Synthesis, cytotoxic activity, and mechanism of action of furo[2,3-c]acridin-6-one and benzo[b]furo[3,2-h]acridin-6-one analogues of psorospermin and acronycine

Compounds possessing the epoxyfuran system present in the natural cytotoxic dihydrofuroxanthone psorospermin (4) fused onto the acridone or benzob]acridone chromophores present in the antitumor acronycine (1) and S23906-1 (3) were prepared. The basic furoacridone and benzofuroacridone cores bearing an isopropenyl substituent at a convenient position were synthesized by condensation of 1,3-dihydroxyacridone (7) or 1,3-dihydroxybenzb]acridin-12(5H)-one (9) with (E)-1,4-dibromo-2-methylbut-2-ene. In both series, the (2R*,1'S*) epoxides, with the same relative configuration as psorospermin, were the most active compounds, exhibiting cytotoxic properties with IC50 values in the 10-100 nM range. As in the acronycine and psorospermin series, the new compounds act through alkylation of the DNA guanine units. However, a strong difference was noted in the DNA alkylation site between the benzopyranoacridone S23906-1, which alkylates DNA guanine units at position N-2 in the minor groove, and the new 13H-benzob]furo3,2-h]acridin-6-one derived epoxide 21, which alkylates DNA guanine units at position N-7 in the major groove.