The total synthesis of FD-895 was completed through a strategy that featured the use of a tandem esterification ring-closing metathesis (RCM) process to construct the 12-membered macrolide and a modified Stille coupling to append the side chain. These studies combined with detailed analysis of all four possible C16-C17 stereoisomers were used to confirm the structure of FD-895 and identify an analog with an enhanced subnanomolar bioactivity.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518397 | PMC |
| http://dx.doi.org/10.1021/ol3023006 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Stereochemical Control of Splice Modulation in FD-895 Analogues.
J Med Chem
May 2023
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358, United States.
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.
View Article and Find Full Text PDFSplice Modulation Synergizes Cell Cycle Inhibition.
ACS Chem Biol
March 2020
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0358, United States.
While recognized as a therapeutic target, the spliceosome may offer a robust vector to improve established therapeutics against other protein targets. Here, we describe how modulating the spliceosome using small molecule splice modulators (SPLMs) can prime a cell for sensitivity to a target-specific drug. Using the cell cycle regulators aurora kinase and polo-like kinase as models, this study demonstrates how the combination of SPLM treatment in conjunction with kinase inhibition offers synergy for antitumor activity using reduced, sublethal levels of SPLM and kinase inhibitors.
View Article and Find Full Text PDFRemediating cancer via splicing modulation.
J Med Chem
September 2013
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, 4072, Australia.
The identification of three distinct but structurally related classes of microbial-derived spliceosome modulators has provided an exciting opportunity for the development of mechanistically new cancer treatments. A team at UC San Diego has undertaken a SAR study on the spliceosome modulator FD-895 that focused on improving compound stability, while retaining potent antiproliferative and splicing activity. This led to the identification of a more potent and stable analog, (17S)-FD-895 (1), and a less active but extremely stable cyclopropane analog 2, which is currently undergoing preclinical evaluation.
View Article and Find Full Text PDFStabilized cyclopropane analogs of the splicing inhibitor FD-895.
J Med Chem
September 2013
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358, United States.
Targeting the spliceosome with small molecule inhibitors provides a new avenue to target cancer by intercepting alternate splicing pathways. Although our understanding of alternate mRNA splicing remains poorly understood, it provides an escape pathway for many cancers resistant to current therapeutics. These findings have encouraged recent academic and industrial efforts to develop natural product spliceosome inhibitors, including FD-895 (1a), pladienolide B (1b), and pladienolide D (1c), into next-generation anticancer drugs.
View Article and Find Full Text PDFStructure of FD-895 revealed through total synthesis.
Org Lett
November 2012
Department of Chemistry and Biochemistry, University of Calfornia, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358, USA.
The total synthesis of FD-895 was completed through a strategy that featured the use of a tandem esterification ring-closing metathesis (RCM) process to construct the 12-membered macrolide and a modified Stille coupling to append the side chain. These studies combined with detailed analysis of all four possible C16-C17 stereoisomers were used to confirm the structure of FD-895 and identify an analog with an enhanced subnanomolar bioactivity.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!