Estrone C15 derivatives--a new class of 17beta-hydroxysteroid dehydrogenase type 1 inhibitors.

Lowering local estradiol concentration by inhibition of the estradiol-synthesizing enzyme 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) has been proposed as a promising new therapeutic option to treat estrogen-dependent diseases like endometriosis and breast cancer. Based on a molecular modelling approach we designed and synthesized novel C15-substituted estrone derivatives. Subsequent biological evaluation revealed that potent inhibitors of human 17beta-HSD1 can be identified in this compound class. The best, compound 21, inhibited recombinant human 17beta-HSD1 with an IC50 of 10nM and had no effect on the activity of recombinant human 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2), the enzyme catalyzing estradiol inactivation. These properties were retained in a cell-based enzyme activity assays. In spite of the estrogen backbone compound 21 did not show estrogen receptor mediated effects in vitro or in vivo. In conclusion, estrone C15 derivative compound 21 can be regarded as a promising lead compound for further development as a 17beta-HSD1 inhibitor.

Structure-activity relationship of quinoline derivatives as potent and selective alpha(2C)-adrenoceptor antagonists.

Starting from two acridine compounds identified in a high-throughput screening campaign (1 and 2, Table 1), a series of 4-aminoquinolines was synthesized and tested for their properties on the human alpha(2)-adrenoceptor subtypes (alpha(2A), alpha(2B), and alpha(2C)). A number of compounds with good antagonist potencies against the alpha(2C)-adrenoceptor and excellent subtype selectivities over the other two subtypes were discovered. For example, (R)-{4-[4-(3,4-dimethylpiperazin-1-yl)phenylamino]quinolin-3-yl}methanol 6j had an antagonist potency of 8.5 nM against, and a subtype selectivity of more than 200-fold for, the alpha(2C)-adrenoceptor. Investigation of the structure-activity relationship identified a number of structural features, the most critical of which was an absolute need for a substituent in the 3-position of the quinoline ring. The 3-position on the piperazine ring was also found to play an appreciable role, as substitutions in that position exerted a significant and stereospecific beneficial effect on the alpha(2C)-adrenoceptor affinity and potency. Replacing the piperazine ring proved difficult, with 1,4-diazepanes representing the only viable alternative.

New inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.

The estradiol-synthesizing enzyme 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1) is mainly responsible for the conversion of estrone (E1) to the potent estrogen estradiol (E2). It is a key player to control tissue levels of E2 and is therefore an attractive target in estradiol-dependent diseases like breast cancer or endometriosis. We selected a unique non-steroidal pyrimidinone core to start a lead optimization program. We optimized this core by modulation of R1-R6. Its binding mode at the substrate-binding site of 17betaHSD1 is complex and difficult to predict. Nevertheless, some basic structure-activity relationships could be identified. In vitro, the most active pyrimidinone derivative showed effective inhibition of recombinant human 17betaHSD1 at nanomolar concentrations. In intact cells overexpressing the human enzyme, IC50 values in the lower micromolar range were determined. Furthermore, the pyrimidinone proved its use in vivo by significantly reducing 17betaHSD1-dependent tumor growth in a new nude mouse model.

Redox-induced coordination isomerization of a phosphoniobenzophospholide.

1-Triphenylphosphoniobenzo[c]phospholide 1 reacts with [M(CO)(5)Br] (M = Mn, Re) and [Mn(CO)(3)(naphthalene)][BF(4)] to give complexes cis-[M(CO)(4)(1)Br] (5 a,b) and [Mn(CO)(3)(1)][BF(4)] (6 a[BF(4)]), respectively, featuring eta(1)(P)- and eta(5)(pi)-coordination of the phosphole ring. The corresponding reactions with [M(2)(CO)(10)] proceed with conservation of the metal-metal bond and yield, depending on the reaction temperature, dinuclear complexes [M(2)(CO)(8)(1)] (M=Mn, 7 a) or [M(2)(CO)(6)(1)(2)] (M=Mn, Re, 8 a,b) with mu(2)-bridging eta(1)(P):eta(2)(Pdbond;C) coordination of the phosphole moiety. All complexes formed were characterized by spectroscopic data; 5 b, 6 a[BF(4)], and 8 a,b were characterized by X-ray diffraction studies as well. The structural and (31)P NMR data of the dinuclear manganese complex 8 a suggest that the interaction between the metal atoms and the eta(2)-bound Pdbond;C double bond moieties is dominated by the L-->M charge-transfer contribution; this hints at a very low back-donation ability of the central M(2)(CO)(6) fragment. Investigation of the reactions of the Mn complexes 6 a and 8 a with Mg or ferrocenium hexafluorophosphate ([Fc][PF(6)]), respectively, revealed that the chemically reversible mutual interconversion between both species was feasible. Likewise, oxidation of the rhenium complex 8 b with [Fc][PF(6)] gave spectroscopic evidence for the formation of a Re analogue of 6 a. Electrochemical studies suggested that the oxidation 8 a-->2 6 a involves two consecutive single-electron-transfer steps, the first of which is electrochemically reversible and produces a metastable radical cation that is detectable by ESR spectroscopy. The mutual interconversion between 6 a and 8 a represents the first case of a reversible coordination isomerization of a phosphaarene that is triggered by a redox process and might stimulate further studies directed at the use of dinuclear phosphaarene complexes in redox-catalysis.

