Bernadette Norberg

Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors

Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC(50) values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results.

On the influence of using a zwitterionic coformer for cocrystallization: structural focus on naproxen–proline cocrystals

Four original cocrystal structures incorporating a zwitterionic amino acid, prolinium, and a therapeutical agent from profen pharmaceutical family, naproxen, are highlighted and characterized in this study. Powder X-ray diffraction and differential scanning calorimetry permits the observation of the formation of the new structures, obtained by liquid-assisted grinding with methanol. Single-crystal X-ray diffraction gives us a precise outlook of the crystalline network, and allows us to accurately determine the main structural supramolecular synthon: column-like motifs, formed by prolinium entities, around whom the pharmaceutical coformer is organized. From comparison with the CSD, a similar structural pattern emerged in several other structures incorporating prolinium moieties, but not in the case of cocrystals incorporating naproxen and other non-zwitterionic coformers. This result leads us to the conclusion that zwitterionic compounds, such as amino acids, can force a pharmaceutical coformer to structure itself following a known common motif guided only by the zwitterionic entity; a very challenging aspect to take into account when developing new solid forms of therapeutical agents.

1-[[4-(Aminoalkoxy)phenyl]sulfonyl]indolizines: a novel class of calcium entry blockers. Relationships between chemical structure, stereoelectronic properties and anticalcic activity

The solid-state structures of a series of 1-[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines have been determined by X-ray analysis. These molecules are known to be representative of a novel class of calcium entry blockers characterized by a new binding site associated with the L-type calcium channel. Previous 2-dimensional structure-activity relationship studies have shown that 1-sulfonylindolizines substituted in the 2 position by an isopropyl group and possessing an aralkylamine substructure were among the most potent calcium antagonists. A comparative study of the 3-dimensional X-ray structures and the electronic properties computed at the ab initio HF level of five 1-sulfonyl, 2-alkyl and 2-phenylindolizine calcium antagonists presenting different types of amine substructures indicates important similarities within the series. This has led us to propose the first pharmacophoric elements for this kind of compound.

Synthesis, structure and biological properties of Z-17α-(2-iodovinyl)-11β-chloromethyl estradiol-17β (Z-CMIV), a high affinity ligand for the characterization of estrogen receptor-positive tumors

Abstract Linkage of a 11β-chloromethyl group to estradiol-17β (E 2 ) dramatically increases the binding affinity of the steroid for the estrogen receptor (ER) with the formation of a quasi-irreversible steroid-receptor complex. We have synthesized the two isomers of 11β-chloromethyl-17α-iodovinyl-estradiol ( E -CMIV and Z -CMIV) by a novel route. Both derivatives demonstrated high binding affinity and selectivity for ER (RBAs: ER = 820 and 1008; SHBG = 1.2 and 0.25, respectively; E 2 = 100). On the basis of X-ray crystallographic data for Z -CMIV and its precursor, we have postulated that Z -CMIV might interact strongly with aromatic amino-acids within a hydrophobic groove of the ER hormone binding domain (HBD) that incorporates pockets corresponding to the 11β and 17α steroid substituents. The binding properties of Z -CMIV labeled with 125 I were investigated, especially its ability to detect and quantify altered ER forms with low binding affinity for E 2 . Sucrose density gradient analysis revealed that Z -CMIV has a higher activation potency than E 2 as it converts a higher proportion of non-activated monomers in the cytosol into activated monomers with the potential to dimerize. In in vitro (MCF-7 cells) and in vivo (rat uterus) determinations of estrogenic activity, Z -CMIV was as potent as E 2 in increasing progesterone receptor (PgR) concentrations and decreasing ER levels and in stimulating uterine growth. [ 125 I]- Z -CMIV could open the way to new applications in the diagnosis and therapy of ER-positive breast cancers, especially those containing altered (variant) ERs.

