Abstract
A series of novel podophyllotoxin (PDT) analogues was synthesized in which the lactone moiety was shifted to C ring. Some of the derivatives were also synthesized with modified A ring. Analogues 23 and 25 exhibited potent in vitro cytotoxicity against colon cancer (CaCO2) cell line. p-Demethylated E-ring analogues exhibited better potency than the corresponding methylated analogues. These analogues showed toxicity comparable to PDT against human erythrocytes albeit at much higher concentrations (100 μg/ml) than their cytotoxicity values. Podophyllotoxin (1, PDT, Fig. 1) is a well known naturally occurring potent cytotoxic aryltetralin lignan isolated from the genus Podophyllum (family: Berberidaceae).1) Two of its known analogues etoposide (2) and teniposide (3) show DNA topoisomerase II inhibition activity2) and are among the frontline antitumour drugs against various cancers, including small cell lung cancer, testicular carcinoma, and Kaposi's sarcoma.3) A different mode of action of 2 and 3 by minor structural modifications of 1 has been attributed to p-demethylation in E-ring, inversion of stereochemistry at C-4 position, and addition of a sugar unit.4)