From plant to cancer drug: lessons learned from the discovery of taxol

Abstract

Many researchers in the natural product sciences dream of discovering a successful drug. For almost all of us, this dream will never be realized. Among the heroes of our past, though, there is a team whose efforts led to the discovery of not one but two new drugs. Dr Monroe Wall and Dr Mansukh Wani isolated and solved the structures for taxol and camptothecin, plant-based compounds that continue to play a critical role in cancer therapy today. Since the 1960s and 1970s when Wall, Wani and collaborators did their seminal work, there have been tremendous technological advances in the natural product sciences. With access to most sophisticated technology, it might be expected that the rate of discovery of new drugs from plants and other sources would have sped up. However, this has not come to pass. Why is this? Is it that the promise of new drug candidates from plant-based sources has been exhausted? Has our fascination with new technologies and with the promise of the genomics revolution caused us to stop investing effort and resources in the practices that are proven to yield success? With this Viewpoint, we share the story of taxol's discovery, highlighting critical challenges that were overcome and considering their relevance to botanical natural products drug discovery today. We hope that consideration of lessons learned from the past will help fuel success by researchers currently studying plants with the goal of discovering promising therapeutic leads.

Fig. 1. The structure of taxol originally postulated by Dr Wani and colleagues is shown above (1). Dr Wani's final goal before publication was to oxidize the OH at the 13-position, resulting in an α,β-unsaturated ketone, which he believed could be more potent than isolated taxol due to the potential for a Michael addition. The fact that he could not generate such an analogue led him to reexamine his data and modify the structure (2) which is how it was published in 1971 and verified decades later by total synthesis.

Nadja Cech (right) Nicholas Oberlies (left)