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Title: Polyamine conjugates as a potential drug delivery system
Author: Warrilow, Philip A. D.
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 1997
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The work in this thesis has covered three main topics; i) cytotoxic polyamine-conjugates ii) radiation protection polyamine-conjugates iii) polyamine conjugates which probe cellular uptake and DNA binding. The synthesis of these conjugates employed selective protection/deprotection steps, taking advantage of the BOC protecting groups regioselectivity of primary over secondary amines when reacting with naturally occurring polyamines. After promising in vitro and in vivo results of the original spermidine-chlorambucil synthesised by Wheelhouse (1990), attempts were made to improve this compound. The terminal amines were ethylated. The new diethyl derivative showed greater inhibition of [C14] labelled spermidine entry into cultured cells, and improved cytotoxicity. Also a new novel cis-platin polyamine conjugate was synthesised and tested for cellular inhibition of radiolabelled spermidine and cytotoxicity. It failed to recognise the polyamine uptake receptor and gave poor [C14] spermidine inhibition results and subsequently cytotoxicity. Two radiation protection polyamine agents were synthesised and tested against the indirect radiation damage pathway, both N1 and N4 mercaptoethyl spermidine. They both showed very good inhibition of [C14] labelled spermidine entry, the N1 derivative being twice as efficient as the N4. Dilute aqueous solutions of DNA were irradiated with various thiols present. Surprisingly the positively charged thiols protected to a similar extent as the negatively charged thiols, as it was expected that the primary mechanism for protection against the indirect effect was bulk water scavenging of the hydroxyl radical. An EDTA-polyamine conjugate was also synthesised and investigated and it showed moderate [C14] labelled spermidine inhibition and cytotoxicity in preliminary experiments. The cytotoxicity was due to the fact that EDTA chelation to iron (II) produces hydroxyl radicals.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available