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Polyammonium conjugates as drug delivery systems.

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posted on 19.11.2015, 08:48 by Richard. Weaver
This thesis describes the novel synthesis of eight polyamine-nitrogen mustard conjugates and two polyamine-nitroxide conjugates. The structure-activity relationship of these compounds with DNA has been investigated. The approach started with the regioselective BOC protection of commercially available norspermidine, spermidine and spermine plus the total synthesis of protected polyamines e.g. homospermidine and spermine. The nitrogen mustards chlorambucil and melphalan were conjugated to the polyamines at primary and secondary nitrogens via a variable length amide linkage to give a structural range of differentially charged polyamine-drug conjugates. The spin label 3-carboxy-proxyl was conjugated to a primary and secondary nitrogen of spermine via an amide linkage to give two novel spermine-spin labelled adducts. Electron paramagnetic resonance spin exchange experiments in the presence of DNA gave an indication of translational motion of spermine on the DNA. The DNA cross-linking of the polyamine-nitrogen mustards identified that: (i) spacing between positive charges does not significantly affect the cross-linking efficiency, (ii) increasing the positive charge of the polyamine increases the cross-linking ability of the conjugates (reflecting the trend in binding ability of charged polyamines) and (iii) primary amino polyamine-drug conjugates are more efficient cross-linkers than the corresponding secondary amino conjugates. The polyamine-nitrogen mustard conjugates also showed the same sequence selectivity as the parent drugs i.e. chlorambucil and melphalan. The N7 position in the major groove of DNA is alkylated. Runs of contiguous guanines provide sites of highest alkylation for chlorambucil and the polyamine-drug conjugates. The results imply that the initial site of alkylation is not dictated by the poly amine moiety binding to specific sites on DNA.


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University of Leicester

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