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Tumour-activated prodrug (TAP) is designed to aim at increasing the prodrug selectivity to kill cancer cells. One strategy to is to design a TAP containing an amine cytotoxin, present as an amide function, which could be released more rapidly in the low pH environment of tumour tissues when amide undergoes hydrolysis. The prodrug model (1) was the subject of the current study. At lower pH its un-ionised carboxylic acid group provides neighbouring catalysis of hydrolysis of the adjacent amide. It was synthesised via ring-opening of the imide (2) which itself was directly synthesised from endo-bicyclo[2.2.2]octa-5-ene-2,3-dicarboxylic anhydride and p-methoxyaniline. The pH-rate profile of (1) was established over the pH range of 3-10, covering rapid hydrolysis of un-ionised acid-amide at lower pH but slower imide formation above pH 8 fro...
Solid tumours are characterised by lower extracellular pH (as low as 5.8 pH) compared to normal healthy cellular pH (actively regulated at pH 7.3). This difference may be exploited with an acid-sensitive anti-tumour prodrug which releases a cytotoxin selectively in tumour tissue. The research reported in this thesis was aimed at synthesising and performing rate studies on an amide prodrug with pH-sensitive rates of reaction in the pH 5 - 8 region. Amide hydrolysis is catalysed by neighbouring carboxylic acid groups in their fully protonated state but not in its ionised state (shown in the figure below), whereby pH sensitivity around pH 5 - 8 can be exploited. The current study was carried out on an amide of Kemp's acid which, due to enforced stereochemistry of carboxylic acid and amide functional groups, has the type of structure condu...
Polyphenols, such as tannins, offer potential as a bio-derived chemical feedstock. Their present utilisation is limited mainly to leather tanning and wood panel adhesives. However, appropriate derivatisation may alter both the chemical and physical properties and thereby allow further utilisation of polyphenols. Derivatisation of polyphenols was achieved by esterification and etherification of the phenol groups. Esterification was achieved by alcoholysis of acid chlorides and transesterification with vinyl esters, while etherification was achieved by the ring opening of propylene oxide. The polyphenols used were resorcinol, catechin, Pinus radiata bark tannin, and Schinopsis lorentzii tannin. The products were characterised using a range of techniques including NMR (1H, 13C and 2D NMR in both the solution and solid state), ESI-MS...
This thesis describes the preparation and reactions of some cyclomanganated chalcones, dienones and aryl ketones. Investigation has previously been undertaken into the reaction of cyclomanganated chalcones and dienones with alkynes to give both pyranyl and cycloheptadienyl Mn(CO)₃ complexes. In the current study, the reaction was further investigated with a cyclomanganated dienone derived from a cyclic ketone which gave only the (pyranyl)Mn(CO)₃ complex (2-6) and not the cycloheptadienyl product as consistent with a mechanism previously proposed. Also extended in the current study was previous work involving the methylmanganese pentacarbonyl-mediated transformation of enynes to cyclopropanated bicyclic compounds and cyclopentanes bearing an exocyclic double bond. In the current study, benzylmanganese pentacarbonyl was used instead of m...
1-Phenyl-2-[(E)-3-phenylprop-2-en-1-oyl-κO]ethenyl-κC1]tetracarbonylmanganese (1a) reacts with PhCCH in CCl4 at room temperature to form [2,4-diphenyl-6-(2-phenylethenyl)pyranyl-η5]tricarbonylmanganese (2a), whose X-ray crystal structure is reported to complement that of its isomer [6-oxo-2,4,7-triphenylcyclohepta-1,4-dienyl-1,2,3,4,5-η]tricarbonylmanganese (3a), previously obtained from the reaction under reflux; but for 1a and PhCCPh the pyranyl complex cannot be isolated before rearrangement to the 3a analogue occurs. More forcing reaction conditions for 1a with Me3SiCCH and for [1-(2-trifluoromethylphenyl)-2-[(E)-3-(2-trifluoromethylphenyl)prop-2-en-1-oyl-κO]ethenyl-κC1]tetracarbonylmanganese (1b) with Me3SiCCH and PhCCH give new analogues of 3a where previously only 2a analogues had been isolated. The reaction in CCl4 under reflux...
