2. Academic Validation
  3. Structure Revision of Trichomide D by Total Synthesis

Structure Revision of Trichomide D by Total Synthesis

  • J Nat Prod. 2022 Jul 22;85(7):1850-1860. doi: 10.1021/acs.jnatprod.2c00440.
Masahito Yoshida 1 2,  Tomoya Matsushita 1,  Shinji Kondo 3,  Hiroko Isoda 4 3 5,  Hideo Kigoshi 1 2 3
Affiliations

Affiliations

  • 1 Degree Programs in Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
  • 2 Department of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
  • 3 Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
  • 4 Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
  • 5 Open Innovation Laboratory for Food and Medicinal Resource Engineering, National Institute of Advanced Industrial Science and Technology and University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
PMID: 35766102 DOI: 10.1021/acs.jnatprod.2c00440
Abstract

A structure revision of trichomide D has been achieved by its total synthesis. The sterically hindered peptide sequence was successfully prepared using not only a conventional amidation with EDCI but also coupling with an Fmoc-protected amino acid chloride derivative. The cyclization precursor was synthesized by coupling of a tetrapeptide with an acylproline derivative and subsequent removal of silyl groups at the N- and C-termini. Macrolactonization using MNBA/DMAPO followed by preparation of a chlorohydrin moiety furnished the proposed structure of trichomide D, whose spectra were not identical to those of the natural product. Finally, we succeeded in the elucidation of the true structure of trichomide D by its total synthesis, and the absolute configuration of the chlorohydrin moiety was revised to be S. The cytotoxicities of the natural product and its synthetic derivatives against MCF-7 and HeLa S3 cells were evaluated by the MTT method, revealing that the configuration of the chlorohydrin moiety is a pivotal factor for exhibiting potent cytotoxicity against Cancer cells.

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