Design, Synthesis, and Evaluation of Psorospermin/Quinobenzoxazine Hybrids as Structurally Novel Antitumor Agents

摘要

Topoisomerase II, an enzyme that catalyzes changes in the topology of DNA, plays several key roles in DNA metabolism and chromosome structure, and it is the primary cytotoxic target for a number of clinically important DNA intercalating agents such as doxorubicin. It seems likely that if these intercalating topoisomerase II poisons are structurally modified to also be DNA alkylating agents, they will have increased dwell time on the topoisomerase II-DNA complex and increased potency and selectivity for cancer cells. On the basis of insights into the mechanisms of action of psorospermin and the qunobenzoxazine A-62176 and molecular modeling studies of these compounds with duplex DNA, we have designed and synthesized a series of novel hybrid DNA-interactive compounds that alkylate DNA most efficiently at sequences directed by topoisomerase II. The epoxydihydrofuran ring of psorospermin was used as a DNA alkylating moiety, and this was fused to the pyridobenzophenoxazine ring of A-62176. The chlorohydrin ring opened form of the epoxide was also prepared and tested. These hybrid compounds showed enhanced DNA alkylating activity in the presence of topoisomerase II, exhibited significant activity against all the cancer cells tested at submicromolar concentrations, and were more potent than both parent compounds. However, the biochemical assays indicated that they lost some of the topoisomerase II and Mg~(2+) dependency for reaction with DNA that is associated with psorospermin and A-62176, respectively.