No description available.

Thesis (Ph.D.)--Murdoch University, 2003. / Thesis submitted to the Division of Science. Bibliography: leaves 151-176.

M.Sc. (Chemistry) / Secondary cancer tumour formation, often called metastasis, remains one of the great scientific challenges in public health. Patients with skeletal metastases have a low survival rate, with great discomforts experienced by the sufferers. Pain, decreased mobility, pathologic bone fractures are some of the effects that these patients have to live with. Significant inroads have been made in using radio pharmaceuticals as a pain palliation treatment for bone metastases. They comprise of a bone seeking phosphonate ligand and a radionuclide. The structural variation of the phosphonate affects to a great extend the effectiveness of the radiopharmaceutical with the greatest shortfall being myelosuppression at high doses. In this study an attempt is made at synthesizing novel bisphosphonates, APDDAM and APDDPE. After several synthetic steps from the protected β-alanine tert butyl ester, the free acid precursor was achieved (as shown in the NMR and elemental analysis) in good yields. Unfortunately the final reaction step to form the bisphosphonate ligand was unsuccessful, with the free acid precursor dissociating in the acidic conditions to form salts. A polymer ligand poly-HEDP was synthesized from its free acid form in relatively low yields. The ligand was used in potentiometric studies with the metal ions Ca(II), Mg(II), Cu(II), Zn(II), Sn(II) and Sn(IV) to evaluate its potential as radiopharmaceutical candidate. The ESTA model formation constants obtained were used in the ECCLES blood plasma model to evaluate the competitive stability of the complexes against biological metal ions and ligands. The Sn(IV)-poly-HEDP complex was shown to be unstable, with a 100 % dissociation. On the other hand the Sn(II)-poly-HEDP showed much improved stability with 100 % of the metal ion remaining bound to the ligand.

M.Sc. / The dimeric structure of Lawesson’s reagent, (RPS2)2 (R = 4–MeOC6H4), or its ferrocenyl analogue (R = ferrocenyl, Fc) leads to symmetrical cleavage through nucleophillic attack by alcohols to form dithiophosphonic acids, which can be readily deprotonated by ammonia to form the corresponding ammonium salts, which can be further reacted with transition-metal halides to form new metal complexes. Among the phosphor-1,1-dithiolates as a generic class of compounds, the dithiophosphates, [S2P(OR)2]-, have been most intensely studied and the dithiophosphonates [S2PR(OR’)]-, the subject of the present study, to a far lesser extent. In this study, a large variety of new dithiophosphonate salts were synthesized from diverse alcohol functionalities derived from cholesterol, estrone, estradiol, pentaerythritol, ethandiol, hydroquinone, resorcinol, glucose and ribose. The salts were oxidized with iodine to yield various S-S oxidative products, of which two X-ray crystal structures of such compounds, the ethandiol and pentaerythritol derivatives, were obtained and they were subjected to further investigation by cyclic voltammetry due to the ferrocenyl-rich functionalities they contain. The reaction of these [S2PR(OR’)]- type salts with a number of gold(I) and palladium(II) precursors, yielded a variety of new complexes. The compounds containing multiple alcohol (hydroxy) sites have been reacted with gold(I) and palladium(II) starting materials ClAu(tht) and PdCl2(PPh3)2, respectively and also with other gold(I) variants, including the mono- and dinuclear phosphines ClAuPPh3, Au2Cl2dppe and Au2Cl2dppa. A new X-ray single crystal structure of a gold(I) complex could be obtained as a decomposition product. New products have been characterized through a combination of solution 1H and 31P NMR, EIS mass spectrometry, IR, elemental analysis, electro-chemistry and single crystal X-ray crystallographic studies.

Phosphorus is an element that is essential for life, and is used in the synthesis of many proteins, carbohydrates and deoxyribonucleic acids. Phosphorus often exists in the form of phosphate when found in the biological systems. Clinical development of possible pharmaceutical agents have used phosphorus in the form of phosphonates to increase the metabolic stability of the potential drug. Some of these phosphonates target the isoprenoid biosynthetic pathway (IBP). The IBP plays an important role in the synthesis of cholesterol and in other aspects of cellular metabolism. The enzymes of the IBP have been the target of possible therapeutic agents for treatment of multiple diseases, including cancer. Often these phosphonic acids are masked by an enzymatically cleavable group in order to increase their bioavailability and activity. Phosphoantigens are small organo-phosphorus molecules that stimulate the expansion of Vγ9Vδ2 T-cells which detect and eliminate infected cells. Both natural and non-natural phosphoantigens have exhibited a wide range of effective concentrations (EC50) for γδ T-cells. The most potent phosphoantigen is E-4-hydroxy-3-methylbut-2-enyl pyrophosphate (HMBPP), which is an intermediate in the bacterial IBP. Nanomolar concentration of this compound stimulate T-cell proliferation. While HMBPP is highly potent, it undergoes rapid decomposition when injected into the blood stream. Synthesis of more stable phosphonate analogues can show better activity for expansion of the γδ T-cell population. Increased activity was observed in T-cell assays after masking the phosphonic acids to increase the bioavailability of the active phosphoantigen. Because some phosphoantigen showed strong activity with masked phosphonic acids, families of phosphonate analogues now have been prepared. Most use selenium dioxide mediated oxidation to incorporate the terminal alcohol and ester exchange to provide prodrugs to study the structure-activity-relationships. The biological activity of these compounds has been investigated and new phosphoantigens were shown to be strong activators of γδ T-cells. Furthermore, the phosphoantigens have been shown to bind to the protein butyrophilin 3A1 (BTN3A1) at an intracellular domain. A second family of phosphoantigen derivatives, masked by a new pH fluorescent cell-cleavable ester, were prepared and tested by our collaborators to explore the compounds’ activity and to investigate the mechanism of action. Finally, a new class of phosphorus compounds alkyl 1, 1, 1-trisphosphonates has been studied to obtain salts that might be biologically active. Trisphosphonates contain a unique arrangement of phosphonate groups on a single carbon and could provide charge states unseen in the more traditional bisphosphonates. A general route to asymmetric trisphosphonates through a step-wise phosphorylation of each phosphonate has been developed. Selective phosphonate ester cleavage would allow for the ability to obtain a multitude of charge states and possible biological activity.

