The paper in Nature Communications is here: https://go.nature.com/2J0bbEC

Plants of the genus Isodon have been used in popular folk medicines in China and Japan since ancient times, and some of these herbs are still in use today. Popular Isodon species include Isodon rubescens (also known as donglincao) and Isodon eriocalyx (under the name Yanshukang) for the treatment of sore throats and inflammation in China, and Isodon japonica and Isodon trichocarpa (under the name enmei-so) for the treatment of gastrointestinal disorders in Japan. ent-Kaurane diterpenoids are the major chemical components of Isodon species, and more than 1000 structurally diverse diterpenoids have been isolated. Isodon diterpenoids have been shown to exhibit a wide range of biological activities, including anti-bacterial, anti-cancer and immunosuppressive activities, while presenting little to no toxicity. Because of this, Isodon diterpenoids have been seen as a promising source of anti-cancer therapeutics. However, many of the Isodon diterpenoids are present in only minute quantities in plants, and show similar levels of anti-cancer activity in cell line studies, making the search for potential compounds a challenging task.

A solution to the above problem could exist in pairing chemical synthesis with multi-level bio-evaluation. A scalable synthesis method would allow us to produce large quantities of compounds, without relying on their extraction from plants. The increased quantities from synthesis would enable us to conduct both cell line and animal studies, to more comprehensively assess the anti-cancer activity of the compounds. In our paper we employed the above strategy to identify, for the first time, a low-abundance Isodon diterpenoid, neolaxiflorin L, as a promising drug candidate with strong anti-cancer effects in animals. This finding is significant, as the compound may otherwise have been neglected due to its low abundance in plants (3 mg per 10 kg dried leaves of I. eriocalyx var. laxiflora, 0.00003% isolation yield) and moderate activity in cell lines.

In summary, we have demonstrated the viability and value of a strategy of chemical synthesis to enable multi-level bio-evaluation, which could be adopted as a general method for the identification of potential compounds from low-abundance natural products.