Divergent synthesis of thapsigargin analogs

Hang Chu; Georg Dünstl; Jakob Felding; Phil S Baran

doi:10.1016/j.bmcl.2018.03.065

Divergent synthesis of thapsigargin analogs

Bioorg Med Chem Lett. 2018 Sep 1;28(16):2705-2707. doi: 10.1016/j.bmcl.2018.03.065. Epub 2018 Mar 23.

Authors

Hang Chu¹, Georg Dünstl², Jakob Felding², Phil S Baran³

Affiliations

¹ Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States.
² Research & Development, LEO Pharma, A/S Industriparken 55, 2750 Ballerup, Denmark.
³ Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States. Electronic address: pbaran@scripps.edu.

Abstract

Thapsigargin (3) is a potent inhibitor of the SERCA-pump protein, with potential for application in a variety of medicinal areas. The efficient and scalable syntheses of thapsigargin (3) and nortrilobolide (2) have been disclosed previously. To demonstrate the modularity of the previous routes, three natural products (compounds 6, 13, 15) and four analogs (compounds 17-20) have been divergently prepared from a common building block featuring varied acyl chains at the C2, C3, and C8 positions. Biological tests revealed that all of the compounds prepared displayed promising activity profiles.

Keywords: Divergent synthesis; Natural products; SERCA inhibition; Total synthesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acylation
Enzyme Inhibitors / chemical synthesis*
Sarcoplasmic Reticulum Calcium-Transporting ATPases / antagonists & inhibitors*
Thapsigargin / analogs & derivatives*
Thapsigargin / chemical synthesis*

Substances

Enzyme Inhibitors
Thapsigargin
Sarcoplasmic Reticulum Calcium-Transporting ATPases

Grants and funding

R35 GM118176/GM/NIGMS NIH HHS/United States