In this study the syntheses of 11 novel lignans are described. Their cytotoxicities are studied in GLC4, a human small cell lung carcinoma cell line, using the microculture tetrazolium (MTT) assay. Ten of these compounds were substituted with a menthyloxy group on the 5-position of the lactone. These compounds can easily be prepared in (novel) 'one-pot', three- or four-step syntheses. In addition, methods for controlling the stereogenic centers are described. Furthermore, five naturally occurring podophyllotoxin-related compounds were tested. The cytotoxicities of all lignan compounds, and of three non-lignan intermediates originating from the syntheses, were compared with the clinically applied anticancer agents etoposide, teniposide, and cisplatin. Most compounds showed moderate to high activities against GLC4, and two of the compounds containing a menthyloxy group showed activities comparable to the reference cytotoxic agents.