Synthesis and characterization of 4,6-O-butylidene-N-(2-hydroxybenzylidene)-beta-D-glucopyranosylamine: crystal structures of 4,6-O-butylidene-alpha-D-glucopyranose, 4,6-O-butylidene-beta-D-glucopyranosylamine and 4,6-O-butylidene-N-(2-hydroxybenzylidene)-beta-D-glucopyranosylamine.

4,6-O-Butylidene-N-(2-hydroxybenzylidene)-beta-D-glucopyranosylamine was synthesized and characterized using analytical, spectral and single-crystal X-ray diffraction methods. 1H and 13C NMR studies showed the presence of the beta-anomer, which has also been confirmed by the crystal structure. The molecular structure of this compound showed the presence of the tridentate ONO ligation-core. Both precursors, 4,6-O-butylidene-alpha-D-glucopyranose and 4,6-O-butylidene-beta-D-glucopyranosylamine were characterized using single crystal X-ray diffraction. The alpha-anomeric nature of the former and beta-anomeric nature of the latter were proposed based on 1H NMR studies and were confirmed by determining the crystal structures. In addition, the crystal structure of 4,6-O-butylidene-beta-D-glucopyranosylamine revealed the C-1-N-glycosylation. In all the three molecules, the saccharide unit exhibits a 4C(1) chair conformation. In the lattice, the molecules are connected by hydrogen-bond interactions. The conformation of 4,6-O-butylidene-N-(2-hydroxybenzylidene)-beta-D-glucopyranosylamine is stabilized via an O-H...N intramolecular interaction, and each molecule in the lattice interacts with three neighboring molecules through hydrogen bonds of the type O-H...O and C-H...O.

Glycosylamines of 4,6-O-butylidene-alpha-D-glucopyranose: synthesis and characterization of glycosylamines, and the crystal structure of 4,6-O-butylidene-N-(o-chlorophenyl)-beta-D-glucopyranosylamine.

A total of nine glycosylamines of 4,6-O-butylidene-alpha-D-glucopyranose were synthesized using primary amines having various groups in their ortho- or para-positions. Among these, six are monoglycosylamines, including one primary glycosylamine, and three are bis-glycosylamines. All these compounds were characterized by 1H, 1H-1H COSY, 1H-13C COSY and 13C NMR spectroscopy and FTIR spectra. The FAB mass spectra provided the molecular weights of the products by exhibiting the corresponding molecular ion peaks. The crystal structure of 4,6-O-butylidene-N-(o-chlorophenyl)-beta-D-glucopyranosylamine revealed the C-1 glycosylation, the beta-anomeric nature, and the 4C1 chair conformation of the saccharide unit in the product. In the lattice two types of dimers exist. While one type of dimer is formed through O-H...O type of interactions, the other type is formed via C-H...O type of interactions. In the direction of these C-H...O type of interactions, the dimeric units are connected to form a chain.

Crystal structure of 4,6-O-ethylidene-N-(2-hydroxybenzylidene)-beta-D-glucopyranosylamine.

4,6-O-Ethylidene-N-(2-hydroxybenzylidene)-beta-D-glucopyranosylamine was synthesized and characterized using analytical, spectral and single-crystal X-ray diffraction methods. The anomeric nature of the saccharide moiety was proposed based on 1H NMR studies and was confirmed by the crystal structure. The lattice structure of this compound was compared with that of its analogues.