Epipodophyllotoxin synthesis

Augmented drug extrusion increased synthesis of the P-glycoprotein that extrudes drugs from the cell (e.g., anthracyclines, vinca alkaloids, epipodophyllotoxins, and paclitaxel) is re-ponsible for multi-drug resistance (mdr-1 gene amplification). 

Fig. 4 Synthesis of epipodophyllotoxin through a Diels-Alder reaction (taken from [39] by permission from Kluwer)...

Shi Q, Wang HK, Bastow KF, Tachibana Y, Chen K, Lee FY, Lee KH. Anhtumor agents 210. Synthesis and evaluation of taxoid-epipodophyllotoxin conjugates as novel cytotoxic agents. Bioorg. Med. Chem. 2001 9 2999-3004. 

Bastow KF, Wang HK, Cheng YC, Lee KH. Antitumor agents 59. 173. Synthesis and evaluation of camptothecin-4P-amino-4 -0-demethyl epipodophyllotoxin conjugates as inhibitors of mammalian DNA topoisomerases and as cytotoxic agents. Bioorg. 60. Med. Chem. 1997 5 1481-1488. 

Podophyllotoxin (5./7), from Podophyllum peltatum, the tropical squirting cucumber , strongly inhibits the polymerization of tubulin and is used in dermatology to destroy warts and other skin neoplasms. Deoxy-podophyllo-toxin, from the berries of the juniper tree, has anti-viral activity. Etoposide, a semi-synthetic derivative of podophyllotoxin, is used clinically for the treatment of otherwise fatal tumours. Chemically it is demethyl-1-0-(4,6-0-ethylidene-)8-D-glucopyranosyl)epipodophyllotoxin. It does not seem to prevent the synthesis of microtubules, but a decrease in DNA synthesis is noted (Loike, 1984). 

Engelhardt U, Sarkar A, Linker T. Efficient enantioselective total synthesis of ( ) epipodophyllotoxin. Angew. Chem. Int. Ed. Engl. 2003 42(22) 2487-2489. 

---