Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis.

We show here that both SHIP1 (Inpp5d) and its paralog SHIP2 (Inppl1) are expressed at protein level in microglia. To examine whether targeting of SHIP paralogs might influence microglial physiology and function, we tested the capacity of SHIP1-selective, SHIP2-selective and pan-SHIP1/2 inhibitors for their ability to impact on microglia proliferation, lysosomal compartment size and phagocytic function. We find that highly potent pan-SHIP1/2 inhibitors can significantly increase lysosomal compartment size, and phagocytosis of dead neurons and amyloid beta (Aß)1-42 by microglia in vitro We show that one of the more-potent and water-soluble pan-SHIP1/2 inhibitors, K161, can penetrate the blood-brain barrier. Consistent with this, K161 increases the capacity of CNS-resident microglia to phagocytose Aß and apoptotic neurons following systemic administration. These findings provide the first demonstration that small molecule modulation of microglia function in vivo is feasible, and suggest that dual inhibition of the SHIP1 and 2 paralogs can provide a novel means to enhance basal microglial homeostatic functions for therapeutic purposes in Alzheimer's disease and, possibly, other types of dementia where increased microglial function could be beneficial.

Discovery and development of small molecule SHIP phosphatase modulators.

Inositol phospholipids play an important role in the transfer of signaling information across the cell membrane in eukaryotes. These signals are often governed by the phosphorylation patterns on the inositols, which are mediated by a number of inositol kinases and phosphatases. The src homology 2 (SH2) containing inositol 5-phosphatase (SHIP) plays a central role in these processes, influencing signals delivered through the PI3K/Akt/mTOR pathway. SHIP modulation by small molecules has been implicated as a treatment in a number of human disease states, including cancer, inflammatory diseases, diabetes, atherosclerosis, and Alzheimer's disease. In addition, alteration of SHIP phosphatase activity may provide a means to facilitate bone marrow transplantation and increase blood cell production. This review discusses the cellular signaling pathways and protein-protein interactions that provide the molecular basis for targeting the SHIP enzyme in these disease states. In addition, a comprehensive survey of small molecule modulators of SHIP1 and SHIP2 is provided, with a focus on the structure, potency, selectivity, and solubility properties of these compounds.

Addition of alkynes to aldehydes and activated ketones catalyzed by rhodium-phosphine complexes.

A mixture of 2-(di-tert-butylphosphino)biphenyl and dicarbonylacetonato rhodium(I) provides an effective catalyst system for the addition of alkynes to aldehydes and activated ketones. In contrast to the more common zinc-catalyzed processes, enolizable 1,2-dicarbonyls are excellent substrates for these rhodium-catalyzed additions. This reaction allows for the formation of propargylic alcohols under mild conditions, tolerating many functional groups (such as carboxylic acids) that are incompatible with other methods. Little selectivity was observed in cases of unsymmetrical 1,2-diketones. Addition of alkynes to aldehydes with an adjacent chirality center usually provides the Felkin addition product with excellent selectivity in some cases. Studies on the catalyst structure show that both the beta-diketonate and a carbon monoxide ligand appear to be bound to the active catalyst. The use of chiral phosphines to induce asymmetry in the propargyl alcohol products provided low enantioselectivity, which may be due to the phosphine having a distal relationship to the reacting centers. Modification of other ligands, such as the beta-diketonate, appears to be a more promising avenue for the development of an enantioselective variant.