Dihydrofolate Reductase Inhibitors as Potential Antitumour Radioaffinity Reagents

Abstract

The principle of this research was to incorporate the radiolabile azido group into the structures of reversible inhibitors of dihydrofolate reductase (DHFR) which on administration would interactwith this enzyme in normal and neoplastic cells. Subsequent selective X- or Y-irradiation of the tumour causes the formation of nitrene intermediates which covalently bond with their immediate surroundings. Various azido, chloro, nitro, amino, acetylamino, diazonium salt and p-substituted-benzenesulphonamido derivatives have been prepared in the following four chemical series:- (i) 2,4-diamino-6-substituted -quinazoline, (ii) 4,6-diamino-1,2 (2H)-2,2-diimenthyol-1-(s1ubstituted- Pphenyl)-s-triazine, (iii) 2,4-diamino-6-(substituted-phenyl) -s-triazine and (iv) 2,4-diamino-5- (3-substituted-4-chlorophenyl) -6-ethylpyrimidines. The hitherto unreported nucleophilic displacement by hydrazine of the amino groups of 2,4-diaminoquinazoline is described: this compoundwhen refluxed in hydrazine hydrate for 6 h yielded 2,4-dihydrazinoquinazoline via 2-amino-4-hydrazinoquinazoline...