Synthesis of Novel Alkylating Agents for Biological Evaluation As Anti-Cancer Prodrugs

Anderson, Fiona Mary (1999) Synthesis of Novel Alkylating Agents for Biological Evaluation As Anti-Cancer Prodrugs. PhD thesis, University of Glasgow.

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Bioreducible antitumour agents are prodrugs which are intended to be inactive in normal ceils, but are able to undergo metabolic reduction in cancer cells to produce toxic species which can damage biomolecules. This reduction can occur readily in solid tumours due to two factors which are unique to them: a) tumour hypoxia; and b) the expression of high levels of reductase enzymes. Each of these factors can promote specific cytotoxicity to the tumour and in principle could create a selective anti-tumour agent. The overall aim of this work was to synthesise powerful alkylating agents and then target them selectively to cancer cells as inactive prodrugs. Following on from previous work on N-oxides of cis- and trans- 2,6-disubstituted-N-methylpiperidine, compounds (A), where X is a carbamate or halogen, were synthesised and subjected to biological evaluation against two human carcinoma cell lines, HT29 and BE cells, under oxic and hypoxic conditions. They showed promising cytotoxicity towards the cancer cells and good DNA crosslinking activity. The DNA sequence specificity of these compounds for guanines warranted further study of structure/activity relationships. To optimise the selectivity and cytotoxicity of this type of compound a series of compounds was formed examining variables such as ring size; number of rings in the system; number of carbons between rings (2-8); stereochemistry; leaving group; number of atoms between nitrogen and the leaving group and the number of potential alkylating sites. These compounds underwent biological evaluation against the human leukaemic K562 cell line. Results from the biological testing were inconclusive in understanding structural/biological activity relationships. An area of chemistry which is as yet unexplored is that of macrocydic alkylating agents as potential anti-cancer agents. A selection of cyclic alkylating agents was synthesised from a ring size of three in the monoalkylating aziridine chloride (B) to larger macrocyclic systems of up to 23 membered rings with the potential of six alkylating functions. Also macrocyclic systems incorporating other heteroatoms in the ring such as oxygen and sulfur were made. The incorporation of other functional groups such as amide or benzyl moieties in the macrocyclic systems was also examined as in the synthesis of (C). Variations on the size of the ring; the number of potential alkylating sites; the number of carbons between the nitrogens; and the number and type of heteroatoms in the macrocyclic system have been examined. The methods used to form these compounds varied depending on available starting materials from high dilution techniques to condensation reactions between amines and esters or acid chlorides. The high dilution method employed the cyclisation between amines protected with tosyl groups, and alcohols, also protected as tosylates. This was followed by sulfonamide cleavage and alkylation using ethylene oxide to obtain the alcohols. The hydroxyl groups were substituted by chlorine atoms to form the alkylating N-chloroethyl moieties. The results of the biological evaluation of the macrocyclic compounds indicated that (C) was an excellent DNA crosslinker and also very cytotoxic to the cancer cell line. The potential hypoxia selectivity was investigated by the formation of nitro benzyl compounds such as (D). Nitrobenzyl quaternary compounds have been shown to undergo fragmentation after one electron reduction to an alkylating system. A selection of the macrocyclic systems formed were developed into o- and p- subtituted nitrobenzyl quaternary compounds. The results of the biological evaluation of these compounds were very disappointing and showed that none of the compounds tested was reduced under hypoxic conditions to give an alkylating agent.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Robins
Keywords: Organic chemistry, Pharmacology
Date of Award: 1999
Depositing User: Enlighten Team
Unique ID: glathesis:1999-76249
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Dec 2019 09:15
Last Modified: 19 Dec 2019 09:15

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