Trixie Wagner

Use of intensity quotients and differences in absolute structure refinement

Differences and quotients can be defined using Friedel pairs of reflections and applied in refinement to enable absolute structure to be determined precisely even for light atom crystal structures.

Spirotetrahydro β-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria.

The antiplasmodial activity of a series of spirotetrahydro β-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC50 of 90 nM. Structure−activity relationships for the optimization of 1 to compound 20a (IC50 = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.

Orally Bioavailable Isothioureas Block Function of the Chemokine Receptor CXCR4 In Vitro and In Vivo

The interaction of the chemokine receptor CXCR4 with its ligand CXCL12 is involved in many biological processes such as hematopoesis, migration of immune cells, as well as in cancer metastasis. CXCR4 also mediates the infection of T-cells with X4-tropic HIV functioning as a coreceptor for the viral envelope protein gp120. Here, we describe highly potent, selective CXCR4 inhibitors that block CXCR4/CXCL12 interactions in vitro and in vivo as well as the infection of target cells by X4-tropic HIV.

Discovery of amino-acetonitrile derivatives, a new class of synthetic anthelmintic compounds

A new series of amino-acetonitrile derivatives (AAD) have been discovered that exhibit high anthelmintic activity against parasitic nematode species such as Haemonchus contortus and Trichostrongylus colubriformis. Significantly, these compounds also demonstrate activity against nematode strains resistant to the currently available broad-spectrum anthelmintics. The discovery, synthesis, structure-activity relationship and biological results are presented.

Aryldiones incorporating a [1,4,5]oxadiazepane ring. Part I: Discovery of the novel cereal herbicide pinoxaden

Derivatives of the new class of 3-hydroxy-4-phenyl-5-oxo-pyrazolines were optimized towards both herbicidal activity on key annual grass weed species and selectivity in small grain cereal crops. The generic structure can be separated into three parts for the analysis of the structure-activity relationships, namely the aryl, the dione with its prodrug forms and the hydrazine moiety. Each area appears to play distinct and different roles in overall expression of biological performance which is further beneficially influenced by adjuvant response and safener action. Pinoxaden 6, a novel graminicide for use in wheat and barley incorporating a [1,4,5]oxadiazepane ring, eventually emerged as a development candidate from the discovery and optimization process.

A non-mathematical introduction to the superspace description of modulated structures

The X-ray analysis of (6R,7aS)-6-(tert-butyl-dimethylsilanyloxy)-1-hydroxy-2-phenyl-5,6,7,7a-tetrahydropyrrolizin-3-one, C19H27NO3Si, revealed a diffraction pattern which is typical for modulated structures: strong Bragg peaks surrounded by weaker reflections which cannot be indexed with the same three reciprocal lattice vectors that are used to describe the strong peaks. For this class of crystal structures the concept of superspace has been developed which, however, for many crystallographers still constitutes a Gordian Knot. As a possible tool to cut this knot the crystal structure of the above-mentioned tetrahydropyrrolizinone derivative is presented as an illustrative example for handling and describing the modulated structure of a typical pharmaceutical (i.e. molecular) compound. Having established a working knowledge of the concepts and terminology of the superspace approach a concise and detailed description of the complete process of peak indexing, data processing, structure solution and structure interpretation is presented for the incommensurately modulated crystal structure of the above-mentioned compound. The superspace symmetry applied is P2(1)(alpha0gamma)0; the (incommensurate) q vector components at 100 K are alpha = 0.1422 (2) and gamma = 0.3839 (8).

Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti-Cancer Properties†

Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factor 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti-fungal and cytotoxic activity. Combined genetic and proteomic approaches identified the eukaryotic translation elongation factor 1α (EF-1α) as the primary target for this compound class. Nannocystin A (1) displayed differential activity across various cancer cell lines and EEF1A1 expression levels appear to be the main differentiating factor. Biochemical and genetic evidence support an overlapping binding site of 1 with the anti-cancer compound didemnin B on EF-1α. This myxobacterial chemotype thus offers an interesting starting point for further investigations of the potential of therapeutics targeting elongation factor 1.

