Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358, United States.
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.
J Med Chem. 2023 May 25;66(10):6577-6590. doi: 10.1021/acs.jmedchem.2c01893. Epub 2023 May 8.
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 17-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.
大环内酯天然产物的高官能化骨架可以获得原子的罕见空间排列，其中立体化学的变化可能对结构和功能产生深远影响。剪接体调节剂具有独特的共识基序，其中大多数调节剂针对 SF3B 剪接体复合物中的关键界面。我们最近进行的 17-FD-895 制备规模合成运动提供了对这种复杂大环内酯的立体化学类似物的独特访问。在这里，我们报告了多种 FD-895 类似物的制备和系统活性评估。这些研究考察了分子中特定手性中心修饰的影响，并突出了剪接体调节剂的药物化学优化的未来方向。
