5-oxazolidinones : Key intermediates to peptidomimetics with latent reactivity and conformational restriction
Oldham, Mark D.
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
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 126.96.36.199.4.28 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).