Ellipticine 1 (5,11-dimethyl-6H-pyrido [4,3-b]carbazole) is a natural product which was isolated in 1959 from a small tropical evergreen tree (Ochrosia elliptica). Over the past 60 years, the planar tetracyclic structure of ellipticine has been the focus of extensive chemical and pharmacological research with a number of ellipticines having well documented anticancer activity, in particular with substitution at the 1-, 2-, 6- and 9-positions. However, due to limitations in synthesis and coherent screening methodology, the full profile of this anticancer class has not yet been achieved and some positions on the tetracycle have received little attention. In order to address this shortfall, we have set out to explore the anticancer activity of this potent natural product by substitution. Herein, we describe the synthesis of novel 11-substituted ellipticines with two specific derivatives showing potency and diverging cellular growth effects. Screening of anticancer activity via topoisomerase II inhibition and NCI 60 cell screening methodology identifies significant potency and potential molecular targets.