Scientists achieve the first total synthesis of a complex alkaloids isolated from plant

Plants are undeniably one of nature’s most promising sources of new medicines, with monoterpenoid indole alkaloids (MIAs) being a great example. Some of intricate compounds are built from multiple-linked chemical units that form highly complex three-dimensional structures. Because of their size and shape, scientists believe such an oligomeric MIAs may be able to interfere with specific protein–protein interactions inside cells—a biological target that conventional small-molecule drugs often struggle to reach. Thus, this unusual capability could make MIAs uniquely suited to combat various diseases. Such is the case for bisleuconothine A, an MIA isolated from plant bark in 2010 that has shown strong activity against breast cancer and lung cancer.

Despite their therapeutic potential, these compounds are extremely difficult to produce synthetically in the laboratory. Their structures contain multiple interconnected rings and several precisely arranged stereocenters, meaning their atoms must be assembled in the correct three-dimensional orientation to preserve their biological activity. Because of this, drug development research involving oligomeric MIAs remains limited. 

To address this issue, a research team led by Professor Hayato Ishikawa from the Graduate School of Pharmaceutical Sciences at Chiba University, Japan, set out to develop a new methodology to efficiently synthesize bisleuconothine A and bousigonine B, two complex and biologically relevant oligomeric MIAs. Their study, published online in the journal Angewandte Chemie International Edition on May 23, 2026, was co-authored by Mr. Satoshi Matsumiya, Ms. Yukine Mizukami, and Dr. Mariko Kitajima, all from Chiba University.

The researchers developed a new organocatalytic reaction, which is driven by small organic molecules rather than metal catalysts, to build a 3-ethylpiperidine scaffold. This is a structural motif that appears in many indole alkaloids and is essential in the synthesis of MIAs. The proposed method relied on a cascade reaction, in which several chemical transformations occur sequentially in a single process. Using only a small amount of catalyst, the team succeeded in producing a highly pure intermediate that could then serve as a common building block for alkaloid structures.

From this shared intermediate, the researchers constructed two different alkaloid fragments and later joined them through a coupling reaction designed to imitate the way plants may naturally assemble these compounds. This bioinspired process enabled the team to produce bisleuconothine A in 20 steps and bousigonine B through an additional final step, marking the first successful total synthesis of the latter.

The researchers believe the new synthetic strategy developed in this study could help accelerate research into complex indole alkaloids and related natural products, paving the way for new therapeutics. “The present method for total chemical synthesis is expected to facilitate the development of new pharmaceutical agents. In particular, bisleuconothine A has exhibited potent anticancer activity, highlighting its potential as a lead compound for anticancer drug development,” says Prof. Ishikawa.

Beyond the two molecules synthesized in this work, the team notes that their method may provide a broader framework for producing other structurally complex natural products. Because it uses a common intermediate that can be transformed into various alkaloid families, the approach could support the efficient synthesis of related compounds in the future. “Current efforts are directed toward the collective total synthesis of additional MIAs based on this newly established methodology, as well as subsequent biological evaluation for drug-discovery applications,” concludes Prof. Ishikawa.

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About Professor Hayato Ishikawa from Chiba University, Japan

Dr. Hayato Ishikawa obtained his Master’s and PhD degrees in Pharmaceutical Sciences from Chiba University in 2001 and 2004, respectively. He currently serves as a Full Professor at the Graduate School of Pharmaceutical Sciences at Chiba University. He specializes in natural product chemistry, organic synthetic chemistry, medicinal chemistry, and pharmaceutical sciences. He has published over 140 papers on these topics. He is also a member of several academic societies, the Pharmaceutical Society of Japan, the Society of Synthetic Organic Chemistry, and the Chemical Society of Japan.

Funding:

The authors gratefully acknowledge financial support through the JSPS KAKENHI Grant Nos. JP24K02141 (Scientific Research (B) for Hayato Ishikawa) and JP24K09873 (Scientific Research (C) for Mariko Kitajima), Grant-in-Aid for transformative research areas (A) “Latent Chemical Space” [JP24H01749] for Hayato Ishikawa from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and a JST SPRING, Grant Number JPMJSP2109, to Satoshi Matsumiya.

Reference:

Authors: Satoshi Matsumiya¹, Yukine Mizukami¹, Akihiro Morita¹, Kazuma Hirata¹, Shinya Shiomi¹, Shota Tominaga¹, Noriyuki Kogure¹, Hiromitsu Takayama¹, Mariko Kitajima¹, and Hayato Ishikawa¹
Affiliations: (1) Graduate School of Pharmaceutical Sciences, Chiba University, Japan
DOI: https://doi.org/10.1002/anie.6698305
 

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