SYNTHESIS OF A SERIES OF CYTOTOXIC 2-ACYL-1,2-DIHYDROELLIPTICINES WHICH INHIBIT TOPOISOMERASE-II

An array of novel 2-acyl-1,2-dihydroellipticines was prepared and eval uated for in vitro cytotoxicity in a variety of human cancer cell line s. The ellipticine analogs were also tested for inhibition of topoisom erase II in both decatenation and cleavable complex formation assays. Some of the new ellipticine derivatives were prepared by acylation of ellipticine with acid chlorides in tetrahydrofuran, followed by reduct ion of the intermediate 2-acylellipticinium ions with sodium cyanoboro hydride. Others were synthesized by acylation of ellipticine with p-ni trophenyl chloroformate, reduction of the 2-acylellipticinium ion with sodium cyanoborohydride, and displacement of the p-nitrophenoxide ani on with a variety of oxygen and nitrogen nucleophiles. The cytotoxicit ies of the new 2-acyl-1,2-dihydroellipticines varied widely, and corre lated well with their topoisomerase II inhibitory activities.