Zum reaktionsverhalten eines vinylidentitanocen-intermediates gegenüber protischen agenzien—selektive synthesen von 1-alkenyltitanocenverbindungen

Abstract A variety of proton donating substrates (ROH, H 2 O) react With the vinylidenetitanocene intermediate [Cp 2 TiC CH 2 ] ( 3 ), which is formed in situ by thermolysis of Cp 2 *TiC(CH 2 )CH 2 CH 2 ( 4 ) or Cp 2 *Ti(CH CH 2 )(CH 3 ) ( 5 ), to yield vinyltitanium derivatives {CP 2 *Ti(CHCH 2 )(OR), RCH 3 ( 8a ), C 2 H 5 ( 8b ), n -C 3 H 7 ( 8c ), i -C 3 H 7 ( 8d ), H ( 11 )}. The formation and properties of other Cp 2 * Ti(CHCH 2 )(X) derivatives (X = F ( 13a ), Cl ( 13b ), Br, ( 13c ), NH 2 ( 14 )), formed directly from the corresponding Cp 2 *TiX 2 complexes and vinyllithium or by anion exchange from Cp 2 *Ti(CHCH 2 )(Cl) ( 13b ), are discussed in the light of the 1 H and 13 C-NMR data. The structure of vinyltitanocenefluoride, Cp 2 *Ti (CHCH 2 F ( 13a ), has been determined: monoclinic, space group P 2 1 In , lattice constants a = 8628(5), b = 15.49(1), c = 15.23(1) A, β = 100.28(5)°. The TiC(σ) bond length is 2.098(6) A and the C(σ) TiF angle is 935(8)°. In the course of attempts to build up cationic [Cp 2 *TiCHCH 2 ] + complexes from 4 Cp 2 *Ti(OSO 2 CF 3 )(Cl) ( 17 ) can be isolated as a subsequent product, characterised by X-ray structure determination.

Conformational Refinement of Hydroxamate-Based Histone Deacetylase Inhibitors and Exploration of 3-Piperidin-3-ylindole Analogues of Dacinostat (LAQ824)

Inspired by natural product HDAC inhibitors, we prepared a series of conformationally restrained HDAC inhibitors based on the hydroxamic acid dacinostat (LAQ824, 7). Several scaffolds with improved biochemical and cellular potency, as well as attenuated hERG inhibition, were identified, suggesting that the introduction of molecular rigidity is a viable strategy to enhance HDAC binding and mitigate hERG liability. Further SAR studies around a 3-piperidin-3-ylindole moiety resulted in the discovery of compound 30, for which a unique conformation was speculated to contribute to overcoming increased lipophilicity and attenuating hERG binding. Separation of racemate 30 afforded 32, the R enantiomer, which demonstrated improved potency in both enzyme and cellular assays compared to dacinostat.

Zum reaktionsverhalten von titanocenvinyliden gegenüber enolisierbaren ketonen: Cp★2Ti(CHCH2)(OC( CH2)C6H11) -ein enolat mit ungewöhnlich gestrecktem TiOC-Winkel

Abstract A variety of enolizable ketones reacts with the titanocenevinylidene intermediate [C★ 2 TCCH 2 ] 2 , which is formed in situ by thermolysis of Cp★ 2 TiC(CH 2 )CH 2 C H 2 1 , to yield under regio- and stereoselective control vinyltitanium enolates 7 in excellent yields. Therefore the formation of Δ 1 - and of E -configurated enolates is preferred. A single-crystal diffraction study of Cp★ 2 Ti(CHCH 2 )(OC(CH 2 )C 6 H 11 ) 7d shows a typical O-bonded monomeric enolate with a short TiO distance of 1.859(2)A and a TiOC angle of 165.9 (2)°. The complexes 7 do not exhibit typical enolate reactivity, especially 7d does not react with neither methyl iodide nor benzaldehyde.