Synthesis and biological evaluation 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. In order to explore the consequences of delivering alkylating agents more effectively to DNA, two series of DNA-targeted para sulfur- and sulfone-substituted difunctional aniline mustards, covalently linked via a methylene chain of variable length to the DNA-intercalating chromophore 9-aminoacridine, have been prepared. One amide-linked analogue was also prepared, to vary the reactivity of the alkylating function. Synthesis of the sulfur and sulfone series employed the use of a methyl ester function as a synthetic equivalent for the amine group required for coupling of the aniline mustard to acridine. The amine function could be unmasked using a modified Curtius procedure in the presence of the mustard moiety. The physicochemical and antitumour properties of these compounds were determined and compared with those of other members of this general class, as well as with the corresponding untargeted mustards. While targeting in this way increased cytotoxicity and in vivo antitumour activity, the targeted mustards did not show improved DNA cross-linking ability. A second series of intercalator-targeted mustards was therefore prepared, where para oxygen-, sulfur-, and sulfone-substituted aniline mustards were attached via an amide group to the DNA-intercalating antitumour agent 5-amino-2-[2-(dimethylamino)ethyl]-1H-benz[de]-isoquinoline-1,3(2H)-dione (Amonafide), which binds to DNA in a different manner than 9-aminoacridine. These compounds also displayed increased cytotoxicity with respect to the parent untargeted mustards but again no general increase in cross-linking ability was observed. In further attempts to improve DNA cross-linking capability two compounds were prepared, each with two spatially-separated monofunctional aniline mustards attached at positions 4 and 9 of the 9-aminoacridine-4-carboxamide chromophore and designed to project one alkylating moiety into each DNA groove. However, these compounds proved to be monoalkylating agents, with only the mustard in the major groove (probably the one attached via the 9 position) reacting. In contrast, a 9-anilinoacridine derivative presenting two spatially-separated weakly-alkylating units (mesylates) to the same DNA groove did show high levels of DNA cross-linking. In order to explore this concept more generally, a series of 9-anilinoacridines bearing appended mesylate and N-methyl carbamate functions at various positions were synthesised and evaluated for their DNA-alkylating and antitumour properties.
School Location:New Zealand
Source Type:Master's Thesis
Date of Publication:01/01/1990