Biologically active peptide analogues
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
Biologically active peptides and their receptors are involved in many of life's essential processes. They are of enormous medical interest as many diseases and illnesses can be treated by agents which block or imitate the function of specific peptides and their receptors. The research described in this thesis encompasses two distinct approaches towards the development of peptidomimetics, analogues which mimic specific biologically active peptides. Chapter one gives a general introduction to the role of peptides in drug discovery and design and some representative examples. Chapters two deals with the rational design of a new cis-hydroxyethylamine peptidomimetic isostere and its application to the development of HIV drugs. Chapter three describes the synthesis of 1,5-disubstituted tetrazole dipeptide compounds, based on the designed isostere, and their extension in the N and C directions. The HIV-1 protease inhibition results of a series of tetrazoles are presented in chapter four. Compounds based on the designed isostere gave reasonable μM Ki values, compared with the nM values of the most potent known HIV protease inhibitors. The hydroxymethylene group was found to be crucial to activity and the QC ligand was shown to be favoured at the P3 site over Cbz. The C3 and C6 configurations adjacent to the tetrazole ring were also shown to influence the activity of the inhibitors. These design principles on which the cis-hydroxyethylamine isostere was based were justified and have given a basis for future development of the structure. A more traditional approach to drug discovery is the exploitation and development of the biological activity of potent natural products. Previous work has established the potent activity of the a.-hydroxyamidoacetal C7-C10 functionality of the sponge metabolites mycalamides A and B. Chapter five describes two synthetic routes to a general α-hydroxyamidoacetal structure (see 5.5), and the synthesis of a series of mycalamide analogues with varying R₁-R₄ substituents, for example the epimers (1'S,2S)- and (1'R,2S)-2-hydroxy-N-(1-methoxybenzyl)-3-phenylpropanamide. The assignment of configuration and antitumour activity of the series of analogues is presented in chapter six. The compounds show modest in vitro antitumour activity. The level of activity appears to be more sensitive to changes at R₂ than R1 and to favour a (1’R)-configuration. The amino acid based analogues (R₁ = NHR) showed comparable or improved activity over the R₁ = OR analogues, and supported the proposal that the series of analogues act as peptidomimetics. Chapter seven details the X-ray crystallographic analysis of a crystal of (DMAP)₅(benzoic acid)₃(H₂O)₁₀, with a unique layered structure in which benzoate anions are two-dimensionally clathrated by water molecules.