Long-sought structure of powerful anticancer natural product

…solved by integrated approach.

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.

Because of its potent anticancer activity, iriomoteolide-1a is an intriguing natural product that attract 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 USA 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 remain 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 4. 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 iriomotelide-1a in human cancer cells. This study paves the way to 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.

This study was published online in Journal of the American Chemical Society as an Article on October 17th, 2024.

Journal: Journal of the American Chemical Society
DOI: 10.1021/jacs.4c11714
Method of Research: Experimental study
Subject of Research: Lab-produced tissue samples
Article Title: “Iriomoteolide-1a and -1b: Structure Elucidation by Integrating NMR Spectroscopic Analysis, Theoretical Calculation, and Total Synthesis”
Article Publication Date: 17-Oct-2024
COI Statement: Tomohiro Obana, Miyu Nakajima, Kazuki Nakazato, Hayato Nakagawa, Keisuke Murata, Masashi Tsuda,* Haruhiko Fuwa* (*Corresponding authors)