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Synthesis, structural elucidation and biological examination of novel lipophilic drug conjugates

Wood, Ian Philip; (1994) Synthesis, structural elucidation and biological examination of novel lipophilic drug conjugates. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The lipidic amino acids 33a-u and their homo-oligomers, the lipidic peptides 33v-au represent a class of compounds that are highly lipophilic, but show polar and conformational behaviour characteristics of amino acids and peptides. A series of lipidic amino acids/peptides was synthesised with a varying degree of lipophilicity due to modifications in the length of the alkyl side chain and/or the lipidic amino acid unit number. Carboxyl protected lipidic amino acid 33r was conjugated to appropriately protected amino acids furnishing a series of dipeptides 53a-t as diastereomeric mixtures. Separation and structure-retention relationships of 16 dipeptides 53b-g and 53j-s were determined on reversed phase stationary phases using Spherisorb ODS and Supercosil™ LC-ABZ stationary phases. Lipidic amino acids 33p, r, and oligomer af were coupled to highly lipophilic compounds furnishing conjugates 54a, d, c, f, g, h, i and k. After carbonyl deprotection, acids 54b, e and i were obtained. Physio-chemical investigations of the conjugates were undertaken using proton nuclear magnetic resonance. Plots of chemical shift versus concentration revealed the formation of aggregates or miscelles at high concentrations and monomers at low concentrations. The cellular uptake of lipidic amino acid 33r and oligomers 33y, al, au were studied using Ehrlich ascites tumour cells to establish uptake by transformed mammalian cells. Cellular uptake of 33r was greater than the oligomers 33y, al and au. Representative lipidic amino acids/peptides were conjugated to drug molecules with the aim of facilitating their passage across cell membranes resulting in an increase in uptake and/or modification of actions. Lipidic amino acids and peptides were utilised in the synthesis of a series of chlorambucil conjugates 56a-f, 57a-e and 58a-b of varying lipophilicity and conjugate linkage. In vitro toxicity assessments were performed on conjugates 56a, b, c, e, 57a-c and 58a to examine and compare their toxicity towards ADJ/PC6 plasmacytoma cells. The lipophilicity and conjugate linkage had an effect on the toxicity of the compounds. A series of benzoquinolizine lipidic amino acid/peptide conjugates 62a-f were synthesised. Initial in vitro experiments using Caco-2 cell cultures were carried out, followed by in vivo oral absorbtion studies to investigate the preferred lipophilicity for optimal uptake of the conjugates. The conjugates showed varying degrees of uptake, all showing higher uptake than the parent. The developement of an attractive synthetic pathway to produce 3,4-disubstitutedbenzyl cyanoprop-2-enoyl lipidic amino acid conjugates 72a-c, 73a-f and 67a-b was undertaken with the aim of producing a membrane active signal transduction inhibitor. Synthesis of BOC-aminotetradecanoyl-L-cysteine adenosine monophosphorodisulphide 80 was undertaken to demonstrate the feasibility of employing the lipidic amino acid system in the delivery of antisense oligonucleotides. In summary, the lipidic amino acid system may be incorporated into a wide variety of drugs and peptides to enhance the passage of the pharmacologically active compounds across biological membranes and/or modify their biological stability and actions.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Synthesis, structural elucidation and biological examination of novel lipophilic drug conjugates
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10104794
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