Updated biotechnological approaches developed for 2,7'-cyclolignan production1

2,7'-Cyclolignans constitute a group of compounds regularly employed in clinical contexts due to their antiviral and anticancer properties as expressed in a number of already available designed drugs. Possibilities for other therapeutic developments are indicated. All commercial preparations actually originate from a single compound, podophyllotoxin, currently extracted from a few limited-in-abundance species of Podophyllum. This supply problem has stimulated considerable interest in the development of alternative strategies offering greater sustainable availability of the compound at affordable costs. Approaches such as plant breeding and micropropagation of the high-producing Podophyllum species have been explored with the aim of establishing production of these compounds. Since 20 years of exploration of the total chemical synthesis of podophyllotoxin has not proved economically viable, extensive research has now been undertaken to find methods for stimulating the accumulation of 2,7'-cyclolignans using tissue cultures. Both undifferentiated and differentiated cell cultures, mainly from Linum, Podophyllum, Juniperus, Callitris, Anthriscus and Forsynthia genera, have been reported. Although considerable progress has been made concerning the concentration and productivity of certain strains of Linum album, no economically viable production system has been established. Exploration and development of biosynthetical pathways leading to 2,7'-cyclolignans may open paths for future metabolic engineering, such as the bioconversion of deoxypodophyllotoxin to epipodophyllotoxin employing a human hepatic enzyme heterologously expressed in Escherichia coli.