Synthesis of SHIP1-Activating Analogs of the Sponge Meroterpenoid Pelorol

• Published in: European journal of organic chemistry Vol. 2012; no. 27; pp. 5195 - 5207
• Main Authors: Meimetis, Labros G., Nodwell, Matt, Yang, Lu, Wang, Xiaoxia, Wu, Joyce, Harwig, Curtis, Stenton, Grant R., Mackenzie, Lloyd F., MacRury, Thomas, Patrick, Brian O., Ming-Lum, Andrew, Ong, Christopher J., Krystal, Gerald, Mui, Alice L. -F., Andersen, Raymond J.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.09.2012; WILEY‐VCH Verlag; Wiley; Wiley-VCH; Wiley Subscription Services, Inc
• Subjects: Alicyclic compounds, terpenoids, prostaglandins, steroids; Biomimetic synthesis; Chemistry; Chemistry, Organic; Enantioselectivity; Enzymes; Exact sciences and technology; Medicinal chemistry; Natural products; Noncondensed benzenic compounds; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; Terpenoids; Enzymes; Medicinal chemistry; Enantioselectivity; Natural products; Terpenoids; Biomimetic synthesis; ASYMMETRIC EPOXIDATION; Water; Hydrogen Chlorides; Pyrocatechol derivatives; Phosphorylation; Resorcinol derivatives; Activation; Chiral compound; Marine environment; Ester; Plant; Amine; Functionalization; Hematopoiesis; Water solubility; Chemical synthesis; Terpenoid; Enzyme; Transferases; Rodentia; Animal origin; Phosphatidylinositol-3,4,5-triphosphate 5-phosphatase; Inflammation; Natural compound; In vitro; Biological activity; 1-Phosphatidylinositol 3-kinase; In vivo; Vertebrata; Mammalia; Cyclization; Mouse; Biomimetic compound; Polyenic compound; Porifera; Absolute configuration; Plant origin; Benzenic compound; Soluble compound; Sponge; Invertebrata
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201200631

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. Two biomimetic routes have been used to synthesize analogs of the SHIP1‐activating sponge meroterpenoid pelorol (1) in high ee. Resorcinol analog 18 is the most effective SHIP1‐activating pelorol analog made to date and racemic 28·HCl, an amino analog, activates SHIP1 in vitro, and has effective antiinflammatory activity in a mouse model (ED50 ≈ 0.1 mg/kg).