Pergamon Bioorganic & Medicinal Chemistry Letters, Vol. 5, No. 21, pp. 2465-2468, 1995 Copyright © 1995 ElsevierScienceLtd Printed in Great Britain. All rights reserved 0960-894X/95 $9.50+0.00 0960-894X(95)00432-7 SELECTIVE CYTOTOXIC CYCLOLIGNANS Marina Gordaliza 1., Jos6 M ~- Miguel del Corral 1, M ~- Angeles Castro 1, M ~- Luisa L6pez-V~izquez 1, Pablo A. Garcfa 1, Arturo San Feliciano 1, M -~ Dolores Garcfa-Gr~ivalos2 1Laboratorio de Qufmica Farmac~utica. Facultad de Farmacia. Universidad de Salamanca. E-37007-Salamanca. Spain. 2pharmaMar SA., Calera 3. Tres Cantos. E-28760-Madrid. Spain Abstract: Several derivatives of podophyllotoxin, lacking the lactone moiety and with nitrogen substituents at C-7 or C-9, have been prepared. They have been evaluated for their cytotoxic activity in P-388, A-549, HT-29 and MEL-28 culture cells. Some of them show a highly selective cytotoxicity towards HT-29 human colon carcinoma. Etoposide and teniposide are two semisynthetic derivatives of podophyllotoxin which have played an important role in a wide variety of cancer chemotherapy protocols. Their use represents a therapeutic advance in the treatment of cancers, such as small-cell lung cancer, testicular cancer, lymphoma, acute lymphocytic leukaemia, etc. 1 However, the main deficiency of these compounds is their cytotoxicity for normal cells and the side effects derived from their lack of selectivity against tumoural cells. In this regard, it is necessary to investigate and prepare new analogues more potent and less toxic, that is, with better therapeutic indexes. Several structure-activity studies on this field suggested that the presence of the lactone moiety is an important fact for displaying high cytotoxic activity, as well as the configuration at C-8'; it is well accepted that the trans-lactones are more potent as antineoplastic than the cis-lactones. 2 Many effort have been addressed to modify the lactone moiety and to prepare heteroanalogues at different positions of the cyclolignan skeleton. 3-5 Over the last five years, our group has been carrying out studies on chemical transformations of podophyllotoxin and analogues and have prepared a large number of cyclolignan derivatives, some of which displaying potent anti-viral and cytotoxic activities.6, 7 More recently, we have reported a new class of cytotoxic agents, called pyrazololignans, which have nitrogen atoms at both C-7 and C-9. They are less potent than podophyllotoxin itself but with IC50 values at t.tM levels despite the lack of the lactone moiety in their structure. 8 In this sense and with the aim of getting more information about tile influence of the heteroatoms in the structure-activity relationship, now we report other new cyclolignans also without the lactone ring and with only one nitrogen substituent at position C-7 or C-9 of the cyclolignan skeleton. They have been tested on cultures of different tumoural cell lines and have shown ,an interesting and selective cytotoxicity against HT-29 human colon carcinoma as it is discussed later in this paper. 2465