Creation of novel antitumor agents having DNA topoisomerase inhibition activity

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Pyrroloiminoquinone marine alkaloids exhibit antitumor activity through DNA topoisomerase inhibition.Consequently, these alkaloids have attracted considerable attention as new leads of antitumor agent. Although several methods to construct pyrroloiminoquinone skeleton have been developed so far, no method to introduce substituents on the desirable position has been establislted.Previously, we have developed a novel strategy to build up the pyrroloiminoquinone core, and achieved the total synthesis of makaluvamined A, D, I and K.Following this study, we have now establised an efficient method to bind a variety of substituents at the C-6 position of the pyrroloiminoquinone core via regioselective lithiation of 5-Boc-TIPS-7-methoxy-1,3,4,5-tetrahydropyrrolo [4,3,2-de] quinoline, which was readily prepared from a key intermediatein the makaluvamine synthesis. This method was successfully applied to the first total synthesis of veiutamine, a new type of pyrroloiminoquinone marine alkaloid having p-hydroxybenzyl group at C-6.In addition, we have developed C-6 and C-2 selective lithiation of 5-Boc-7-methoxy-1-methyl-1,3,4,5- tetrahydropyrrolo [4,3,2-de] quinoline and synthesized a number of its derivatives. In conclusion, we believe these methods developed in this study enable to produce a variety of pyrroloiminoquinone marine alkaloids and their analogues. The subsequent structure-activity relationship studies of these compounds would allow to create a new type of anticancer agent.