Two semi-synthetic indolocarbazole derivatives, ED-11O and NB- 506, have been described as potent inhibitors of topoisomerase I, an enzyme critical for cell viability and an important target for anticancer drug design. These analogues showed impressive in vitro and in vivo antitumor activities. Few topoisomerase 1 inhibitors of this class are known, and most are semi-synthetic derivatives of microbial natural products, severely limiting the structural diversity examined for biological activity. We will prepare, via total synthesis, a series of indolocarbazoles core structures, as well as structural analogues. The compounds will be evaluated for inhibition of human topoisomerase I, and this activity will be correlated with in vitro cytotoxicity against a panel of human tumor cell lines. The long range goal of this project is to identify a candidate for development as a clinically useful antitumor agent.
| Zembower, D E; Zhang, H; Lineswala, J P et al. (1999) Indolocarbazole poisons of human topoisomerase I: regioisomeric analogues of ED-110. Bioorg Med Chem Lett 9:145-50 |
