Induction of petite formation in Saccharomyces cerevisiae by experimental antitumour agents. Structure--activity relationships for 9-anilinoacridines.

A series of 9-anilinoacridine derivatives has been compared in terms of DNA binding, ability to inhibit the growth of L1210 murine leukaemia cells in vitro, and ability to induce the formation of respiration-deficient (petite) mutations in Saccharomyces cerevisiae. The acridine ring in the derivatives was either unsubstituted, or substituted with amino groups at the 3 and/or 6 positions. The 9-anilino group was para-substituted with a variety of substituents. 3-Aminoacridine, 3,6-diaminoacridine (proflavine) and ethidium were included for comparison. The results show that: (i) at least one acridinyl amino group is necessary for conferring petite inducing activity in the yeast system; (ii) for 3-amino-9-anilinoacridine congeners, small anilino substituents provide compounds which resemble proflavine in their ability to produce petite mutants, whereas large substituents abolish activity; (iii) the 3,6-diamino-substituted anilinoacridines resemble ethidium rather than proflavine in being highly efficient inducers of petites; (iv) the requirements for optimal activity in L1210 leukaemia cell cultures are different to those for petite formation in yeast. It is concluded that the size of the anilino substituent, as well as its contribution to DNA binding, is critical in conferring biological activity in each system.