108609-67-2Relevant articles and documents
Synthesis and biological evaluation of phosphatidylinositol phosphate affinity probes
Conway, Stuart J.,Gardiner, James,Grove, Simon J. A.,Johns, Melloney K.,Lim, Ze-Yi,Painter, Gavin F.,Robinson, Diane E. J. E.,Schieber, Christine,Thuring, Jan W.,Wong, Leon S.-M.,Yin, Meng-Xin,Burgess, Antony W.,Catimel, Bruno,Hawkins, Phillip T.,Ktistakis, Nicholas T.,Stephens, Leonard R.,Holmes, Andrew B.
supporting information; experimental part, p. 66 - 76 (2010/04/29)
The synthesis of the complete family of phosphatidylinositol phosphate analogues (PIPs) from five key core intermediates A-E is described. These core compounds were obtained from myo-inositol orthoformate 1 via regioselective DIBAL-H and trimethylaluminium-mediated cleavages and a resolution-protection process using camphor acetals 10. Coupling of cores A-E with phosphoramidites 34 and 38, derived from the requisite protected lipid side chains, afforded the fully-protected PIPs. Removal of the remaining protecting groups was achieved via hydrogenolysis using palladium black or palladium hydroxide on carbon in the presence of sodium bicarbonate to afford the complete family of dipalmitoyl- and amino-PIP analogues 42, 45, 50, 51, 58, 59, 67, 68, 76, 77, 82, 83, 92, 93, 99 and 100. Investigations using affinity probes incorporating these compounds have identified novel proteins involved in the PI3K intracellular signalling network and have allowed a comprehensive proteomic analysis of phosphoinositide interacting proteins. The Royal Society of Chemistry 2010.
Substrate specificity in short-chain phospholipid analogs at the active site of human synovial phospholipase A2
Wheeler,Blanchard,Andrews,Fang,Gray-Nunez,Harris,Lambert,Mehrotra,Parks,Ray,Smalley Jr.
, p. 4118 - 4129 (2007/10/02)
The substrate specificity at the active site of recombinant human synovial fluid phospholipase A2 (hs-PLA2) was investigated by the preparation of a series of short-chain phospholipid analogs and measurement of their enzymatic hydrolysis at concentrations well below the critical micelle concentration. Substrates used in the study included 1,2-dihexanoylglycerophospholipids, 1,2-bis(alkanoylthio)glycerophospholipids, and 1-O-alkyl-2- (alkanoylthio)phospholipids. Turnover was observed for only a few of the 1,2- dihexanoylglycerophospholipids, and the rate of hydrolysis was very low, near the limit of detection of the assay. In contrast, selected 2-(alkanoylthio)- glycerophospholipids were hydrolyzed by hs-PLA2 at much higher rates at concentrations well below their critical micelle concentration (cmc). Thus, the 1,2-bis(hexanoylthio)glycerophosphatidylmethanol exhibits a k(cat)/K(M) = 1800 L mol-1 s-1. Over the calculated log P (cLogP) range of 3-9, cLogP and log(k(cat)/K(M)) were linearly related for compounds with straight-chain sn-1 and sn-2 substituents. At comparable cLogP's, the sn-1 ethers and thioesters were hydrolyzed at comparable rates. A negative charge in the phosphate head group was required for enzyme activity. Unsaturation, aromaticity, and branching in the sn-2 substituent reduce turnover dramatically. The same structural modifications in the sn-1 substituent have less effect on turnover. Certain of these substrates, e.g., 1,2- bis(hexanoylthio)glycerophosphatidylmethanol, may be useful in assaying for active site inhibitors of PLA2. The structure-activity relationships established here for substrates should serve as a reference for the structure-activity relationships of substrate-based inhibitors.
