RESUMEN

Three Ag(I) bis(phenanthroline-oxazine) complexes with varying lipophilicity were synthesised and characterised. The solution stoichiometry of 1:2 Ag(I):ligand was determined for each complex by the continuous variation Job's plot method using NMR spectroscopy. NMR studies were also carried out to investigate the fluxional behaviour of the Ag(I) complexes in solution. The biological activity of the silver(I) complexes and the corresponding ligands towards a clinical strain of Candida albicans MEN was studied using broth microdilution assays. Testing showed the choice of media and the duration of incubation were key determinants of the inhibitory behaviour towards Candida albicans, however, the difference between freshly prepared and pre-prepared solutions was insignificant in minimal media. The activity of the metal-free ligands correlated with the length of the alkyl chain. In minimal media, the methyl ester phenanthroline-oxazine ligand was effective only at 60 µM, limiting growth to 67% of the control, while a 60 µM dose of the propyl ester analogue limited fungal growth at < 20% of the control. MIC50 and MIC80 values for the propyl and hexyl ester analogues were calculated to be 45 and 59 µM (propyl), and 18 and 45 µM (hexyl). Moreover, in a study of activity as a function of time it was observed that the hexyl ester ligand maintained its activity for longer than the methyl and propyl analogues; after 48 h a 60 µM dose held fungal growth at 24% of that of the control. Complexation to Ag(I) was much more effective in enhancing biological activity of the ligands than was increasing the ester chain length. Significantly no difference in activity between the three silver(I) complexes was observed under the experimental conditions. All three complexes were substantially more active than their parent ligands against Candida albicans and AgClO4 and the three silver(I) bis(phen-oxazine) complexes have MIC80 values of < 15 µM. The ability of the silver(I) complexes to hold fungal growth at about 20% of the control even after 48 h incubation at low dosages (15 µM) showcases their superiority over the simple silver(I) perchlorate salt, which ceased to be effective at dosages below 60 µM at the extended time point.

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RESUMEN

A series of phenanthroline-oxazine ligands were formed by a cyclisation reaction between L-tyrosine amino acid esters and 1,10-phenanthroline-5,6-dione (phendione). The methyl derivative of the phenanthroline-oxazine ligand 1 was complexed with Ag(I), Mn(II) and Cu(II) to form [Ag(1)2]ClO4, [Mn(1)3](ClO4)2 and [Cu(1)3](ClO4)2. The activity of these metal complexes was tested against the bacteria Escherichia coli and Staphylococcus aureus. Each of the metal complexes was more active than 1 against S. aureus and the Mn(II) and Cu(II) complexes also showed greater activity than 1 towards E. coli. The effect of increasing the length of the alkyl moiety on the phenanthroline-oxazine ligands and their corresponding tris homoleptic Cu(II) complexes was investigated. In all cases both the ligands and their complexes were more active against Gram-positive S. aureus than against Gram-negative E. coli. Differences in the lipophilicity of the ligands and their corresponding Cu(II) complexes did alter the antibacterial activity, with the hexyl and octyl derivatives and their complexes showing the greatest activity and comparing well with clinically used antibiotics. The most active Cu(II) complexes and their respective ligands were also active against Methicillin-resistant S. aureus (MRSA). In vivo toxicity studies, conducted using the Galleria mellonella model, showed that all of the compounds were well tolerated by the insect larvae.

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Isoxazolo-pyrene tethered calix[4]arenes selectively detect copper(II) ions without interference from related perchlorate ions. The fluorescence emission of the probes, synthesised by nitrile oxide alkyne cycloaddition, and characterised by spectroscopic and crystallographic data, is rapidly reduced by Cu(II) ions. Detection limits are in the micromolar or sub-micromolar range (0.3-3.6 µM) based on a 1 : 1 sensor:analyte interaction. Voltammetric behaviour and 1 H NMR data provide new insights into the sensing mechanism which is dependent on the calixarene substitution pattern. When the calixarene lower rim is fully substituted, Cu(II) detection occurs through a traditional chelation mechanism. In contrast, for calixarenes 1,3-disubstituted on the lower rim, detection takes place through a chemodosimetric redox reaction. The isolation of a calix[4]diquinone from the reaction with excess Cu(ClO4 )2 provides confirmation that the sensor-analyte interaction culminates in irreversible sensor oxidation.

RESUMEN

Strain promoted cycloaddition is presented as a tool for RNA conjugation on the solid phase; RNA-cyclooctyne conjugates are prepared by cycloaddition to both azide (strain-promoted azide-alkyne cycloaddition, SPAAC) and nitrile oxide dipoles (strain-promoted nitrile oxide-alkyne cycloaddition, SPNOAC). The conjugation is compatible with 2'-OMe blocks and with 2'-O-TBDMS protection on the ribose moieties of the sugar. Nitrile oxide dipoles are found to be more reactive click partners than azides. The conjugation proceeds within 10 min in aqueous solvents, at room temperature without any metal catalyst and tolerates dipoles of varying steric bulk and electronic demands, including pyrenyl, coumarin and dabcyl derivatives.

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Rapid, catalyst free, solid phase modification of DNA by strain promoted cyclooctyne-nitrile oxide click chemistry is reported; the reaction is characterised by mild conditions, occurring in an aqueous environment under atmospheric conditions at room temperature and is complete in 10 minutes.

