Synthesis, Reactivity and Biological Activity of 17β-HSD1 Inhibitors Based on a Thieno[2,3-d]pryrimidin-4(3H)-one Core

Breast cancer is the most common cancer in women in Western countries. In the early stages of development most breast cancers are hormone-dependent, and estrogens, especially estradiol, have a pivotal role in their development and progression. One approach to the treatment of hormone-dependent breast cancers is to block the formation of the active estrogens by inhibiting the action of the steroid metabolising enzymes. 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is a key enzyme in the biosynthesis of estradiol, the most potent female sex hormone. The 17beta-HSD1 enzyme catalyses the final step and converts estrone into the biologically active estradiol. Blocking 17beta-HSD1 activity with a specific enzyme inhibitor could provide a means to reduce circulating and tumour estradiol levels and thus promote tumour regression. In recent years 17beta-HSD1 has been recognised as an important drug target. Some inhibitors of 17beta-HSD1 have been reported, however, there are no inhibitors on the market nor have clinical trials been announced. The majority of known 17beta-HSD1 inhibitors are based on steroidal structures, while relatively little has been reported on non-steroidal inhibitors. As compared with 17beta-HSD1 inhibitors based on steroidal structures, non-steroidal compounds could have advantages of synthetic accessibility, drug-likeness, selectivity and non-estrogenicity. This study describes the synthesis of large group of novel 17beta-HSD1 inhibitors based on a non-steroidal thieno[2,3-d]pyrimidin-4(3H)-one core. An efficient synthesis route was developed for the lead compound and subsequently employed in the synthesis of thieno[2,3-d]pyrimidin-4(3H)-one based molecule library. The biological activities and binding of these inhibitors to 17beta-HSD1 and, finally, the quantitative structure activity relationship (QSAR) model are also reported. In this study, several potent and selective 17beta-HSD1 inhibitors without estrogenic activity were identified. This establishment of a novel class of inhibitors is a progressive achievement in 17beta-HSD1 inhibitor development. Furthermore, the 3D-QSAR model, constructed on the basis of this study, offers a powerful tool for future 17beta-HSD1 inhibitor development. As part of the fundamental science underpinning this research, the chemical reactivity of fused (di)cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-ones with electrophilic reagents, i.e. Vilsmeier reagent and dimethylformamide dimethylacetal, was investigated. These findings resulted in a revision of the reaction mechanism of Vilsmeier haloformylation and further contributed to understanding the chemical reactivity of this compound class. This study revealed that the reactivity is dependent upon a stereoelectronic effect arising from different ring conformations.

Structure of ethyl 1,2,2-tricyano-3-(4-nitrophenyl)-cyclopropane-1-carboxylate

C15HIoN404, monoclinic, P2~/c, a = 10.694(8), b = 11.743 (8), c - 12.658 (8) A, fl = 113.10 (7) °, V = 1462.1 A 3, Z = 4, O m = 1 "38, O c = 1.408 g cm -3, t,t(MoKa, ~, = 0.7107 ]~) = 0.99 cm -i, F(000) = 640. The structure was solved by direct methods and refined to an R value of 0.054 using 1398 intensity measurements. The relative magnitudes of interaction of the substituents and the extent to which a ring can accommodate interactions with substituents are discussed.

We are what we eat: The demise of the ethical grocery shopper

In 1954, American consumer behaviour academic, Gregory Stone identified four different types of consumers. Consisting of 150 in-depth interviews, Stone’s research found there was an “economic” shopper, who was after bargains, a “personalising” shopper, who liked interaction with staff, and an “apathetic” shopper, who was disillusioned and unengaged in shopping activity. Then there was the “ethical” grocery shopper – consumers who demonstrated a moral obligation to patronise local merchants, purchase locally produced products and felt the need to “shop where they ought to”. This ethical shopper was willing to sacrifice lower prices, convenience and range, in order to “help the little guys out”.The idea of the ethical shopper has since taken hold in mainstream retailing. But my new research has suggested that socially responsible consumption may be a thing of the past.

Impacts of level of utilisation by grazing on an Astrebla (Mitchell grass) grassland in north-western Queensland between 1984 and 2010. 2. Plant species richness and abundance

