These authors contributed equally to the research.
Synthesis of SHIP1-Activating Analogs of the Sponge Meroterpenoid Pelorol†
Version of Record online: 3 AUG 2012
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
European Journal of Organic Chemistry
Volume 2012, Issue 27, pages 5195–5207, September 2012
How to Cite
Meimetis, L. G., Nodwell, M., Yang, L., Wang, X., Wu, J., Harwig, C., Stenton, G. R., Mackenzie, L. F., MacRury, T., Patrick, B. O., Ming-Lum, A., Ong, C. J., Krystal, G., Mui, A. L. .-F. and Andersen, R. J. (2012), Synthesis of SHIP1-Activating Analogs of the Sponge Meroterpenoid Pelorol . Eur. J. Org. Chem., 2012: 5195–5207. doi: 10.1002/ejoc.201200631
Dedicated to the memory of Ernesto Fattorusso
- Issue online: 10 SEP 2012
- Version of Record online: 3 AUG 2012
- Manuscript Received: 8 MAY 2012
- Natural products;
- Medicinal chemistry;
- Biomimetic synthesis;
Two biomimetic approaches have been used to synthesize analogs of the SHIP1-activating sponge meroterpenoid pelorol (1). One approach started from the chiral pool plant natural product sclareolide, which has the same absolute configuration as pelorol. The second approach utilized an enantioselective polyene cyclization to efficiently access both absolute configurations of the pelorol meroterpenoid skeleton and to prepare A-ring functionalized compounds. Selected analogs have been evaluated for water solubility and biological activity. It was found that the undesirable catechol and ester functionalities in 1 could be removed to give MN100 (3), without a decrease in SHIP1-activating ability. A further refinement led to the resorcinol analog 18, which is the most effective SHIP1-activating pelorol analog made to date. The HCl salt of ent-28, a C-3 amino analog of 18, is about 500,000-fold more soluble in water than MN100 (3). (±)-28·HCl activates SHIP1 in vitro, inhibits Akt phosphorylation in stimulated MOLT-4 (SHIP+) cells, and is active in a dose-dependent manner in a mouse model of inflammation when administered by oral gavage (ED50 ≈ 0.1 mg/kg). Pelorol analogs ent-28 or (±)-28 are promising chemical tools for further preclinical in vivo evaluation of the potential of SHIP1 activators as therapeutics for treating hematopoietic diseases involving aberrant activation of PI3K cell signaling.