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An efficient, catalyst free, 1,3-dipolar cycloaddition strategy to conjugate nucleosides and nucleotides with isoxazoles under atmospheric conditions and in an aqueous environment is reported. The protocol involves chloramine-T as a practical reagent to induce in situ nitrile oxide formation and the alkyne partner is attached to the sugar residue or the nucleobase. The reactions are regiospecific, fast and high yielding.

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A fast and practical metal free conjugation of ribonucleosides and 2'-OMe 4-mer oligoribonucleotides has been accomplished by a nitrile oxide alkyne click cycloaddition reaction on the solid-phase, the methodology is suited to modification at either, or both, the 3'- or the 5'-terminus of the oligoribonucleotide substrate.

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Solid-phase oligonucleotide conjugation by nitrile oxide-alkyne click cycloaddition chemistry has been successfully demonstrated; the reaction, compatible with all nucleobases, requires no metal catalyst and proceeds under physiological conditions.

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The reaction between the heteroaromatic N-oxides 1a, 1b and 1c with dimethyl acetylenedicarboxylate or methyl propiolate furnishes 1,3-benzodiazepines, the products of ring transformations of primarily formed cycloadducts. The structures of 8a and 10a have been confirmed by X-ray crystallographic analysis. The aldonitrone 1c also reacts with N-methylmaleimide and with phenyl vinyl sulfone to furnish the first examples of primary cycloaddition products from quinazoline 3-oxides.

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A novel synthesis of 1,2-disubstituted 1,2-dihydroquinazoline 3-oxides 8 and the first ever examples of 1,3-dipolar trapping of these nitrones to homonuclear dipolarophiles is described. The new dipoles 8 reacted with N-methyl maleimide, generating diastereomeric adducts 14-16. In the reaction between 8 and dimethyl acetylenedicarboxylate, primary cycloadducts 17 and/or stable rearrangement products, azomethine ylides 18, are formed depending on the substitution pattern of the dipole. The structure of 18c is unambiguously assigned by X-ray crystallographic analysis. An X-ray crystal structure determination is also presented for the cyclopropylisoxazoloquinazoline 22 formed by a [3 + 2] addition of 8a to 21, the dimethyl acetylenedicarboxylate tetramer.

RESUMEN

Preparation of a series of terminally and internally substituted delta-alkenyl and delta-alkynyl esters 6, 7 and 9, potential precursors to oxazin-2-one nitrones, has been attempted. Condensation between pyruvic or benzoylformic acid and the appropriate alcohol proceeded smoothly in some cases whilst allylic transposition was a major feature in other cases--most especially during reactions with alpha-vinylbenzyl alcohol. Oximation of pyruvic acid derivatives furnished E-oxime isomers whilst benzoylformic acid derivatives afforded mixed geometrical isomers. The E-oxime of 4a1 carrying an internal Me group undergoes facile thermal cyclisation affording nitrones 1c and 1d in good yield. Oximes E-5a,b with a terminal methyl substituent on the alkene moiety furnish nitrone only under the influence of an external electrophile [PhSeBr/AgBF4]. A terminal Ph substituent on 5c,d prohibits formation of the cyclic dipole irrespective of reaction conditions, and whilst 5d reacts to afford a bicyclic isoxazolofuranone 13 by an IOOC reaction (intramolecular oxime olefin cyclisation) 5c remains thermally inert. Finally delta-alkynyl oximes 9c,d also failed to cyclise. The regio- and stereochemical characteristics of the cycloadditions between the new dipoles and electron poor olefinic dipolarophiles have been investigated. The conditions needed for reaction were rather forcing since the dipoles are somewhat stabilised by the adjacent alkoxycarbonyl group. All reactions proceeded regiospecifically to give adducts with 5-substituted isoxazolidine rings whilst diastereoselectivity varied with the choice of dipolarophile and the steric demands of the nitrone substituents. The phenylselenyl dipole 10a could not be trapped by any dipolarophiles bar dimethyl acetylenedicarboxylate.

RESUMEN

alpha-Keto amides 10a,b, formed from reaction of pyruvic or benzoylformic acid with allyl amine are found to present as single rotameric forms whilst their tertiary amido analogues 10c, d present as two rotamers in solution at rt. The hydroxyimino derivatives 8 share the conformational characteristics of their parents. The geometrical make-up of the new alpha-amidooximes is seen to depend on the structure of the starting acid and on the degree of substitution of the amido group. The oxime 8a derived from pyruvic acid and allyl amine is formed solely as the (E)-isomer whilst its tertiary amido analogue 8c is formed as both (E)- and (Z)-isomers. Oximes derived from benzoylformic acid have the opposite selectivity with both geometrical isomers forming from the secondary amide 8b and only the (Z)-isomer from the tertiary amide 8d. With the exception of 8b all oximes were configurationally stable with (Z)-isomers reacting to form isoxazolopyrrolidinones 11--compounds with a relatively rare bicyclic nucleus and (E)-isomers cyclising to piperazin-5-one nitrones 1--ketopiperazine N-oxides have to date only appeared once in the literature. New nitrones were trapped with phenyl vinyl sulfone, dimethyl acetylenedicarboxylate and methyl propiolate yielding isoxazolidine and isoxazoline fused piperazinones 13, 15, 21 and 22. Cycloadducts from dimethyl acetylenedicarboxylate and 8a, b are thermally labile and their rearrangement provides a novel route to pyrrolopiperazinones 16. The structure of a representative isoxazolopyrrolidinone, 11c, and a 2,3-dihydroisoxazoline fused piperazinone, 21b, are unambiguously solved following x-ray structural analysis.