Tumour Inhibitory Acridine Derivatives

Abstract

Increased antitumour selectivity may be expected from the combination of radiotherapy and cancer chemotherapy. Radiosensitizing agents which have been employed for this purpose are reviewed in the first chapter. The acridine nucleus with its purported DNA intercalation capability has been used in the design of antitumour agents. A review of the extensive structure-activity relationship studies in this area is found in Chapter 2. Irreversible and selective attachments of acridine molecules to the DNA of cancer cells ts expected to inhibit the proliferation of these cells permanently. Nitrenes are electrophilic species which may react with nucleophilic centres in DNA, and can be generated by irradiation of azido compounds. Azido derivatives of 9-antlinoaeridine should therefore prove to be effective irreversible antitumour radiosensitizing agents. The chemistry and pharmacology of azides and nitrenes are discussed in Chapter 3. In the Discussion, the synthesis and characterisation of 9-anilinoaeridines are described. Raney nickel-hydrazine hydrate reduction of nitroanilino derivatives gives the corresponding amines. Azido derivatives are formed when the para and meta aminoanilinoacriladines are diazotised and reacted with aqueous sodium azide. Diazotisation of the ortho aminoanilinoacridine affords 9-(benzotriazol-1-yl)acridine; thermolysis of this compound produces 13H-quin[4,3,2-kl]acridine. Photolysis studies of the azides suggest that their degree of decomposition is proportional to the irradiation time and inversely proportional to the irradiation wavelength. L1210 mouse leukaemic cell culture is selected as the biologtcal model for the detection of photosensitization by azides. The growth characteristics of L1210 cells are presented in Chapter 6. The additional cytotoxicity of the photosensitization by azido compounds ts probably due to the photogeneration of reactive (nitrene) spectes since it is proportional to the irradiation time of cell cultures treated with these azido agents. Both the model azide azidobenzenesulphonamide and the azidoanilinoaeridines exhibit photosensitization effects. Thorough control experiments demonstrate and isolate such photosensitization properties.