Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening.

4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and ß with low nanomolar affinity and <20-fold selectivity for α over ß and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERß (compound 42; 170-fold selectivity).

Synthesis, structure and photophysical properties of [UO2X2(O=PPh3)2] (X = Cl, Br, I).

The synthesis of a series of uranyl compounds via oxidation of [Li(THF)4][UX5(THF)] (X = Cl, Br, I) in the presence of Ph3P=O is described. The solid state structures of [Li(O=PPh3)(MeCN)2]2[UO2Cl4], [UO2Br2(O=PPh3)2] and [Li(O=PPh3)4][I3], formed as a by-product from the oxidation of [Li(THF)4][UI5(THF)], is reported. The electronic absorption spectra and photoluminescence spectra of [UO2X2(O=PPh3)2] (X = Cl, Br, I) have been measured and no significant changes in the position of the emission (515-530 nm) or the lifetimes (ca. 1 µs) are observed in this series. However a bathochromic shift is observed in the U-X LMCT band in the electronic absorption spectrum.

Preparation and characterisation of novel chlorothiazide potassium solid-state salt forms: Intermolecular self assembly suprastructures.

Chlorothiazide (CTZ) is a poorly soluble diuretic agent. The aim of the present work was to produce and characterise a potassium salt form of chlorothiazide which has the potential advantages of improved aqueous solubility and potassium supplementation. A number of novel potassium salt forms of CTZ (CTZK) were prepared: CTZK monohydrate (form I), CTZK dihydrate (form II), anhydrous CTZK (form III), CTZK monohydrate hemiethanolate (form IV) and a desolvate of CTZK monohydrate hemiethanolate (form V). These salt forms were characterised by thermal analysis, PXRD, NMR, elemental analysis, FTIR, Karl Fisher titrimetry, ICP-MS and GC-MS. The ethanol-free CTZK forms were also characterised by dynamic vapour sorption analysis (DVS). CTZK form I was stable (in the DVS) over the range 0-60% RH. The dihydrate form of the salt was stable (in the DVS) over a broader range of relative humidities, 10-90% RH at 25°C. CTZK form II was less hygroscopic at high humidities (70-90% RH) than the previously reported CTZNa dihydrate. Single crystal X-ray analysis indicated that chlorothiazide potassium, crystallised from water or water/acetone mixture, formed a dihydrated polymeric-like intermolecular self-assembly (ISA) suprastructure. The ISA coordination was determined to be: (CTZ)(3)·K·(H(2)O)(2)(CTZ)(2)·(H(2)O)(2)·K·(CTZ)(3) (monoclinic, space group: C2/c, single crystal cell parameters: a=18.328(4)Å, b=7.3662(16)Å, c=19.993(5)Å, α=90°, ß=99.729(3)°, γ=90°). When CTZK was crystallised from ethanol, a monohydrate hemiethanolate ISA was formed, described as (CTZ)(3)·K·CTZ·(H(2)O)(2)·CTZ·K·(CTZ)(2) (triclinic, space group: P-1, single crystal cell parameters: a=7.078(3)Å, b=9.842(5)Å, c=21.994(11)Å, α=87.522(13)°, ß=84.064(14)°, γ=78.822(12)°). The aqueous solubility of CTZK dihydrate, was determined to be 78.71±1.82mg/ml, approximately 400-fold higher than chlorothiazide, indicating a biopharmaceutical advantage associated with the potassium salt form.

Novel synthesis and pharmacological evaluation as alpha2-adrenoceptor ligands of O-phenylisouronium salts.

The synthesis of nine new mono- and bis-O-phenylisouronium compounds (2, 6b-10b and 12b-14b) and their Boc-protected isourea precursors (2a, 6a-10a and 12a-14a) is described. The carbodiimide 4, which was formed, had been suggested as the reactive intermediate species and driving force of the reaction. All final substrates were tested as potential alpha(2)-ARs ligands in human brain tissue by means of radioligand binding experiments and were compared to the potential antidepressant 1, as well as other related guanidine containing derivatives.