Podophyllotoxins: current status and recent developments.

Abstract

Podophyllotoxin is a natural product isolated from Podophyllum peltatum and Podophyllum emodi and has long been known to possess medicinal properties. Etoposide (VP-16), a podophyllotoxin derivative, is currently in clinical use in the treatment of many cancers, particularly small cell lung carcinoma and testicular cancer. This compound arrests cell growth by inhibiting DNA topo-isomerase II, which causes double strand breaks in DNA. VP-16 does not inhibit tubulin polymerization, however, its parent compound, podophyllotoxin, which has no inhibitory activity against DNA topoisomerase II, is a potent inhibitor of microtubule assembly. In addition to these two mechanisms of action, an unknown third mechanism of action has also been proposed for some of the recent modifications of podophyllotoxins. Owing to its severe toxic side effects a number of modifications have been done on podophyllotoxin structure. Some of the congeners exhibited potent antitumor actiivity, of which etoposide and teniposide are in clinical use, NK 611 is in phase II clinical trials and many compounds are in the same line. Recent developments on podophyllotoxins have led structure-activity correlations which have assisted in the design and synthesis of new podophyllotoxin derivatives of potential antitumor activity. Modification of the A-ring gave compounds having significant activity but less than that of etoposide, whereas modification of the B-ring resulted in the loss of activity. One of the modifications in the D-ring produced GP-11 which is almost equipotent with etoposide. E-ring oxygenation did not affect the DNA cleavage which led to the postulation of the third mechanism of action. It has also been observed that free rotation of E-ring is necessary for the antitumor activity. The C4-substituted aglycones have a significant place in these recent developments. Epipodophyllotoxin conjugates with DNA cleaving agents such as distamycin increased the number of sites of cleavage. The substitution of a glycosidic moiety with arylamines produced enhanced activity. Modification in the sugar ring resulted in the development of the agent, NK 611 which is in clinical trial at present. This article review, the progress of podophyllotoxins from its early applications in folk medicine to the most recent modifications and the mechanism(s) of action, pharmacology and the structure-activity relationships.