2. Academic Validation
  3. Synthesis and antiproliferative activity of a tetrahydrofuran analog of FR901464

Synthesis and antiproliferative activity of a tetrahydrofuran analog of FR901464

  • Bioorg Med Chem Lett. 2024 May 15:104:129739. doi: 10.1016/j.bmcl.2024.129739.
Ivanna Pohorilets 1,  Jacob P Beard 1,  Julia L Driscoll 1,  John C Schmitz 2,  Kazunori Koide 3
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Pittsburgh 219 Parkman Avenue, Pittsburgh, PA 15260, United States.
  • 2 Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine 5150 Centre Avenue, Pittsburgh, PA 15232, United States; Cancer Therapeutics Program, UPMC Hillman Cancer Center 5117 Centre Ave, Pittsburgh, PA 15232, United States.
  • 3 Department of Chemistry, University of Pittsburgh 219 Parkman Avenue, Pittsburgh, PA 15260, United States; Cancer Therapeutics Program, UPMC Hillman Cancer Center 5117 Centre Ave, Pittsburgh, PA 15232, United States. Electronic address: [email protected].
PMID: 38599298 DOI: 10.1016/j.bmcl.2024.129739
Abstract

FR901464 is a natural product that exhibits antiproliferative activity at single-digit nanomolar concentrations in Cancer cells. Its tetrahydropyran-spiroepoxide covalently binds the spliceosome. Through our medicinal chemistry campaign, we serendipitously discovered that a bromoetherification formed a tetrahydrofuran. The tetrahydrofuran analog was three orders of magnitude less potent than the corresponding tetrahydropyran analogs. This study shows the significance of the tetrahydropyran ring that presents the epoxide toward the spliceosome.

Keywords

Anticancer activity; Bromonium ion; Epoxide; RNA splicing; Tetrahydrofuran.

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