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ABSTRACT: We report the conformational analysis of a series of 3-hydroxy-N'-((naphthalen-2-yl)methylene)naphthalene-2-carbohydrazides. This class of compounds has recently been reported as androgen receptor (AR)-coactivator disruptors for potential application in prostate cancer therapy. Definition of the E/Z isomerism around the imine linker group (hydrazide) is significant from a mechanistic point of view. A detailed study using theoretical calculations coupled with experimental techniques has allowed us determine an initial preference for the E isomer. The biological activity of newly synthesized compounds at the androgen receptor, along with a series of structural analogs, was determined and provides the basis for preliminary qualitative structure-activity relationship analysis.
Journal of Chemical Information and Modeling 08/2012; 52(9):2387-97. · 4.68 Impact Factor
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ABSTRACT: Herein we report the intra- and inter-molecular assembly of a {V(5)O(9)} subunit. This mixed-valent structural motif can be stabilised as [V(5)O(9)(L(1-3))(4)](5-/9-) (1-3) by a range of organoarsonate ligands (L(1)-L(3)) whose secondary functionalities influence its packing arrangement within the crystal structures. Variation of the reaction conditions results in the dodecanuclear cage structure [V(12)O(14)(OH)(4)(L(1))(10)](4-) (4) where two modified convex building units are linked via two dimeric {O(4)V(IV)(OH)(2)V(IV)O(4)} moieties. Bi-functional phosphonate ligands, L(4)-L(6) allow the intramolecular connectivity of the {V(5)O(9)} subunit to give hybrid capsules [V(10)O(18)(L(4-6))(4)](10-) (5-7). The dimensions of the electrophilic cavities of the capsular entities are determined by the incorporated ligand type. Mass spectrometry experiments confirm the stability of the complexes in solution. We investigate and model the temperature-dependent magnetic properties of representative complexes 1, 4, 6 and 7 and provide preliminary cell-viability studies of three different cancer cell lines with respect to Na(8)H(2)[6]·36H(2)O and Na(8)H(2)[7]·2DMF·29H(2)O.
Dalton Transactions 03/2012; 41(10):2918-26. · 3.84 Impact Factor
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ABSTRACT: In this paper, the synthesis and the spectroscopic investigation of new colorimetric receptors for anions 3-6, possessing a glycol chain at the 4-position of the pyridyl ring, and 1 and 2, which lack such a chain, and the X-ray crystal structure of 2 is presented. Structures 3-6 are able to bind to anions in competitive media, such as alcohol or in a mixture of methanol and water, where the anion recognition gives rise to changes in the absorption spectra, which is red-shifted, in 1:1 or 1:2 (sensor/anion) stoichiometry. The anion recognition for 1 and 2 was also investigated in organic solvents and in a 4:1 mixture of DMSO/H(2)O. The binding of 1 to anions such as acetate, phosphate, and fluoride was also evaluated using (1)H NMR in DMSO-d(6).
The Journal of Organic Chemistry 02/2012; 77(7):3115-26. · 4.45 Impact Factor
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ABSTRACT: In the title compound, [MnCl(2)(C(18)H(18)N(8))], the geometry around the Mn(II) centre is distorted square-pyramidal. In the crystal structure, mol-ecules pack via weak C-H⋯N and C-H⋯Cl inter-actions.
Acta Crystallographica Section E Structure Reports Online 12/2011; 67(Pt 12):m1676. · 0.35 Impact Factor
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ABSTRACT: The synthesis and conformational analysis of a series of pyridin-2-yl guanidine derivatives using NMR, X-ray crystallography, and B3LYP/6-31+G** theoretical studies are reported. A remarkable difference was observed in the (1)H NMR spectra of the guanidinium salts as compared with their N,N'-di-Boc protected and neutral analogues. This difference corresponds to a 180° change in the dihedral angle between the guanidine/ium moiety and the pyridine ring in the salts as compared to the Boc-protected derivatives, a conclusion that was supported by theoretical studies, X-ray data, and NMR analysis. Moreover, our data sustain the existence of two intramolecular hydrogen-bonding systems: (i) between the pyridine N1 atom and the guanidinium protons in the salts and (ii) within the tert-butyl carbamate groups of the Boc-protected derivatives. To verify that the observed conformational control arises from these intramolecular interactions, a new series of N-Boc-N'-propyl-substituted pyridin-2-yl guanidines were also prepared and studied.
