Aryltetralin lignans: Chemistry, pharmacology and biotransformations

Podophyllotoxin derivatives like etoposide 7a, etophos 7b, and teniposide 7 c are used clinically as potent chemotherapeutic agents for a variety of tu mors including small cell lung carcinoma, testicular cancer, and malignant lymphoma. These compounds derived from a series of modifications which converted podo phyllotoxin la from an entity that interacted with tubulin and blocks mitos is to one that induced a block in late S or early G2 by interacting with to poisomerase II. Synthetic studies on podophyllotoxin derivatives can be divided in four gen eral approaches (the oxo-ester route, the dihydroxy acid route, the tandem conjugate addition route and the Diels-Alder route). Albeit a number of syn thetic sequences afforded products with excellent enantiopurities, the low overall yields still disqualify synthesis as an alternative for naturally p roduced materials. An alternative route based on the enzyme-catalyzed cyclization of synthetic intermediates to analogues of the podophyllotoxin family is being explored . Synthetic dibenzylbutanolides, which were revealed by biosynthetic studies to be the precursors of aryltetralin lignans, have been treated with enzyme s derived from cell cultures of Podophyllum peltatum, Catharanthus roseus, Nicotiana sylvestris and Cassia didymobotrya. The ciclyzation process afforded however compounds with a different stereoc hemistry in the C ring. The obtainment of a novel compound with a benzylidenebenzylbutirolactone st ructure still leaves considerable scope for exploring biotransformations in order to obtain podophyllotoxin analogues via a combination of synthetic c hemistry and biotechnological methods.