synthesis of a complex oxime library using chemical domain shuffling.

[reaction: see text] The synthesis of a complex hybrid oxime library is reported utilizing convergent ligation of alkoxyamine and carbonyl monomers via "chemical domain shuffling". Initial biological screening of the library against human small cell lung carcinoma (A549) cells led to the identification of a novel hybrid dimer in contrast to the corresponding monomeric compounds which were found to be inactive.

Gallium(III)-Promoted Halocyclizations of 1,6-Diynes.

Cyclization of 1,6-diynes promoted by stoichiometric Ga(III) halides produces vinyl halides in good to excellent yields. Under acidic conditions, initially formed iodocyclization products undergo in situ Friedel-Crafts cyclizations, giving access to iodoindenopyridines. Application of the vinyl halides in cross-coupling reactions has been explored, and mechanistic aspects of the cyclization are discussed.

A homo Diels-Alder approach to bicyclo[4.2.1]nonanes.

[reaction: see text] A new, high-yielding route to functionalized bicyclo[4.2.1]nonanes has been achieved utilizing homo Diels-Alder chemistry with subsequent Zeise's dimer-catalyzed opening of the cycloadduct.

Remodeling of fumagillol: discovery of an oxygen-directed oxidative Mannich reaction.

An efficient, two-step construction of highly complex alkaloid-like compounds from the natural product fumagillol is described. This approach, which mimics a biosynthetic cyclase/oxidase sequence, allows for rapid and efficient structure elaboration of the basic fumagillol scaffold with a variety of readily available coupling partners. Mechanistic experiments leading to the discovery of an oxygen-directed oxidative Mannich reaction are also described.

Identification of a broad-spectrum inhibitor of viral RNA synthesis: validation of a prototype virus-based approach.

There are no approved therapeutics for the most deadly nonsegmented negative-strand (NNS) RNA viruses, including Ebola (EBOV). To identify chemical scaffolds for the development of broad-spectrum antivirals, we undertook a prototype-based lead identification screen. Using the prototype NNS virus, vesicular stomatitis virus (VSV), multiple inhibitory compounds were identified. Three compounds were investigated for broad-spectrum activity and inhibited EBOV infection. The most potent, CMLDBU3402, was selected for further study. CMLDBU3402 did not show significant activity against segmented negative-strand RNA viruses, suggesting proscribed broad-spectrum activity. Mechanistic analysis indicated that CMLDBU3402 blocked VSV viral RNA synthesis and inhibited EBOV RNA transcription, demonstrating a consistent mechanism of action against genetically distinct viruses. The identification of this chemical backbone as a broad-spectrum inhibitor of viral RNA synthesis offers significant potential for the development of new therapies for highly pathogenic viruses.

Direct binding of a hepatitis C virus inhibitor to the viral capsid protein.

Over 130 million people are infected chronically with hepatitis C virus (HCV), which, together with HBV, is the leading cause of liver disease. Novel small molecule inhibitors of Hepatitis C virus (HCV) are needed to complement or replace current treatments based on pegylated interferon and ribavirin, which are only partially successful and plagued with side-effects. Assembly of the virion is initiated by the oligomerization of core, the capsid protein, followed by the interaction with NS5A and other HCV proteins. By screening for inhibitors of core dimerization, we previously discovered peptides and drug-like compounds that disrupt interactions between core and other HCV proteins, NS3 and NS5A, and block HCV production. Here we report that a biotinylated derivative of SL209, a prototype small molecule inhibitor of core dimerization (IC(50) of 2.80 µM) that inhibits HCV production with an EC(50) of 3.20 µM, is capable of penetrating HCV-infected cells and tracking with core. Interaction between the inhibitors, core and other viral proteins was demonstrated by SL209-mediated affinity-isolation of HCV proteins from lysates of infected cells, or of the corresponding recombinant HCV proteins. SL209-like inhibitors of HCV core may form the basis of novel treatments of Hepatitis C in combination with other target-specific HCV drugs such as inhibitors of the NS3 protease, the NS5B polymerase, or the NS5A regulatory protein. More generally, our work supports the hypothesis that inhibitors of viral capsid formation might constitute a new class of potent antiviral agents, as was recently also shown for HIV capsid inhibitors.

Indium(III)-catalyzed hydrative cyclization of 1,7-diynyl ethers.

A new hydrative cyclization of 1,7- and 1,8-diynyl ethers is reported. Using catalytic InI(3) and p-TSA as a cocatalyst, several 2,2-disubstituted tetrahydrofurans with exocyclic enone appendages were prepared. Reaction optimization and scope, mechanistic insight, and further transformation to a C-nucleoside analog are presented.