Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.696523
Title: Polyamines and their potential exploitation in drug delivery
Author: Travis, Natalie Gail
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 1998
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Abstract:
The novel polyamine-conjugates synthesised and presented in this thesis were used to investigate the following; i) the structural specificity of the polyamine uptake system, ii) the intracellular location of polyamines and mechanism of uptake and iii) the proteins involved in the polyamine transport mechanism. Synthetic methods were developed to synthesise N,N-dialkylated polyamines in high yields utilising the protecting group BOC, the phase transfer catalyst tetra-butylammonium hydrogen sulphate and an alkyl bromide. This methodology was used to synthesise a range of terminally ethylated polyamine-chlorambucil and polyamine-MANT conjugates. Synthetic procedures were also devised employing high dilution factors and an excess of spermine, to allow the selective protection of N1 on spermine with either a BOC or MANT group, thus providing routes for the synthesis of photoaffinity polyamine-conjugates. The promising results obtained from competitive inhibition uptake studies and cytotoxicity studies for N1,N12-diethyl spermine-chlorambucil, in terms of low Ki and IC50 values coupled with the potential reduced neurotoxicity, suggest that this compound should undergo further investigation as a potential anticancer agent. Confocal laser scanning microscopy images provided evidence that the diethyl polyamine- MANT conjugates and their parent conjugates were not associated with the nuclear DNA. The conjugates were observed in granular structures, non-uniformly distributed within the cytoplasm. The novel, non-radioactive fluorescent photoaffinity polyamine-conjugate N1-MANT-N12-ASA spermine was used in an attempt to isolate the polyamine transport protein. Cultured cells treated with the conjugate were subsequently found to be fluorescent, suggesting a stable covalent linkage between the conjugate and the cells. Isolation and separation of the plasma membranes on a SDS-PAGE gel resulted in fluorescent bands being viewed at the running front of the gel.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.696523  DOI: Not available
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