Chemoinduction of cytotoxic selectivity in Podophyllotoxin-related lignans

Abstract

Lignans are widely distributed in the plant kingdom, and display a variety of biological activities which have attracted the attention of the scientific community for decades. Several representative compounds of the cyclolignan class, such as podophyllotoxin and its semisynthetic derivative, etoposide, are currently used for the clinical treatment of warts and malign neoplasms. Other cyclolignans are involved in antineoplastic and antiarthritic clinical trials. Numerous podophyllotoxin-related compounds have been prepared through modification of nearly all the positions on the cyclolignan skeleton in the search of new, more selective and less toxic anticancer drugs. Our group has been interested in the chemoinduction of drug selectivity for several years, and we have designed and prepared new podophyllotoxin derivatives by modification mainly on the C and D-rings of the podophyllotoxin skeleton. Those derivatives, bearing an electrophilic functionality at C-9, have shown, both in vitro and in vivo, a high degree of selectivity against colon carcinoma, and less cytotoxicity for other neoplastic systems and normal kidney fibroblasts. The main structural modifications found in the literature for the podophyllotoxin skeleton in the past decade, including those from our research group, are presented in this article.