Nancy N. Tsou

Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K

The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The non-basic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compounds are 10- to 20-fold more potent than the corresponding amide derivatives. Compound 8 is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.

Design, Synthesis, and In Vivo Efficacy of Glycine Transporter-1 (GlyT1) Inhibitors Derived from a Series of [4-Phenyl-1-(propylsulfonyl)piperidin-4-yl]methyl Benzamides

Design, Synthesis, and In Vivo Efficacy of Glycine Transporter-1 (GlyT1) Inhibitors Derived from a Series of [4-Phenyl-1(propylsulfonyl)piperidin-4-yl]methyl Benzamides Craig W. Lindsley,* Zhijian Zhao, William H. Leister, Julie O’Brien, Wei Lemaire, David L. Williams, Jr. , Tsing-Bau Chen, Raymond S. L. Chang, Maryann Burno, Marlene A. Jacobson, Cyrille Sur, Gene G. Kinney, Douglas J. Pettibone, Philip R. Tiller, Sheri Smith, Nancy N. Tsou, Mark E. Duggan, P. Jeffrey Conn, e] and George D. Hartman

Isolation and structure elucidation of parnafungins, antifungal natural products that inhibit mRNA polyadenylation.

The Candida albicans Fitness Test, a whole-cell screening platform, was used to profile crude fermentation extracts for novel antifungal natural products with interesting mechanisms of action. An extract with intrinsic antifungal activity from the fungus Fusarium larvarum displayed a Fitness Test profile that strongly implicated mRNA processing as the molecular target responsible for inhibition of fungal growth. Isolation of the active components from this sample identified a novel class of isoxazolidinone-containing natural products, which we have named parnafungins. These natural products were isolated as an interconverting mixture of four structural- and stereoisomers. The isomerization of the parnafungins was due to a retro-Michael ring-opening and subsequent reformation of a xanthone ring system. This interconversion was blocked by methylation of an enol moiety. Structure elucidation of purified parnafungin derivatives was accomplished by X-ray crystallography and NMR analysis. The biochemical target of these natural products has been identified as the fungal polyadenosine polymerase. Parnafungins demonstrated broad spectrum antifungal activity with no observed activity against gram-positive or gram-negative bacteria. The intact isoxazolidinone ring was required for antifungal activity. In addition, the natural products were efficacious in a mouse model of disseminated candidiasis.

Diastereoselective Friedel−Crafts Alkylation of Indoles with Chiral α-Phenyl Benzylic Cations. Asymmetric Synthesis of Anti-1,1,2-Triarylalkanes

The reactions of chiral benzyl carbocations bearing alpha-phenyl substituents with N-sulfonylated indoles afford 1,1,2-triarylalkanes with anti-selectivities. This outcome is a reversal of facial diastereoselectivity relative to Bachs alpha-alkyl-bearing benzyl cations. The reactions are promoted by either a Brønsted acid (TFA) or Lewis acid (BF3.OEt2), offering differential diastereoselectivities and reactivities. The electronic properties of both reacting partners strongly influence the reaction rates and the product diastereoselectivities and appear to operate under kinetic control. This chemistry provides an efficient access to sterically congested tetrasubstituted ethanes.

Conformational Analysis and Receptor Docking of N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (Taranabant, MK-0364), a Novel, Acyclic Cannabinoid-1 Receptor Inverse Agonist

X-ray crystallographic, NMR spectroscopic, and computational studies of taranabant afforded similar low-energy conformers with a significant degree of rigidity along the C11-N13-C14-C16-C17 backbone but with more flexibility around bonds C8-C11 and C8-O7. Mutagenesis and docking studies suggested that taranabant and rimonabant shared the same general binding area of CB1R but with significant differences in detailed interactions. Similar to rimonabant, taranabant interacted with a cluster of aromatic residues (F(3.36)200, W(5.43)279, W(6.48)356, and Y(5.39)275) through the two phenyl rings and with F(2.57)170 and L(7.42)387 through the CF 3-Pyr ring. The notable distinction between taranabant and rimonabant was that taranabant was hydrogen-bonded with S(7.39)383 but not with K(3.28)192, while rimonabant was hydrogen-bonded with K(3.28)192 but not with S(7.39)383. The strong hydrogen bonding between the amide NH of taranabant and hydroxyl of S(7.39)383 was key to the superior affinity of taranabant to CB1R.

