Physicochemical and biological properties of some acridine-linked aniline mustards

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dc.contributor.author Boritzki, Theodore en
dc.date.accessioned 2007-07-28T06:46:15Z en
dc.date.available 2007-07-28T06:46:15Z en
dc.date.issued 1993 en
dc.identifier THESIS 94-082 en
dc.identifier.citation Thesis (PhD--Chemistry)--University of Auckland, 1993 en
dc.identifier.uri http://hdl.handle.net/2292/1114 en
dc.description Full text is available to authenticated members of The University of Auckland only. en
dc.description.abstract Six series of acridine mustards were evaluated with respect to their chemical reactivity and their in vitro and in vivo cytotoxicity and compared to the corresponding simple aniline mustards. The alkylating groups were linked to the DNA-intercalating 9-aminoacridine chromophore by an alkyl chain varying in length from two to four bonds. Aniline mustard was attached through a link group X which was varied to provide a series of compounds with widely varying chemical reactivity but with similar geometry. Rates of mustard hydrolysis, alkylation of 4-(4-nitrobenzyl)pyridine, and alkylation of calf thymus DNA related only to the electronic properties of the link group X. The attachment of 9-aminoacridine caused a decrease in the solvolysis and alkylation rates compared to the corresponding simple mustards. Displacement of DNA-bound ethidium and Scatchard analysis showed that the acridine mustards bound to DNA and RNA with similar affinity to 9-aminoacridine. A computer simulation (ACMUSIM) was developed to model the kinetics of the alkylation of RNA and DNA in cells. The results suggest that the preference of the acridine mustards to reversibly bind to DNA over RNA is insufficient to effectively target alkylation to DNA. A gel electrophoresis assay and an ethidium fluorescence assay both showed that the more reactive acridine mustards (X = -O-, -CH2-, -S-) could react with DNA to form inter-strand cross-links. The rate of DNA cross-link formation was measured for the O-linked acridine mustard (-(CH2)5-) 2a and found to be about half the rate of monoadduct formation. A second computer simulation (ACMUSEQ) was developed to model monoadduct and cross-link formation on DNA. This model predicted the observed monadduct/cross-link ratio of products for compound 2a after parameter adjustment to allow for monoadduct formation at sites where cross-linking could not occur. The major DNA adducts formed by two monofunctional and two bifunctional acridine mustards (X= -CH2-, N = 2 and X = -O-, N = 5) were isolated and identified. The acridine mustards with shorter linker length reacted primarily with DNA guanine (N-7) with lesser amounts of adenine (N-3) and phosphate alkylation. The O-linked monomustard reacted primarily with DNA adenine at N-1. Addition of Mg2+ ions switched this preference to adenine at N-3. The O-linked bis-mustard reacted with DNA adenine (N-1 and N-3) and guanine (N-7). The in vitro growth inhibition of the acridine mustards correlated well with the electronic properties of the link group X. The targeted mustards were more potent than the corresponding simple mustards but their IC50 values varied much less with linker group electronic properties. Most of the targeted mustards showed in vivo activity against P388 murine leukemia. The acridine mustards were more dose-potent and more active than either chlorambucil or the corresponding simple aniline mustards. en
dc.language.iso en en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA9953523514002091 en
dc.rights Restricted Item. Available to authenticated members of The University of Auckland. en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.title Physicochemical and biological properties of some acridine-linked aniline mustards en
dc.type Thesis en
thesis.degree.discipline Chemistry en
thesis.degree.grantor The University of Auckland en
thesis.degree.level Doctoral en
thesis.degree.name PhD en
dc.rights.holder Copyright: The author en


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