Reaction of 1,5-diphenyl-3-(2-pyridyl)pentane-1,5-dione (5a) with 2.5 moles of benzylpentacarbonylmanganese in petroleum spirit under reflux gives a small amount of the symmetric di-aryl-manganated product [1,5-diphenyl-κC2-3-(2-pyridyl)pentane-1,5-dione-κO1κO5]bis-(tetracarbonylmanganese) (7a), but mostly [1,5-diphenyl-κC2-3-(2-pyridyl-κN)pentan-2-yl- κC2-1,5-dione-κO1κO5]tetracarbonylmanganesetricarbonylmanganese (6a) which is manganated at only one aryl carbon [by Mn(CO)4] but also [by Mn(CO)3 with N and O coordination] at the methylene carbon adjacent to the Mn(CO)4-coordinated ketone carbonyl. The latter is a rare example of direct cyclomanganation at a saturated carbon and the only known case adjacent to a carbonyl group; the X-ray crystal structure of 6a is reported. With 3 moles of benzylpentacarbonylmanganese the yield of 6a r...
1,5-Diphenylpenta-1,4-dien-3-ones (4) are cyclometalated with benzylpentacarbonylmanganese to form [[1-phenyl-2-((E)-3-phenylprop-2-en-1-oyl-κO)]ethenyl-κC1]tetracarbonylmanganese derivatives (5). Coupling of 5 with alkynes in some cases gives [4-phenyl-2-(2-phenylethenyl)pyranyl-η5]tricarbonylmanganese complexes (6) analogous to those previously reported for β-manganated chalcones, but in other cases an alternative cyclisation pathway subsequent to insertion of alkyne into the C---Mn bond leads to [6-oxo-4,7-diphenylcyclohepta-1,4-dienyl-1,2,3,4,5-η]tricarbonylmanganese complexes (7). The X-ray crystal structure determination is reported for one such compound, [6-oxo-2,4,7-triphenylcyclohepta-1,4-dienyl-1,2,3,4,5-η]tricarbonylmanganese (7a), derived from 1,5-diphenylpenta-1,4-dien-3-one and phenylacetylene. The 7-phenyl group is found...
Nucleotides have been routinely supplemented to infant formulas due to the important roles they play in metabolism and to replicate the higher concentrations typically found in human milk. A method utilising anion exchange solid-phase extraction clean-up and liquid chromatography was developed for the rapid, routine determination of supplemented cytidine 5′ monophosphate, uridine 5′ monophosphate, inosine 5′ monophosphate, guanosine 5′ monophosphate, and adenosine 5′ monophosphate in bovine milk-based infant formula. Chromatographic analyses were performed using a C18 stationary phase with gradient elution, UV detection, and quantitation by an internal standard technique. A single-laboratory validation was performed, with recoveries of 92–101% and repeatability of 1.0–2.3%. An extension study demonstrated the expansion in scope to ...
The title compound, [Mn(C₁₀H₉O₃)(CO)₄], is formed by orthomanganation of 3'-acetoxyacetophenone at the sterically crowded ortho site. The atoms of the benzene and the cyclometallated rings are coplanar to within <0.018 Å, and there are no significant intramolecular interactions between the Mn(CO)₄ group and the adjacent acetoxy group.
Laurate esters of catechin and condensed tannins were synthesized by both transesterification and conventional acylation techniques. Transesterification was developed as an alternative route to prepare flavonoid fatty acid esters as a prerequisite to advancing potential applications. Resorcinol, catechin, and two condensed tannins were transesterified with vinyl esters, and the resulting products were compared to those formed with lauroyl chloride. The esterified products, including catechin pentalaurate, were characterized both chemically and thermally. Transesterification produced partially substituted derivatives, with a preference for substitution at the catechol ring. Melt features were identified at or below 50°C, which were dependent upon the level of substitution. In addition, the tannin laurates showed thermal stability to at ...
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