The synthesis and antitumour properties of some DNA-directed alkylating agents
Abstract (Summary)Restricted Item. Print thesis available in the University of Auckland Library or available through Inter-Library Loan. Bifunctional alkylating agents are an important class of clinically useful antitumour drugs which prevent cell replication by cross-linking DNA. However, these reactive compounds also alkylate other cellular macromolecules as well as DNA. This not only lowers the potency of the drugs, but also leads to the majority of the DNA lesions being monoadducts rather than diadducts. The disadvantages resulting from this are the high doses of drugs required in the clinic, and the mutagenic properties arising from a high ratio of monoalkylation to dialkylation. With these factors in mind a series of DNA-targeted aniline mustards were prepared and their physicochemical and biological properties, together with those of other members of the class and their corresponding untargeted counterparts were evaluated in vitro and in vivo. Two series of oxygen- and methylene- substituted aniline mustard functions were linked to the amino group of the DNA-intercalating 9-aminoacridine chromophore by a methylene chain of variable length attached at the mustard 4-position. An amide and a carbonyl-linked analogue with contrasting reactivities were also prepared. Synthesis of these compounds involved the use of a methyl ester function as a precursor for the amine needed for the coupling of the aniline mustard moiety to the acridine chromophore. Rates of hydrolysis were dependent on mustard reactivity for both series bur the attachment of 9-aminoacridine had no effect. Although targeting increases potency (up to 100-fold) over the untargeted mustards, the ratio of monoalkylation to dialkylation was not improved. A second series of compounds was synthesised where the mustard was attached to a well known regioselective chromophore (amsacrine) at either the 9-anilino or the acridine ring. Preliminary biological results showed that these compounds were generally less potent than the 9-aminoacridine series, but were more efficient DNA cross-linkers especially the 4-carboxamide analogues. A minor groove alkylating analogue (215) was also synthesised in an attempt to improve the DNA cross-linking ability. The molecule was based on the polybenzamide bisquaternary ammonium backbone, the two arms of a mustard moiety being separated and placed at meta positions on the two outer phenyl rings. Preliminary results showed a higher degree of cross-inking ability (1 in 10 alkylating events) with this compound compared with the former series. The compound alkylates adenines in the opposite strand, followed by interstrand cross-linking in the minor groove.
School Location:New Zealand
Source Type:Master's Thesis
Date of Publication:01/01/1990