Synthesis of SHIP1‐Activating Analogs of the Sponge Meroterpenoid Pelorol

Abstract

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.

Discovery and Development of Small Molecule SHIP Phosphatase Modulators

“…Several analogs of pelorol were synthesized and tested for SHIP1 activity . This study led to the discovery of tolyl analogue 2 (AQX‐016A), which exhibited improved biological activity .…”

“…Additional studies by Aquinox Pharmaceuticals have resulted in the development of even more pelorol‐based SHIP1 agonists. One focus appears to be increasing the water solubility of these terpene‐based structures, leading to the development of amine‐containing structures like 4 , which was only slightly less active than AQX‐MN100 ( 3 ) . Unexpectedly, this molecule contains the enantiomeric configuration of the terpenoid structure as compared to pelorol, with the analog possessing the same configuration as pelorol having a weaker effect on upregulating SHIP1.…”

Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes

“…IL6 failed to induce STAT3 association with SHIP1, even though STAT3 becomes tyrosine phosphorylated to the same extent as in response to IL10. Remarkably, treatment of cells with the small molecule SHIP1 allosteric regulator ZPR-151 (previously called 28·HCl ( Meimetis et al., 2012 )), a more water-soluble derivative of ZPR-MN100 ( Figure 7 A), is sufficient to induce association of SHIP1 and STAT3 ( Figure 2 B). The ability of ZPR-151 to induce association of SHIP1 and STAT3 suggests the binding of ZPR-151 may induce a conformational change that can alter SHIP1's association with other proteins.…”

“…In response to extracellular signals, SHIP1 can be recruited to the cell membrane and one of its actions can be to turn off phosphoinositide 3-kinase (PI3K) signaling ( Brown et al., 2010 ) by dephosphorylating the PI3K product PIP 3 into PI(3,4)P 2 ( Fernandes et al., 2013 ; Huber et al., 1999 ; Krystal, 2000 ; Pauls and Marshall, 2017 ). We have shown that SHIP1 phosphatase activity is allosterically activated by its product PI(3,4)P 2 and that small molecules of the pelorol family (ZPR-MN100 and ZPR-151) also allosterically enhance SHIP1 phosphatase activity ( Meimetis et al., 2012 ; Ong et al., 2007 ). These data suggest that stimulating SHIP1 phosphatase activity with small molecule SHIP1 activators could be used to treat inflammatory diseases caused by inappropriately sustained PI3K production of PI(3,4)P 2 .…”

SHIP2: Structure, Function and Inhibition

“…It has been suggested that these compounds allosterically activate SHIP1 by binding to the putative C2 domain . A racemic pelorol analogue ( 30 a and 30 b ) is as potent as AQX‐MN100 in activating SHIP1 but has better pharmacological properties . Pelorol derivatives with the core structure 31 have been the subject of a patent application but few biological data are given.…”