2. Academic Validation
  3. Stereochemical Control of Splice Modulation in FD-895 Analogues

Stereochemical Control of Splice Modulation in FD-895 Analogues

  • J Med Chem. 2023 May 25;66(10):6577-6590. doi: 10.1021/acs.jmedchem.2c01893.
Warren C Chan 1,  Kelsey A Trieger 1,  James J La Clair 1,  Catriona H M Jamieson 2,  Michael D Burkart 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358, United States.
  • 2 The Division of Regenerative Medicine, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California 92093, United States.
PMID: 37155693 DOI: 10.1021/acs.jmedchem.2c01893
Abstract

Highly functionalized skeletons of macrolide Natural Products gain access to rare spatial arrangements of atoms, where changes in stereochemistry can have a profound impact on the structure and function. Spliceosome modulators present a unique consensus motif, with the majority targeting a key interface within the SF3B spliceosome complex. Our recent preparative-scale synthetic campaign of 17S-FD-895 provided unique access to stereochemical analogues of this complex Macrolide. Here, we report on the preparation and systematic activity evaluation of multiple FD-895 analogues. These studies examine the effects of modifications at specific stereocenters within the molecule and highlight future directions for medicinal chemical optimization of spliceosome modulators.

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