f) Pergamon PII: S0040-4020(97) 10042-4 Tetrahedron, Vol. 53. No. 46, pp. 15743-15760, 1997 © 1997 ElsevierScienceLtd All rights reserved.Printedin Great Britain 0040-4020/97 $17.00 + 0.00 Preparation and Cytotoxicity of Podophyllotoxin Derivatives Lacking the Lactone Ring Marina Gordaliza 1., M a Angeles Casll'O 1, Jos~ M ~ Miguel del CoiTal 1, M ~ Luisa L6pez-V/tzquez 1, Pablo A. Garcfa 1, Arturo San Feliciano 1, M a Dolores Garcfa-Gnivalos2, Howard Broughton 3 lLaboratorio de QufmicaFarmac6utica. Facultad de Farmacia. Universidadde Salamanca. E-37007-Salamanca. Spain. 2pharmaMar S.A., Calera 3. Tres Cantos. E-28760-Madrid. Spain 3Computational Chemistry. Merck Sharp & Dohme Research Laboratories. Hariow, Essex CM20 2QT, England. Abstract. Several eyclolignans lacking of the lactone moiety can easily be prepared from naturally occurring lignans such as podophyllotoxinand deoxypodophyllotoxinby simple chemical transformations. Their cytotoxicity has been studied in four tumoral cell lines. Most of the compounds show similar effects in all the neoplastic systems tested, except the aldehyde 9 (methyl 9-deoxy-9-oxo-ct-apopicropodophyllate) and the hydrazones 16 and 17 which show a highly selective cytotoxicity towards HT-29 human colon carcinoma. Additionally, several molecular modeling studies have been done with aldehyde 9 and the corresponding saturated aldehyde 13 in comparison with podophyllotoxin. © 1997 Elsevier Science Ltd. INTRODUCTION The lignan family of natural products includes compounds with important antineoplastic and antiviral properties such as podophyllotoxin and two of its semisynthetic derivatives, etoposide and teniposide I. The latter are included in a wide variety of cancer chemotherapy protocols. 2 Due to these biological activities, lignans, and especially cyclolignans, have been the object of numerous studies which are compiled in several reviews. 3 The sources for new compounds could be plants, semisynthetic derivatization of natural products or total synthesis. All these studies are focused to prepare better and safer anticancer drugs. The mechanism by which podophyllotoxin blocks cell division is related to its inhibition of rnierotubule assembly 4 in the mitotic apparatus; it is a competitive inhibitor of colchicine binding to tubulin. However, etoposide and teniposide were shown not to be inhibitors of microtubule assembly 5 which suggested that their antitumor properties were due to another mechanism of action, via their interaction with DNA. DNA topoisomerase II has been reported to be involved in the process of inducing DNA breakage and etoposide and 15743