Design, Synthesis And Bioactivity Evaluation Of Novel Derivatives Of Camptothecin And Pyrroloiminoquinone As Topoisomerase I Inhibitors

DNA topoisomerase I (Topo I) can manage the topological state of the DNA in the cell by passing one strand of the DNA through the break in the opposing strand and subsequently relegates the cleaved single strand DNA. Topo I plays an important role in the process of DNA replication, transcription and DNA repair and recombination. The relegation step is blocked by Topo I inhibitors, thereby enhancing the formation of persistent DNA breaks and causing cell death. As Topo I is highly expression in tumor cells, it is an ideal target for cancer molecular targeting therapy.Camptothecin derivatives as Topo I inhibitors have been widely used to treat tumors in clinic. Nowadays, four camptothecin derivatives have been applied in clinic. Unfortunately, Resistance to CPTs has been increasing year after year with the extensive use in clinic. In order to overcome the multi-drug resistance and further enhance the antitumor activities of camptothecins, we synthesized a series of a-ring modified hexacyclic camptothecin analogues. The new ring in our designation is a good way to lock the hydroxyl group in A ring which was reported to have positive correlation with exocytosis of BCRP and increase the interaction site between ligands and receptors. The results of biological activity test showed that the targeted compounds keep the antitumor activites equal to camptothecin.Pyrroloiminoquinones, which include Tsitsikammamines and wakayin, mainly derived from marine, are excellent inhibitors of Topo I, but there are few researches aim to improve their enzymatic activities because of their short history. Some researches shows that rigid plane structure was necessary for the Topo I inhibition as they can embed in the cavity formed by DNA breaking. Therefore, we try to eliminate the single bond between phenyl/indyl and pyrrole by oxidative coupling and finally get pentacyclic rigid plane structures. The results of biological activity test showed that the targeted compounds exhibited week Topo I inhibitions but strong Indoleamine 2,3-dioxygenase (IDO) inhibitions.