No / Ab initio calculations, combined with experimental studies on the anaerobic hydrolysis of phosphaalkynes under thermal and photochemical conditions suggest a potential, exogenous source of reduced oxidation state phosphorus for the early Earth.

<p> The catalytic asymmetric transformation of carbonyl compounds via iminium and enamine intermediates using chiral amines as organocatalyst has grown remarkably over last decade. Various "metal-free" reactions including aldol, Mannich, Michael, alkylation and Knoevenagel types have now been reported efficiently using simple amino acids as the sole organocatalysts. Amongst these, proline has proven to be particularly useful as a general catalyst in such catalytic asymmetric syntheses due to its unique properties. Nonetheless, proline suffers inherent fundamental disadvantages as an organocatalyst in terms of its solubility in organic media, limiting reactions to polar aprotic solvents such as DMF or DMSO. We have been interested in the synthesis of derivatives of proline incorporating functional groups that would render the chiral secondary amine fully soluble in organic solvents such as THF or dichloromethane and others that could be employed in aqueous media. The synthesis of these catalysts and their application towards the asymmetric synthesis will be presented.</p> <p> The thesis also describes isolation and identification of natural products and synthesis of their semi-stabilised derivatives. Sakuranetin and dihydrowagonine were isolated from Prunus avium plant parts, menisadurilide was isolated from Dicentra spectabilis extracts while narciclasine was isolated from Narcissus pseudonarcissus plant parts. Semi-synthetic derivative, trans-dihydronarciclasine was prepared from natural product narciclasine. Both the derivatives were subjected to antifungal and human cytochrome inhibition activity and their correlation is explained. The Amaryllidaceae family alkaloids and their semi-synthetic derivatives were subjected to biological testing and an important structural property is correlated to their activities.</p> / Thesis / Master of Science (MSc)

In the first part of this thesis, it is aimed to develope methods for the synthesis of trisubstituted pyrrrole derivatives. 2-Aminopyrrroles, alkoxy and sulfonyl substittitued pyrrole derivatives as well as pirolinones show interesting biological activities and are precursor of well know drugs. Although there is a number of methods for the synthesis of pyrroles, the synthesis of 2-aminopyrroles is limited to few works and is not widely known. Therefore, it is still an important goal in organic chemistry to improve methods for the synthesis of multifunctionalized pyrrole derivatives and pyrrolinones. Alkylation of &amp / #946 / -dicarbonyl compounds with bromoacetonitrile furnishes &amp / #945 / - cyanomethyl-&amp / #946 / -dicarbonyl compounds. The condensation reaction of &amp / #945 / - v cyanomethyl-&amp / #946 / -dicarbonyl compounds with amines catalyzed by p-TsOH affords the corresponding enamines and further base catalyzed cyclization furnishes 2- aminopyrroles in high yields, moreover, zinc perchlorate-catalyzed addition of amines, alcohols and thiols to the nitrile carbon of &amp / #945 / -cyanomethyl-&amp / #946 / -ketoesters followed by annulation gives the 5-alkoxy and 5-alkylsulfanylpyrrole-3-carboxylates in high yields. In the second part of the thesis, reactions of a broad range of acyl phosphonates with &amp / #945 / -bromo acetophenones at room temperature in the presence of different bases were described to afford two diastereomeric epoxy phosphonates in good yields and high diastereoselectivities. The diastereoselectivity of this reaction is easily controlled by changing the base. Accordingly, changing the base from Cs2CO3 to DBU changes the diatereomeric ratio (trans/cis) from 5/3 to 9/1. Furthermore, the treatment of trans isomer with DBU shows a complete conversion to the corresponding cis isomer. Additionally, these highly functionalized epoxyphosphonates are shown to be useful intermediates to give several reactions

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Additional advisors: Houston Boyd, Tracy Hamilton, Christopher Lawson, Charles Watkins. Description based on contents viewed Feb. 8, 2008; title from title screen. Includes bibliographical references.

Title from title page of PDF (University of Missouri--St. Louis, viewed March 22, 2010). Non-Latin script record Includes bibliographical references.