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Title: 5-oxazolidinones : Key intermediates to peptidomimetics with latent reactivity and conformational restriction
Authors: Oldham, Mark D.
Issue Date: 1997
Abstract: This thesis examines the synthesis of peptidomimetics of the type 4.23 and 5.23. Compound 4.23 was designed to possess latent reactivity for the specific inactivation of α-chymotrypsin. Compound 5.23 is a conformationally restricted tripeptide. Chapter 2 describes the synthesis of 5-oxazolidinones, from an optically active amino acid, and the assignment of the configuration of the isomers. A method for the small scale preparation of 5-oxazolidinones was developed. The X-ray crystal structures of 1.48, 2.31 and 2.34 are reported. Chapter 3 describes the synthesis of the key synthetic intermediates 3.18, 3.19 and 3.22 via the stereospecific alkylation of 5-oxazolidinones 1.48, 2.41 and 2.38, respectively. The formation of self-addition products in the alkylation of 5-oxazolidinones was investigated and reaction conditions were found that suppressed their formation. The X-ray crystal structures of 3.18, 3.19, 3.44, 3.45 and 3.46 are reported. Chapter 4 describes the design and synthesis of potential mechanism-based inhibitors 4.23. 4.31. 4.34. 4.40. 4.43 and 4.47 for the selective inactivation of α-chymotrypsin. A general method for the synthesis of peptidomimetics containing an N-[(alkylsulfonyl)oxy]succinimide moiety was established. The X-ray crystal structures of and 4.45 are reported. Chapter 5 describes the synthesis of the tripeptidomimetic 5.23. containing the α.α-alkylaminosuccinimide moiety (a β-turn Type II conformation template), from the oxazolidinone 3.18 by a series of reactions involving amino acid couplings, cyclisation and deprotection. Chapter 6 examines the conformations of a series of oxazolidinone and succinimide X-ray crystal structures. The geometries of the heterocycles and hydrogen bonding patterns are discussed. Chapter 7 describes the a-chymotrypsin and elastase inhibition assays. Compounds 4.23, 4.31, 4.34 and 4.47 were found to be reasonable but slow irreversible inhibitors of α-chymotrypsin. The specificity towards chymotrypsin over elastase was influenced by the P₁ and P₂ substituents of the inhibitors. Chapter 8 examines the anti-tumour, anti-microbial and anti-viral activity of a number of the synthesised compounds. The anti-tumour assay revealed some promising compounds (e.g. 3.24, 4.25. 5.20. 5.23 and 8.02) with high activity for cancerous cells and no cytotoxicity towards non-cancerous BSC-1 cells. The anti-bacterial and anti-fungal assays identified a number of compounds with reasonable activity (e.g. 1.24 and 4.47).
Publisher: University of Canterbury. Chemistry
Degree: Doctor of Philosophy
URI: http://hdl.handle.net/10092/7304
Rights: Copyright Mark D. Oldham
Rights URI: http://library.canterbury.ac.nz/thesis/etheses_copyright.shtml
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