Epi-Podophyllotoxin

Di-0-dichloroacetyl-l-0-benzyloxycarbonyl-(4,6-0-ethylidene)-p-D-glucopyranose Palladium on carbon 4 -Demethyl-epi-podophyllotoxin Zinc acetate dihydrate Boron trifluoride etherate Trimethylsilyl trifluoromethane sulfonate Celite/basic alumina column... 

Demethyl-epi-podophyllotoxin (1 mmol) and 2,3-di-0-dichloroacetyl-(4,6-0-ethyiidene)-p-D-giucopyranose (2 mmol) were introduced into dry dichloromethane under anhydrous condition. When the temperature was stabilized to -20°C to -30°C, boron trifluoride etherate (1.5 mmol) was added slowly with stirring. Reaction was continued at this temperature and monitored by thin layer chromatography. After the completion of the reaction as evidenced by TLC, the solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude intermediate product 4 -demethyl-epi-podophyllotoxin-4-(2,3-di-0-dichloroacetyl-4,6-0-ethylidene)-p-D-glucopyranose. This crude product was then converted to etoposide by following the procedure as above described. The yield of final product etoposide was about 60%. 

Induction of strand breakage may result from inhibition of topoisomerase. The epi-podophyllotoxins etoposide and tenoposide interact with topoisomerase II, which functions to split, transpose, and reseal DNA strands (p.276) these agents cause strand breakage by inhibiting resealing. The te-cans topotecan and irinotecan are derivatives of camptothecin from the fruits of a Chinese tree (Camptotheca acuminata). They inhibit topoisomerase I, which induces breaks in single-strand DNA. 

Sinkule, J.A. Evans, W.E. High-performance liquid chromatographic analysis of the semisynthetic epi-podophyllotoxins teniposide and etoposide using electrochemical detection. J.Pharm.Sci., 1984, 73, 164-168... 

Although not listed in the tables, at least four other natural product drugs have given yeoman service in the antitumor area. The first of these is paclitaxel (Taxol ) which sold US 1.6 billion in 2000 this is followed by the vinca alkaloids vinblastine and vincristine. Completing the quartet are the natural product-derived epi-podophyllotoxin derivatives teniposide and etoposide and the materials derived from camptothecin, topotecan and CPT-11. These will probably not be the only natural product drugs in the antitumor field, as can be seen by inspection of Table 6.3, where Cragg and Newman recently reported on the source... 

Numerous analogs of epi-podophyllotoxin, bearing amine and ether substituents at C4 have been reported. Several of these semi-synthetic drugs derived from podophyllotoxin, including etoposide and teniposide, are used clinically in cancer therapy. 

Although many C4 substituted epi-podophyllotoxins have been reported, there are few reports of dimers. The syntheses of several ether-linked dimers are reported here. These covalently linked analogs of epi-podophyllotoxin should provide further insight into the two-drug model and potentially provide novel antitumor agents. 

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