Total Synthesis, Stereochemical Revision, and Biological Assessment of Iriomoteolide-2a

Keita Sakamoto, Akihiro Hakamata, Arihiro Iwasaki, Kiyotake Suenaga, Masashi Tsuda, Haruhiko Fuwa

研究成果: Article

抄録

Iriomoteolide-2a is a marine macrolide metabolite isolated from a cultured broth of the benthic dinoflagellate Amphidinium sp. HYA024 strain. This naturally occurring substance was reported to show remarkable cytotoxic activity against human cancer cell lines HeLa and DG-75 and in vivo antitumor activity against murine leukemia P388 cell line. Herein, the total synthesis, stereochemical revision, and biological assessment of iriomoteolide-2a are reported in detail. Total synthesis of the proposed structure 1 of iriomoteolide-2a featured a late-stage convergent assembly of three components by a Suzuki–Miyaura coupling, an esterification, and a ring-closing metathesis. However, the NMR data of synthetic 1 were not identical to those of the natural product. Careful analysis of the NMR data of the authentic material and synthesis/NMR analysis of appropriately designed model compounds led to consideration of four possible stereoisomers 2–5 as candidates for the correct structure. Accordingly, total syntheses of 2–5 were achieved by taking advantage of the convergent strategy, and comparison of the NMR spectra of synthetic 2–5 with those of the natural product led to the conclusion that 5 shows the correct relative configuration of iriomoteolide-2a. The absolute configuration of this natural product was finally established through chiral HPLC analysis of synthetic 5/ent-5 with the authentic sample. The antiproliferative activity of the synthetic compounds was assessed against HeLa and A549 cells to show that, in contrast to expectation, synthetic 5 and ent-5 were only marginally active in these cell lines. This work clearly underscores the vital role of total synthesis in the establishment of the structure and biological activity of natural products.

元の言語English
ジャーナルChemistry - A European Journal
DOI
出版物ステータスPublished - 2019 1 1

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Biological Products
Nuclear magnetic resonance
Cells
Lead compounds
Stereoisomerism
Macrolides
Esterification
Metabolites
Bioactivity

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Organic Chemistry

これを引用

Total Synthesis, Stereochemical Revision, and Biological Assessment of Iriomoteolide-2a. / Sakamoto, Keita; Hakamata, Akihiro; Iwasaki, Arihiro; Suenaga, Kiyotake; Tsuda, Masashi; Fuwa, Haruhiko.

:: Chemistry - A European Journal, 01.01.2019.

研究成果: Article

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AU - Sakamoto, Keita

AU - Hakamata, Akihiro

AU - Iwasaki, Arihiro

AU - Suenaga, Kiyotake

AU - Tsuda, Masashi

AU - Fuwa, Haruhiko

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AB - Iriomoteolide-2a is a marine macrolide metabolite isolated from a cultured broth of the benthic dinoflagellate Amphidinium sp. HYA024 strain. This naturally occurring substance was reported to show remarkable cytotoxic activity against human cancer cell lines HeLa and DG-75 and in vivo antitumor activity against murine leukemia P388 cell line. Herein, the total synthesis, stereochemical revision, and biological assessment of iriomoteolide-2a are reported in detail. Total synthesis of the proposed structure 1 of iriomoteolide-2a featured a late-stage convergent assembly of three components by a Suzuki–Miyaura coupling, an esterification, and a ring-closing metathesis. However, the NMR data of synthetic 1 were not identical to those of the natural product. Careful analysis of the NMR data of the authentic material and synthesis/NMR analysis of appropriately designed model compounds led to consideration of four possible stereoisomers 2–5 as candidates for the correct structure. Accordingly, total syntheses of 2–5 were achieved by taking advantage of the convergent strategy, and comparison of the NMR spectra of synthetic 2–5 with those of the natural product led to the conclusion that 5 shows the correct relative configuration of iriomoteolide-2a. The absolute configuration of this natural product was finally established through chiral HPLC analysis of synthetic 5/ent-5 with the authentic sample. The antiproliferative activity of the synthetic compounds was assessed against HeLa and A549 cells to show that, in contrast to expectation, synthetic 5 and ent-5 were only marginally active in these cell lines. This work clearly underscores the vital role of total synthesis in the establishment of the structure and biological activity of natural products.

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