Integrated approach elucidates the long-sought structure of a natural powerful anticancer product

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A collaborative effort by the research groups of Professor Haruhiko Fuwa from Chuo University and Professor Masashi Tsuda from Kochi University has culminated in the structure elucidation and total synthesis of anticancer marine natural products, iriomoteolide-1a and -1b. These natural products were originally isolated from the marine dinoflagellate collected off the Iriomote Island, Okinawa, Japan.

This study is published in the Journal of the American Chemical Society.

Because of its potent anticancer activity, iriomoteolide-1a is an intriguing natural product that attracts immense attention from the chemical community around the globe. However, it was quite challenging to determine its stereostructure by means of NMR spectroscopy, which is the gold standard method for structure determination of natural products.

Several chemical synthesis groups from U.S. and China made intensive efforts to elucidate the stereostructure of this natural product without much success. Consequently, iriomoteolide-1a is known as "(one of) current challenging molecules for configurational assignment," and its stereostructure has remained elusive for more than a decade.

In this study, researchers devised an integrated approach based on NMR spectroscopic analysis, theoretical calculation, and total synthesis. Careful inspection of the authentic NMR data, with the aid of molecular mechanics-based conformational searches, was helpful for narrowing the number of candidate stereoisomers from 4,096 to just four.

NMR chemical shift calculation suggested a single stereoisomer as the most likely structure, and its validation by total synthesis enabled successful elucidation of the stereostructure of iriomoteolide-1a for the first time.

The stereostructure of iriomoteolide-1b was also determined in a similar manner. Moreover, researchers confirmed the nanomolar cytotoxic activity of synthetic iriomoteolide-1a in human cancer cells. This study paves the way for further investigations into the biological mode-of-action and structure–activity relationship of this intriguing natural product.

More broadly, this study demonstrates the power of integrating NMR spectroscopic analysis, theoretical calculation, and total synthesis in the structure elucidation of complex natural products and will facilitate future natural product drug discovery and chemical biology.

More information: Tomohiro Obana et al, Iriomoteolide-1a and -1b: Structure Elucidation by Integrating NMR Spectroscopic Analysis, Theoretical Calculation, and Total Synthesis, Journal of the American Chemical Society (2024). DOI: 10.1021/jacs.4c11714

Journal information: Journal of the American Chemical Society

Provided by Chuo University