Antitumor properties of podophyllotoxin and related compounds

The lignan family of natural products includes compounds with important ant ineoplastic and antiviral properties such as podophyllotoxin and two of the ir semisynthetic derivatives, etoposide and teniposide. The latter are incl uded in a wide variety of cancer chemotherapy protocols. Due to these biolo gical activities, lignans, and especially cyclolignans, have been the objec tive of numerous studies focused to prepare better and safer anticancer dru gs. The mechanism by which podophyllotoxin blocks cell division is related to i ts inhibition of microtubule assembly in the mitotic apparatus. However, et oposide and teniposide were shown not to be inhibitors of microtubule assem bly which suggested that their antitumor properties were due to another mec hanism of action, via their interaction with DNA and inhibition of DNA topo isomerase II. Other podophyllotoxin derivatives has also been reported whic h retained or even improved the cytotoxic activity, but these were weak inh ibitors of topoisomerase II in vitro; the data revealed that such analogs e xhibit a different, as yet unknown, mechanism of action. The main deficiency of these compounds is their cytotoxicity for normal cel ls and hence side effects derived from their lack of selectivity against tu moral cells. In this regard it is necessary to investigate and prepare new more potent and less toxic analogs, that is, with better therapeutic indice s. It is well accepted from structure-activity studies in this field that t he trans-lactones are more potent as antineoplastics than the cis-lactones. Not only the configuration of the D ring is an important factor for high c ytotoxic activity, but also a quasi-axial arrangement of the E ring is nece ssary. On this basis, studies on lignans have been addressed to modify the lactone moiety and prepare analogs with heteroatoms at different positions of the cyclolignan skeleton. Our group has been working during the last few years on chemical transforma tions of podophyllotoxin and analogs and we have prepared a large number of cyclolignan derivatives some of which display potent antiviral, immunosupp ressive and cytotoxic activities. We have reported several new cytotoxic ag ents with nitrogen atoms at C-7 or C-9 or at both C-7 and C-9: imine deriva tives, oxime derivatives, pyrazoline-, pyrazo- and isoxazoline-fused cyclol ignans. At present, we are preparing mainly new compounds by modifications of the A and E cyclolignan-rings. They are being tested on cultures of diff erent tumoral cell lines (P-388 murine leukemia, A-549 human lung carcinoma , HT-29 human colon carcinoma and MEL-28 human melanoma) and some of them h ave shown an interesting and selective cytotoxicity.