The Journal of Organic Chemistry 11/2011; 76(22):9216-27. · 4.45 Impact Factor
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ABSTRACT: The title compound, [CuCl(2)(C(18)H(18)N(8))]·2CH(3)OH·H(2)O, contains a penta-coordinated Cu(II) atom bonded to the tridentate 4,6-bis-[(E)-1-methyl-2-(pyridin-2-yl-methyl-idene)hydrazin-yl]pyrimidine ligand and two Cl atoms. The geometry around the Cu(II) atom is distorted square-pyramidal. The mol-ecules pack in the crystal structure via O-H⋯Cl, O-H⋯N, C-H⋯Cl and C-H⋯O hydrogen bonds, C-H⋯π and π-π inter-actions [centroid-centroid distances of the pyrimidine-pyridine and pyridine-pyridine inter-actions are 3.750 (3) and 3.850 (3) Å, respectively], forming sheet-like assemblies.
Acta Crystallographica Section E Structure Reports Online 08/2011; 67(Pt 8):m1073-4. · 0.35 Impact Factor
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ABSTRACT: The structure-activity relationships of antiproliferative β-lactams, focusing on modifications at the 4-position of the β-lactam ring, is described. Synthesis of this series of compounds was achieved utilizing the Staudinger and Reformatsky reactions. The antiproliferative activity was assessed in MCF-7 cells, where the 4-(4-ethoxy)phenyl substituted compound 26 displayed the most potent activity with an IC(50) value of 0.22 μM. The mechanism of action was demonstrated to be by inhibition of tubulin polymerisation. Cell exposure to combretastatin A-4 and 26 led to arrest of MCF-7 cells in the G2/M phase of the cell cycle and induction of apoptosis. Additionally, mitotic catastrophe for combretastatin A-4 and for 26 was demonstrated in breast cancer cells for the first time, as evidenced by the formation of giant, multinucleated cells.
European journal of medicinal chemistry 07/2011; 46(9):4595-607. · 3.27 Impact Factor
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ABSTRACT: The formation of self-assembly complexes between the ligands 1 (SS) and 2 (RR) and terbium or europium was undertaken and shown (using various spectroscopic titrations) to give rise to the exclusive formation of 2:1 (L:Ln) stoichiometry and not the anticipated 3:1 stoichiometry.
Chemical Communications 07/2011; 47(25):7119-21. · 6.17 Impact Factor
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ABSTRACT: A series of 6-alkenyl-3-phenylcyclohex-2-enones has been synthesised and the structures of the products obtained from them on irradiation have been determined. The 6-propenyl compounds afforded a tricyclic 'parallel' [2 + 2] cycloaddition product and a bicyclic enone resulting from hydrogen abstraction in the biradical intermediate. The 6-butenyl and 6-pentenyl analogues gave 'crossed' cycloaddition products only. Although the regiochemistry of these cycloaddition reactions cannot be explained in terms of the 'rule of five', it is compatible with the concept of 'biradical conformation control' which is based on a consideration of the energy and structure of the possible 1,4-biradical intermediates.
Organic & Biomolecular Chemistry 03/2011; 9(8):2959-68. · 3.70 Impact Factor
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ABSTRACT: A series of azetidin-2-ones substituted at positions 1, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin-binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring in order to enhance the antiproliferative effects displayed by combretastatin A-4 and prevent the cis/trans isomerisation that is associated with inactivation of combretastatin A-4. The series of azetidinones was synthetically accessible via the Staudinger and Reformatsky reactions. Of a diverse range of heterocyclic derivatives, 3-(2-thienyl) analogue 28 and 3-(3-thienyl) analogue 29 displayed the highest potency in human MCF-7 breast cancer cells with IC(50) values of 7 nM and 10nM, respectively, comparable to combretastatin A-4. Compounds from this series also exhibited potent activity in MDA-MB-231 breast cancer cells and in the NCI60 cell line panel. No significant toxicity was observed in normal murine breast epithelial cells. The presence of larger, bulkier groups at the 3-position, for example, 3-naphthyl derivative 21 and 3-benzothienyl derivative 26, resulted in relatively lower antiproliferative activity in the micromolar range. Tubulin-binding studies of 28 (IC(50)=1.37 μM) confirmed that the molecular target of this series of compounds is tubulin. These novel 3-(thienyl) β-lactam antiproliferative agents are useful scaffolds for the development of tubulin-targeting drugs.
