William R. Roush

Horner-wadsworth-emmons reaction: Use of lithium chloride and an amine for base-sensitive compounds

Abstract A mild olefination procedure, utilizing LiCl and an amine, has been developed for use with base-sensitive aldehydes and phosphonates.

Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand

T-helper cells that produce interleukin-17 (TH17 cells) are a recently identified CD4+ T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors α and γt (RORα and RORγt, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand—the first in a new class of compound—that is specific to both RORα and RORγt and which inhibits TH17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORα and RORγt, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors’ transcriptional activity. SR1001 inhibited the development of murine TH17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human TH17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORα and RORγt to inhibit specifically TH17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.

Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of Plasmodium falciparum by Peptidyl Vinyl Sulfones

ABSTRACT The Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3 appear to be required for hemoglobin hydrolysis by intraerythrocytic malaria parasites. Previous studies showed that peptidyl vinyl sulfone inhibitors of falcipain-2 blocked the development of P. falciparum in culture and exerted antimalarial effects in vivo. We now report the structure-activity relationships for inhibition of falcipain-2, falcipain-3, and parasite development by 39 new vinyl sulfone, vinyl sulfonate ester, and vinyl sulfonamide cysteine protease inhibitors. Levels of inhibition of falcipain-2 and falcipain-3 were generally similar, and many potent compounds were identified. Optimal antimalarial compounds, which inhibited P. falciparum development at low nanomolar concentrations, were phenyl vinyl sulfones, vinyl sulfonate esters, and vinyl sulfonamides with P2 leucine moieties. Our results identify independent structural correlates of falcipain inhibition and antiparasitic activity and suggest that peptidyl vinyl sulfones have promise as antimalarial agents.

Blocking Lactate Export by Inhibiting the Myc Target MCT1 Disables Glycolysis and Glutathione Synthesis

Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here, we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1 and that elevated MCT1 levels are manifest in premalignant and neoplastic Eμ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, reductions in glucose transport, and in levels of ATP, NADPH, and ultimately, glutathione (GSH). Reductions in GSH then lead to increases in hydrogen peroxide, mitochondrial damage, and ultimately, cell death. Finally, forcing glycolysis by metformin treatment augments this response and the efficacy of MCT1 inhibitors, suggesting an attractive combination therapy for MYC/MCT1-expressing malignancies.

A novel and specific NADPH oxidase-1 (Nox1) small-molecule inhibitor blocks the formation of functional invadopodia in human colon cancer cells

The NADPH oxidase (Nox) proteins catalyze the regulated formation of reactive oxygen species (ROS), which play key roles as signaling molecules in several physiological and pathophysiological processes. ROS generation by the Nox1 member of the Nox family is necessary for the formation of extracellular matrix (ECM)-degrading, actin-rich cellular structures known as invadopodia. Selective inhibition of Nox isoforms can provide reversible, mechanistic insights into these cellular processes in contrast to scavenging or inhibition of ROS production. Currently no specific Nox inhibitors have been described. Here, by high-throughput screening, we identify a subset of phenothiazines, 2-acetylphenothiazine (here referred to as ML171) (and its related 2-(trifluoromethyl)-phenothiazine) as nanomolar, cell-active, and specific Nox1 inhibitors that potently block Nox1-dependent ROS generation, with only marginal activity on other cellular ROS-producing enzymes and receptors including the other Nox isoforms. ML171 also blocks the ROS-dependent formation of ECM-degrading invadopodia in colon cancer cells. Such effects can be reversed by overexpression of Nox1 protein, which is suggestive of a selective mechanism of inhibition of Nox1 by this compound. These results elucidate the relevance of Nox1-dependent ROS generation in mechanisms of cancer invasion and define ML171 as a useful Nox1 chemical probe and potential therapeutic agent for inhibition of cancer cell invasion.

Diisopropyl tartrate modified (E)-crotylboronates: highly enantioselective propionate (E)-enolate equivalents

Etude de la reaction enantioselective des enantiomeres chiraux (+) et (−) du butene-2yl-2 dioxaborolanne-1,3,2dicarboxylate-4,5 de diisopropyle avec les aldehydes chiraux suivants: O-cyclohexylidene-2,3 desoxy-4 threose et O-isopropylidene-2,3 glyceraldehyde; la reaction a lieu sur le groupe formyl

Regioselectivity of the reactions of trialkylaluminum reagents with 2,3-epoxyalcohols: Application to the synthesis of α-chiral aldehydes

Abstract Treatment of optically active 2,3-epoxyalcohols with trialkylaluminum reagents followed by periodate cleavage constitutes a convenient synthesis of α-chiral aldehyde derivatives, especially when the branching alkyl group is methyl.

Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ.

The retinoic acid receptor-related receptors (RORs) are members of the nuclear receptor (NR) superfamily of transcription factors. Several NRs are still characterized as orphan receptors because ligands have not yet been identified for these proteins. Here, we describe the identification of a synthetic RORα/RORγ ligand, SR1078. SR1078 modulates the conformation of RORγ in a biochemical assay and activates RORα and RORγ driven transcription. Furthermore, SR1078 stimulates expression of endogenous ROR target genes in HepG2 cells that express both RORα and RORγ. Pharmacokinetic studies indicate that SR1078 displays reasonable exposure following injection into mice, and consistent with SR1078 functioning as a RORα/RORγ agonist, expression of two ROR target genes, glucose-6-phosphatase and fibroblast growth factor 21, were stimulated in the liver. Thus, we have identified the first synthetic RORα/γ agonist, and this compound can be utilized as a chemical tool to probe the function of these receptors both in vitro and in vivo.

Diisopropyl tartrate modified (E)-γ-[(cyclohexyloxy)dimethylsilyl]- and (E)-γ-(dimethylphenylsilyl)allylboronates: Chiral Reagents for the Enantio- and Diastereoselective synthesis of anti 1,2-diols and 2-butene-1,4-diols via the formal α- and γ-hydroxyallylation of aldehydes

Abstract Enantioselective synthesis of 4-substituted (E)-2-butene-1,4-diols and anti 1,2-diols are described. Highly diastereoselective reactions of aldehydes and the chiral PhMe 2 Si- and (C 6 H 11 O)Me 2 Si- substituted allylboronates 25 and 26 provide anti homoallylic 29 and 50 , respectively. Epoxidation of 29 with dimethyl dioxirane followed by acid catalyzed Petersen rearrangement of the intermediate epoxysilanols provides butene-1,4-diols 27 with excellent enantioselectivity (81–87% e.e.). Tamao oxidation of 50 provides anti diols 22 (64–72% e.e). These procedures give excellent results especially in matched double asymmetric reactions with a range of oxygenated, chiral aldehydes (Figures 1 and 2). These methods promise to find application in diastereoselective syntheses of carbohydrates from acyclic precursors.

Stereoselective synthesis of (Z,E)-2-bromo-1,3-dienes via the palladium (O) catalyzed cross coupling reactions of 1,1-dibromoolefins and vinylboronic acids

Abstract (Z,E)-2-Bromo-1,3-dienes are synthesized via stereoselective Pd° catalyzed cross coupling reactions of 1,1-dibromoolefins and vinylboronic acids.