Bisindole cladoniamides, nanomolar inhibitors of colon cancer cell line HCT-116, contain a rare, indolotryptoline substructure. In this report, the structures of xenocladoniamides A-E (9-13) are described. Compounds 9-13 are generated from a cladoniamide heterologous production system where O-methyltransferase gene claM3 has been inactivated. The results suggest that O-methylation, installed by enzyme ClaM3, is critical to maintaining the structural integrity of the indolotryptoline scaffold. Xenocladoniamides D and E are modestly cytotoxic against colon cancer cell line HCT-116.