Bioorganic & medicinal chemistry 02/2011; 19(7):2306-25. · 2.82 Impact Factor
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ABSTRACT: 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°, β=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)°, β=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.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 02/2011; 42(3):220-9. · 2.61 Impact Factor
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ABSTRACT: Chlorothiazide (CTZ), unlike other thiazide diuretics, can form salts. An injectable formulation containing the sodium salt is available; however neither the physicochemical characteristics of the salt nor its solid state form have been previously reported. This work reports on the crystal structure of chlorothiazide sodium. The structure was investigated by single crystal X-ray and nuclear magnetic spectroscopy (NMR) analyses and compared to chlorothiazide, while the solid state characteristics were assessed by thermal analysis, powder X-ray diffraction, infrared spectroscopy, dynamic moisture sorption and solubility analysis. The crystal structure of chlorothiazide sodium was determined to be triclinic; the crystal space group type was P-1. Chlorothiazide sodium presented a self-assembly polymeric-type suprastucture, where the unit cell comprised two chlorothiazide molecules bonded together with sodium cations through the water bridges. The coordinate centre comprised the following: (CTZ)(3)·(H(2)O)·Na(H(2)O)(2)Na·(H(2)O)·(CTZ)(3). The crystalline material was determined to be a monosodium dihydrate, stable in the range of 10-90% relative humidity (RH) at 25°C. Additional processing of the salt resulted in a crystalline anhydrous form which was stable in the range 0-20% RH at 25°C. The aqueous solubility of the chlorothiazide sodium dihydrate at 37°C was found to be approximately 400-fold higher than that of chlorothiazide, which may present biopharmaceutical advantages for the salt compared to the non-salt form.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 12/2010; 41(5):603-11. · 2.61 Impact Factor
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ABSTRACT: We report here a facile synthetic and analytical approach that allows us to identify and characterize functionalized polyoxomolybdate clusters that form upon the partial reduction of Mo(VI) salts in the presence of organoarsonate ligands. We demonstrated that electrospray ionization mass spectrometry, in combination with X-ray crystallography, provides an extremely powerful tool, allowing us to exploit slight perturbations of the ligand structures for the preparation of a series of unprecedented cluster compounds. Redox-active transition metals that adopt cubane or related structures are of particular interest because of their resemblance to active sites of enzymes. Our investigations underline the stability of the hybrid compounds in solution, an essential requirement for potential applications as catalysts. Supplemental analyses include measurements of the magnetic properties, NMR, IR, UV/vis, and bond-valence-sum analyses. Our results highlight the possibility of exploring real-time growth reactions of polyoxometales that emerge in solution and transform to produce hybrid organic-inorganic polyoxometalate clusters.
Inorganic Chemistry 12/2010; · 4.60 Impact Factor
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ABSTRACT: The synthesis and antiproliferative activity of a new series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. These novel compounds are also substituted at position 3 of the β-lactam ring with an aryl ring. A number of analogues showed potent nanomolar activity in human MCF-7 and MDA-MB-231 breast cancer cell lines, displayed in vitro inhibition of tubulin polymerization, and did not cause significant cytotoxicity in normal murine breast epithelial cells. 4-(4-Methoxyaryl)-substituted compound 32, 4-(3-hydroxy-4-methoxyaryl)-substituted compounds 35 and 41, and the 3-(4-aminoaryl)-substituted compounds 46 and 47 displayed the most potent antiproliferative activity of the series. β-Lactam 41 in particular showed subnanomolar activity in MCF-7 breast cancer cells (IC₅₀= 0.8 nM) together with significant in vitro inhibition of tubulin polymerization and has been selected for further biochemical assessment. These novel β-lactam compounds are identified as potentially useful scaffolds for the further development of antitumor agents that target tubulin.
Journal of Medicinal Chemistry 11/2010; 53(24):8569-84. · 4.80 Impact Factor
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ABSTRACT: The synthesis and photophysical evaluation of three diaryl thiourea-based anion receptors (4–6) for comparison with their urea counterparts (1–3) is outlined. These anion receptors posses an acetamide functionality on one of the aryl groups and an electron-withdrawing CF3 group on the other. By varying the position of the acetamide group, in the o-, m- and p-positions of 4–6, respectively, the anion binding ability was both tuneable and found to be, in some cases, significantly different from that seen for the urea analogues 1–3. The binding affinities of the receptors 4–6, as well as the binding stoichiometries, were evaluated using UV–vis absorption spectroscopy in MeCN. However, these receptors were not sufficiently emissive to quantify the anion recognition using fluorescence. The results confirmed strong binding of these receptors to anions such as fluoride, acetate, phosphate, pyrophosphate and chloride. Nevertheless, the overall results obtained did not conform to the anticipated trends seen for 1–3, which is most likely due to the enhanced binding affinity of the thiourea analogues 4–6. The binding interactions were also investigated by using 1H NMR which confirmed that these receptors interacted with the anions in a stepwise manner, where the primary anion binding interaction occurred at the thiourea side, which led to an activation of the acetamide moiety towards the second anion binding interaction, an example of an allosteric activation mode.