The occurrence of interstitial species in Astrebla grasslands in Australia are influenced by grazing and seasonal rainfall but the interactions of these two influences are complex. This paper describes three studies aimed at determining and explaining the changes in plant species richness and abundance of the interstitial species in a long-term sheep utilisation experiment in an Astrebla grassland in northern Queensland. In the first study, increasing utilisation increased the frequency of Dactyloctenium radulans (Button grass) and Brachyachne convergens (Downs couch) and reduced that of Streptoglossa adscendens (Mint bush). In the second study, seasonal rainfall variation between 1984 and 2009 resulted in large annual differences in the size of the seed banks of many species, but increasing utilisation consistently reduced the seed bank of species such as Astrebla spp. and S. adscendens and increased that of species such as B. convergens, D. radulans, Amaranthus mitchellii (Boggabri) and Boerhavia sp. (Tar vine). In the third study, the highest species richness occurred at the lightest utilisation because of the presence of a range of palatable forbs, especially legumes. Species richness was reduced as utilisation increased. Species richness in the grazing exclosure was low and similar to that at the heaviest utilisation where there was a reduction in the presence of palatable forb species. The pattern of highest species richness at the lightest grazing treatment was maintained across three sampling times, even with different amounts of seasonal rainfall, but there was a large yearly variation in both the density and frequency of many species. It was concluded that the maintenance of highest species richness at the lightest utilisation was not aligned with other data from this grazing experiment which indicated that the maximum sustainable wool production occurred at moderate utilisation.

Preparation of Industrially Important Hydroxy Acids and Diacids from 2,2-Disubstituted Propane-1,3-Diols and Linear Primary Diols by Green Chemistry Methods

Environmentally benign and economical methods for the preparation of industrially important hydroxy acids and diacids were developed. The carboxylic acids, used in polyesters, alkyd resins, and polyamides, were obtained by the oxidation of the corresponding alcohols with hydrogen peroxide or air catalyzed by sodium tungstate or supported noble metals. These oxidations were carried out using water as a solvent. The alcohols are also a useful alternative to the conventional reactants, hydroxyaldehydes and cycloalkanes. The oxidation of 2,2-disubstituted propane-1,3-diols with hydrogen peroxide catalyzed by sodium tungstate afforded 2,2-disubstituted 3-hydroxypropanoic acids and 1,1-disubstituted ethane-1,2-diols as products. A computational study of the Baeyer-Villiger rearrangement of the intermediate 2,2-disubstituted 3-hydroxypropanals gave in-depth data of the mechanism of the reaction. Linear primary diols having chain length of at least six carbons were easily oxidized with hydrogen peroxide to linear dicarboxylic acids catalyzed by sodium tungstate. The Pt/C catalyzed air oxidation of 2,2-disubstituted propane-1,3-diols and linear primary diols afforded the highest yield of the corresponding hydroxy acids, while the Pt, Bi/C catalyzed oxidation of the diols afforded the highest yield of the corresponding diacids. The mechanism of the promoted oxidation was best described by the ensemble effect, and by the formation of a complex of the hydroxy and the carboxy groups of the hydroxy acids with bismuth atoms. The Pt, Bi/C catalyzed air oxidation of 2-substituted 2-hydroxymethylpropane-1,3-diols gave 2-substituted malonic acids by the decarboxylation of the corresponding triacids. Activated carbon was the best support and bismuth the most efficient promoter in the air oxidation of 2,2-dialkylpropane-1,3-diols to diacids. In oxidations carried out in organic solvents barium sulfate could be a valuable alternative to activated carbon as a non-flammable support. In the Pt/C catalyzed air oxidation of 2,2-disubstituted propane-1,3-diols to 2,2-disubstituted 3-hydroxypropanoic acids the small size of the 2-substituents enhanced the rate of the oxidation. When the potential of platinum of the catalyst was not controlled, the highest yield of the diacids in the Pt, Bi/C catalyzed air oxidation of 2,2-dialkylpropane-1,3-diols was obtained in the regime of mass transfer. The most favorable pH of the reaction mixture of the promoted oxidation was 10. The reaction temperature of 40°C prevented the decarboxylation of the diacids.

Polarized Ethylenes: Structures of (l,3-Dimethyl-2-imidazolidinylidene)malononitrile and (l,3-Dimethyl-2-perhydropyrimidinylidene)malononitrile

Crystal structures of the title compounds, (I) and (II), have been determined by three-dimensional diffraction methods. Crystals of CsHIoN 4 (I) are monoclinic, space group P21/a with Z = 4, Mr= 162, a = 7.965 (1), b = 16.232 (2), c = 7.343 (1) A, fl = 113.54 (1) °, V = 890.7 A 3, D,n = 1.218, D x = 1.208 gcm -3, g(Cu Ka, 2 = 1.5418/~) = 6.47 em -1, F(000) = 344. The crystals of C9H12N4 (II) are orthorhombic, space group P21en, with Z = 4, Mr = 176, a = 7.983 (3), b = 8.075 (2), c = 14.652 (3) ./k, V = 44.43/~3, Dm= 1.219, D x = 1.237 g cm -3, #(Mo Ka, ). = 0.7107 ,/k) = 0.868 cm -1, F(000) = 376. Both structures were solved by direct methods and refined to R = 5.8% for (I) and 5.3 % for (II). The C-C double-bond distances are 1.407 (3) in (I) and 1.429 (6)/~ in (II), appreciably longer than normal. The steric and push-pull effects result in rotation about the C=C bond, the rotation angles being 20.2 (3) in (I) and 31.5 (6) o in (II).