8,11-dihydroxy-6-[(aminoalkyl)amino]-7H-benzo[e]perimidin-7-ones with activity in multidrug-resistant cell lines: Synthesis and antitumor evaluation

The synthesis of dihydroxybenzoperimidine derivatives, which are chromophor e-modified dihydroxyanthracenediones with an additional pyrimidine ring inc orporated into the chromophore, is reported. These derivatives are structur ally related to the antitumor agent mitoxantrone. Their synthesis was carri ed out by the reaction of 6-amino-8,11-dihydroxy-7H-benzo[e]perimidin-7-one (5) or 6,8,11-trihydroxy-7H-benzo[e]perimidin-7-one (10) with a number of respective (alkylamino)alkylamines. The dihydroxybenzoperimidine derivative s exhibited in vitro cytotoxic activity against murine leukemia L1210 and h uman leukemia HL60 cell lines comparable to that of mitoxantrone. These com pounds also exhibited a range of in vitro activity against the human MDR-ty pe resistant leukemia K562R cell line with the MDR phenotype. The most acti ve compound of this series, namely 6a, exhibited potent in vitro cytotoxic activity against a panel of human cell lines. Furthermore, in contrast to b oth mitoxantrone and doxorubicin, it displayed little cross-resistance in c ell lines characterized by a MDR phenotype. Cell cycle analysis in the sens itive HT-29 and mitoxantrone-resist;ant MT-29/Mx (not identified resistance mechanism) cell lines has revealed that both mitoxantrone and 6a induce a G2/M block. However, while the proportion of apoptotic cells after mitoxant rone treatment is similar for both sensitive and resistant cell lines, it i s much lower for 6a. Compound 6a tested against P388 murine leukemia in viv o displayed a significant antitumor effect (%T/C 196 at an optimal dose of 10 mg/kg). The property of overcoming the cross-resistance was maintained a lso in in vivo efficacy studies, where no difference was observed in the an titumor activity of compound 6a against the A2780 human tumor xenograft and its MDR A2780/Dx subline. We conclude that benzoperimidines, if properly s ubstituted, constitute a novel class of compounds that can overcome multidr ug resistance.