Supramolecular Chemistry. 10/2010; 22(10):586-597.
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ABSTRACT: [Cr(phen)(2)(X(2)dppz)](3+) {X = H, Me, or F} have been synthesised, characterised, and chromatographically resolved into their constituent Delta and Lambda enantiomers. The DNA-binding interactions of each of the racemic complexes were investigated, with the results of linear dichroism, thermal denaturation, and emission quenching studies indicative of intercalative binding to CT-DNA with a significant electrostatic contribution. UV/Vis absorption titrations suggest strong DNA binding by each of the racemic complexes, with the methylated analogue [Cr(phen)(2)(Me(2)dppz)](3+) exhibiting the largest equilibrium binding constant. Emission quenching and UV-Vis titrations of the enantiomers of [Cr(phen)(2)(dppz)](3+) imply similar binding affinities for the Delta and Lambda isomers, although significant differences between the circular dichroism spectra of the enantiomers in the presence of DNA connote differences in binding orientation and/or conformation between the two.
Dalton Transactions 04/2010; 39(16):3990-8. · 3.84 Impact Factor
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ABSTRACT: The prepn. of a ketone, F3C(CF2)5(CH2)2CO(CH2)2(CF2)5CF3, with two long chain perfluoroalkyl groups is reported via the coupling reaction of a perfluorinated alkylzinc reagent and a perfluoro-acid chloride. Using its unique thermomorphic properties, this ketone has been investigated in the heterogeneous removal of heavy metals M2+ (M = Sn, Cd, Pb, Hg) and As5+ from aq. solns. and org. solvents. In addn., a comprehensive 13C NMR study of one of the intermediates in the synthesis, 2H,2H,3H,3H-perfluoronanoic acid, has allowed the detn. of all 1 J C-F and 2 J C-F coupling consts. Also reported is the crystal structure of the acid CF3(CF2)5CH(CH3)CO2H. [on SciFinder(R)]
Journal of Fluorine Chemistry 01/2010; 131(5):621-626. · 2.03 Impact Factor
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ABSTRACT: The design, synthesis, and X-ray crystallographic analysis of three simple diaryl-urea based anion receptors possessing an amide moiety on one of the aryl groups, and an electron withdrawing CF(3) group on the other, is described. The three receptors differ only in the position of the amide functionality relative to the hydrogen bonding urea moiety (being para, meta, and ortho for 1, 2, and 3, respectively). This simple modification was shown to have a significant effect on the anion recognition ability, the strength of the recognition process, and the stoichiometry (host/guest) for these sensors. We demonstrate, by using both UV-vis absorption and (1)H NMR spectroscopy, that these factors are caused by the ability of the amide moiety to both modulate the anion binding selectivity and the sensitivity of the urea moiety. We also demonstrate that, in the case of 1 and 2, this anion recognition at the urea moiety leads to concomitant activation (through enhanced inductive effect) in the amide functionality toward anions, which leads to the formation of an overall 1:2 (sensor/anion) binding stoichiometry for these receptors. This "activation" we describe as being an example of a "positive allosteric activation" by the urea site, caused directly by the first anion binding interaction, which to the best of our knowledge, has not been previously demonstrated for anion recognition and sensing.
The Journal of Organic Chemistry 12/2008; 73(23):9235-44. · 4.45 Impact Factor
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ABSTRACT: The design, synthesis and physical evaluation of 1, a visible colorimetric 'naked eye' pyridyl based bis-amidothiourea sensor for anions, is described. This charge neutral sensor gives rise to significant changes in the absorption spectra upon interactions with several important biological anions such as AMP and ADP in 4:1 DMSO-H(2)O solution, while ATP was not detected. These colorimetric changes are due to the formation, or the combination of hydrogen bonding complexes and/or deprotonation between these anions and 1.
Organic & Biomolecular Chemistry 12/2008; 6(22):4089-92. · 3.70 Impact Factor
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ABSTRACT: 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.
Bioorganic & medicinal chemistry 10/2008; 16(17):8210-7. · 2.82 Impact Factor