Benzamide derivatives as blockers of Kv1.3 ion channel

The voltage-gated potassium channel, Kv1.3, is present in human T-lymphocytes. Blockade of Kv1.3 results in T-cell depolarization, inhibition of T-cell activation, and attenuation of immune responses in vivo. A class of benzamide Kv1.3 channel inhibitors has been identified. The structure-activity relationship within this class of compounds in two functional assays, Rb_Kv and T-cell proliferation, is presented. In in vitro assays, trans isomers display moderate selectivity for binding to Kv1.3 over other Kv1.x channels present in human brain.

Crystallization-induced diastereoselection: asymmetric synthesis of substance P inhibitors.

A novel three-component condensation followed by a crystallization-induced asymmetric transformation is used to build this key substance P inhibitor intermediate in a short synthetic sequence.

Identification of prostaglandin D2 receptor antagonists based on a tetrahydropyridoindole scaffold.

A new series of indole-based antagonists of the PGD(2) receptor subtype 1 (DP1 receptor) was identified and the progress of the structure-activity relationship study to the identification of potent and selective antagonists is presented. Selective DP1 antagonists with high potency and selectivity were prepared. Of particular interest is the DP1 antagonist 26 with a K(i) value of 1 nM for the DP1 receptor and an IC(50) value of 4.6 nM in a DP1 functional assay for the inhibition of the PGD(2) induced cAMP production in platelet rich plasma (PRP).

PREUSSOMERIN D FROM THE ENDOPHYTE HORMONEMA DEMATIOIDES

Preussomerin A, an aromatic bis-ketal, was first isolated from the coprophilous fungus Preussia isomera Cain during a study of interspecies competition among dung inhabiting fungi (Weber et al., 1990). Upon further investigation, a group of compounds closely related to preussomerin A was isolated from the same organism and identified as preussomerin B, C, D, E, and F, some of which exhibited significant antifungal and antibacterial properties (Weber and Gloer, 1991). We report the isolation and antibiotic activity of preussomerin D (FIG. 1) from the endophytic fungus Hormonema dematioides Lagerberg & Melin recovered from living plant tissue of a coniferous tree. During a comparative study of fungal endophytes from apparently healthy living leaves and twigs of Chamaecyparis thyoides (L.) B.S.P. (white Atlantic cedar) collected from the Pine Barrens in the intercoastal region of New Jersey, H. dematioides was isolated infrequently from four of five study sites (Bills and Polishook, 1992). One particular isolate JP 184 was recovered from disinfected living foliage collected near Dover Forge, Ocean Co., New Jersey during the spring of 1990. When submitted for natural products screening, this fungus produced in vitro a cytotoxic compound L-733,757 that later proved by silica gel chomatography, mass spectrometry, high pressure liquid chromatography (HPLC), and nuclear magnetic resonance (NMR) to be chemically identical to preussomerin D. Hormonema dematioides, a slow-growing black yeast usually associated with conifer wood, is characterized by basipetal conidiogenesis and dark, thick-walled hyphae with cells wider than long, often with longitudinal septa (FIG. 2) (Hermanides-Nijhof, 1977). It is morphologically similar to and often isolated from coniferous tissue along with Aureobasidium pullulans (de Bary)

Isolation and structure elucidation of coleophomones A and B, novel inhibitors of bacterial cell wall transglycosylase

Abstract The discovery, structure and absolute stereochemistry of coleophomones A and B are described, two structurally novel natural products that inhibit bacterial transglycosylase activity. Coleophomone A represents a new ring system, containing a highly condensed structure which undergoes a reversible retroaldol reaction to form coleophomone B.