Molecular analysis of the β-polymorphic form of trielaidin: crystal structure at low temperature

This work reports on the structure of trielaidin [EEE, 1,2,3-tri(trans-9-octadecenoyl)glycerol], a trans unsaturated triglyceride present in many refined fatty materials (margarines, chocolate products etc.). Firstly, the polymorphism, i.e. the existence of different crystalline forms at various temperature ranges, was defined. Secondly, the crystal growth was examined. By developing a particular growing system, monocrystals of the most stable polymorphic form, i.e. the beta-form, were obtained. To reduce thermal vibrations the X-ray data were collected at low temperature (173 K) and the structure was solved using direct methods. The structure was then analyzed in terms of conformation and crystal packing and compared with those of the other known triglycerides.

The importance of screening solid-state phases of a racemic modification of a chiral drug: thermodynamic and structural characterization of solid-state phases of etiracetam

In this contribution different solid-state forms of the racemic compound (RS)-2-(2-oxo-pyrrolidin-1yl)-butyramide are studied from a structural and thermal point of view. Three different solid-state phases were identified, including two polymorphs and one hydrate phase. Comparison is made with the structure of the (S)-enantiomer, for which only one solid-state phase is known. The basic structural motif found in both polymorphs of the racemic compound is similar, but the basic motif observed for the hydrate differs. These synthons could in principle be used in future polymorph prediction studies to screen for possible alternative forms of the enantiopure compound. Based on the structure of the hydrate, further efforts should therefore be made in order to identify a hydrate structure of the enantiopure compound. Studying the different phases of a racemic compound can therefore help to guide polymorphic screening of an enantiopure compound.

Terbogrel, a dual-acting agent for thromboxane receptor antagonism and thromboxane synthase inhibition

Terbogrel, (E)-6-[4-(3-tert-butyl-2-cyanoguanidino)phenyl]-6-(3-pyridyl)hex-5 -enoic acid, C(23)H(27)N(5)O(2), a mixed thromboxane A(2) receptor antagonist and thromboxane A(2) synthase inhibitor, shows a hairpin-like conformation stabilized by an intramolecular hydrogen bond. A structural feature characteristic of the thromboxane A(2) synthase inhibitor mode is observed: a distance of 8.4257 (19) A between the pyridine N atom and the carboxyl group.

Synthesis of selenones: a comparative study

The propensity of several reagents to oxidize selenides to selenones has been evaluated; the scope and limitations of the methods are presented.

Synthesis and Absolute Structure Determination of Camphanoate Derivatives of Five Bicyclo[3.1.0]hexane Compounds

The relative and absolute stereochemistry of five compounds, (1R,2S,4R,5S)-exo-2-acetoxy-3,3-dimethylbi-cyclo[3.1.0]hexan-exo4-yl camphanoate, C 20 H 28 O 6 , (I), (1R,25,4R,55,6R)-exo-2-acetoxy-3,3,exe-6-trimethylbi-cyclo[3.1.0]hexan-exo-4-yl camphanoate, C 21 H 30 O 6 , (II), (1R,25,4R,55,65)-exo-2-acetoxy-3,3,endo-6-trimethyl-bicyclo [3.1.0] hexan- exo- 4-yl camphanoate, C 21 H 30 -O 6 , (III), (1S,2S,4R,5R,6S)-exo-2-acetoxy-endo-6-(3-butenyl)-3,3,exe-6-trimethylbicyclo[3.1.0]hexan-exo-4-yl-camphanoate, C 25 H 36 O 6 , (IV), and (1S,2S,4R,5R,6S)-endo-2-acetoxy-3,3,exo-6-trimethylbicyclo[3.1.0]hexan-endo-4-yl camphanoate, C 21 H 30 O 6 , (V), (camphanoate is 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate) have been determined and the conformation of the five-membered ring of each one is discussed. These compounds were synthesized by an enantioselective esterase-catalysed hydrolysis followed by acylation with camphanoyl chloride.

cis-4,6-Dimethyl-2-phenyl-1,3-diselenane

In the crystal of the title compound, C12H16Se2, the packing is explained by quadrupolar interactions, and the 1,3-diselenane cycle adopts a chair conformation. This compound was synthesized using diselenocyanate and benzaldehyde.