Divergent Total Synthesis of Isoflavone Natural Products and Their Potential as Therapeutic Agents for TTR Amyloidosis

J Nat Prod. 2024 Nov 22;87(11):2604-2614. doi: 10.1021/acs.jnatprod.4c00812. Epub 2024 Oct 27.

Abstract

We have achieved the divergent total synthesis of nine isoflavone natural products 1-9 starting from commercially available 2,4,6-trihydroxyacetophenone as a starting material. The isoflavone skeleton of 1-9 was constructed by the Suzuki-Miyaura coupling reaction as the key reaction. Investigation of the potential of 1-9 as therapeutic agents for transthyretin (TTR) amyloidosis revealed that millexatin F (3) showed the best efficacy in ex vivo competitive binding experiments and thioflavin-T fluorescence studies. Therefore, millexatin F (3) is promising as a seed compound for a novel TTR amyloidosis therapeutic agent.

MeSH terms

  • Amyloid Neuropathies, Familial / drug therapy
  • Amyloidosis / drug therapy
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacology
  • Biological Products* / chemical synthesis
  • Biological Products* / chemistry
  • Biological Products* / pharmacology
  • Humans
  • Isoflavones* / chemical synthesis
  • Isoflavones* / chemistry
  • Isoflavones* / pharmacology
  • Molecular Structure
  • Prealbumin / metabolism

Substances

  • Isoflavones
  • Biological Products
  • Prealbumin
  • Benzothiazoles

Supplementary concepts

  • Amyloidosis, Hereditary, Transthyretin-Related