Analogues of rutaecarpine, a quinazolinocarboline alkaloid, were synthesized by structurally modifying the A-ring to yield 10-methoxy (llb), 11-methoxy (llc), and 10,11 methylenedioxy (lid) derivatives. Analogues llc,d displayed activity superior to rutaecarpine when evaluated against several tumor cell lines in vitro. Rutaecarpine lla, which has been isolated from the fruits of Evodia rutaecarpa, and its naturally occurring derivatives belonging to the class quinazolinocarboline alkaloids are known to possess cardiotonic and analgesic properties and have been used for the treatment of gastrointestinal disorders and migraine. No published data are available concerning the cytotoxicity screening of the rutaecarpine analogues. In a continuing program to develop natural products with antitumor activity, our laboratory has been engaged in the design and synthesis of rutaecarpine analogues. The original investigations were focused on how substituent changes in the A-ring of the molecule would affect antitumor activity. Assay results from the NCI's in vitro primary cytotoxicity screen were used to facilitate the discovery and design of new, selective, cytotoxic leads with improved antitumor activities compared to rutaecarpine for further antitumor mechanistic investigations. In this paper, we will present the synthesis and cytotoxic evaluation of rutaecarpine (lla) and a series of analogues (lib-d) with alkoxy groups at the C-10 and C-11 positions.