application): The goal of this Phase II project is the synthesis and evaluation of indolocarbazole analogues as poisons of human topoisomerase I (Topo I), an enzyme which represents an attractive target for development of antitumor agents. The Phase I study involved synthesis of all four """"""""symmetrical"""""""" regioisomers of ED-110, a semi-synthetic Topo I poison. That study identified a regioisomer, which was approximately l0-fold more potent against Topo I, when directly compared to ED-11O. Additionally, the compound showed enhanced in vitro antitumor activity against HT29 colon, OVCAR-3 ovarian, and DU-145 prostate cancer cell lines relative to ED-110. During the course of this Phase II project, the synthetic methodology used to synthesize our lead compound will be optimized. Several series of analogues will be synthesized in an effort to identify compounds having enhanced antitumor activity relative to the lead compound. A solid phase synthetic method will be developed to allow rapid generation of a library of indolocarbazole analogues. All new synthetic compounds will be evaluated for inhibition of human Topo I activity. Analogues active against Topo I will be screened for in vitro antitumor activity, as well as assessed for activity against other target enzymes, including topoisomerase II, protein kinase C, and protein kinase A. Finally, promising analogues will be selected for evaluation of acute toxicity, pharmacokinetics, and in vivo antitumor activity.
There are currently only two clinical anticancer agents that operate via poisoning of topoisomerase I, Camptosar and Hycamtin. Both of these agents are based upon the same parent compound camptothecin. An indolocarbazole analogue that possessed anticancer activity with the appropriate toxicity profile would have enormous market potential. Such as agent could be used alone or in combination with existing antitumor agents, especially in patients who develop resistance to existing medications.
| Zembower, David E; Xie, Yongping; Koohang, Ali et al. (2012) Methylenedioxy- and ethylenedioxy-fused indolocarbazoles: potent human topoisomerase I inhibitors and antitumor agents. Anticancer Agents Med Chem 12:1117-31 |
| Iyer, Mani S; Palomo, Martin; Schilling, Kevin M et al. (2002) Efficient reversed-phase purification of a hydrophobic reaction product following Mitsunobu-mediated glycosylation. J Chromatogr A 944:263-7 |
