Small cells for big ideas: The cytotoxic podophyllotoxin and the long journey in discovering its biosynthetic pathway

Abstract

For more than 70 years the plant-derived cytotoxic podophyllotoxin is still a focal point for many research groups. The relationship between the structure of podophyllotoxin and podophyllotoxin derivatives, and their biological activity, allowed the design of novel drugs to combat malignancies. The quests for safer drugs and biomass production through aseptic cultivation have been gaining momentum in the last decade or two, supported by the advances in the computer technologies, information sharing and bioinformatics/molecular biology. The recently discovered enzymatic conversions that lead directly to etoposide aglycone not only filled the gaps in the lignan biosynthetic pathway, but also offered an exciting direction for future research. This book chapter opens with a short summary of the structure of podophyllotoxin and podophyllotoxin-based drugs, and their biological targets. Compelling discoveries and unexpected turns of the lignan biosynthetic pathway are discussed next, followed by benchmark studies in the aseptic cultivation of the plants producing it.