Phospholipase C inhibitor

The concept is not limited to analogs of simple linear organophosphates (e.g. phosphoenol pyruvate analog as inhibitor of 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase [71]) but can be extended to cyclic phosphates (e.g. cyclic phosphoinositol analog as a phospholipase C inhibitor [72]) and transition state analogs (e. g. purine nucleoside phosphorylase (PNP) inhibitor [73]) (Scheme 4.30). 

Calaporoside (57) (Vol. 28, p. 258) is a phospholipase C inhibitor. Deacetyl calaporoside, which is itself an inhibitor of the GABAa receptor ion channel, has been synthesized, in a process which had 3 1 selectivity in favour of the P-linkage using 2-naphthyl tetra-0-benzyl-1-thio-D-mannopyranoside as glycosyl donor, and NIS-TfOH as activator. The glycoside 58, lacking the mannonic acid unit, was also made along with its ot-anomer. Both of these compounds, as well as both anomers of deacetyl calaporoside, have PLC inhibitory activity at similar levels. 

Aoki M, Itezono Y, Shirai H, Nakayama N, Sakai A, Tanaka Y, Yamaguchi A, Shinuna N, Yokose K (1991) Structure of a Novel Phospholipase C Inhibitor, Vinaxanthone (Ro 09-1450), Produced by Penicillium vinaceum. Tetrahedron Lett 32 4737... 

Altronic acid deriv. Prod, by Caloporus dichrous. Phospholipase C inhibitor. Oil. [a] — 32 (c, 1.1 in MeOH). 

Umemura, A., Mabe, H., Nagai, H., Sugino, F. (1992) Action of phospholipases A2 and C on free fatty acid release during complete ischemia in rat neocortex. Effect of phospholipase C inhibitor and N-methyl-D-aspartate antagonist. Journal of Neurosurgery, 76, 648-651. 

Figure 10. The G-protein cascades in smooth muscle catalyze the exchange GDP for GTP on G-protein. Following the binding of GTP, the trimeric G-protein splits into an a-GTP part and a P-y part. The a-GTP part ordinarily then combines with its specific apoenzyme to constitute the active enzyme. For the activation of the contractile activation path, the enzyme is phospholipase C and the second messenger products are IP3 and DAG. The IP3 in the myoplasm binds to Ca channels in the SR membrane, opening them. Other second messengers include the inhibitors of contractile activity, cGMP and cAMP.

Two possible pathways for the biosynthesis of 2-AG have been proposed (1) a phospholipase C (PLC) hydrolysis of membrane phospholipids followed by a second hydrolysis of the resulting 1,2-diacylglycerol by diacylglycerol lipase or (2) a phospholipase Ai (PLA,) activity that generates a lysophospholipid, which in turn is hydrolyzed to 2-AG by lysophospholipase C (Fig. 5) (Piomelli, 1998). Alternative pathways may also exist from either triacylglycerols by a neutral lipase activity or lysophosphatidic acid by a dephosphorylase. The fact that PLC and diacylglycerol lipase inhibitors inhibit 2-AG formation in cortical neurons supports the contention that 2-AG is, at least predominantly, biosynthesized by the PLC pathway (Stella, 1997). However, a mixed pathway may also be plausible. 

Wallner, B.P., Mattaliano, R.J., Hession, C., Cate, R.L., Tizard, R., Sinclair, L.K., Foeller, C., Chow, E.P., Browning, J.L., Ramachandran, K.L. and Pepinsky, R.B. (1986). Cloning and expression of human lipocortin, a phospholipase A2 inhibitor with potential anti-inflammatory activity. Nature 320 77-80. 

Ortiz, A.R., Pastor, M., Palomer, A., Cruciani, G., Gago, F., and Wade, R.C. Reliability of comparative molecular field analysis models effects of data scaling and variable selection using a set of human synovial fluid phospholipase A2 inhibitors. /. Med. Chem. 1997, 40, 1136-1148. 

Prostacyclin, a potent inhibitor of platelet aggregation, is derived from metabo-lisation of arachidonic acid by endothelial cells, and shear stress increases its production rate [12]. It is postulated that this effect is due to perturbations of the permeability of the plasma membrane changing the cytosolic Ca + content and leading to an increase in phospholipase C activity (through the by-passing of the receptor requirement), which contributes to a higher production of arachidonic metabolites. 

Akaterpin (372) is an inhibitor of phosphatidylinositol-specific phospholipase C from a Callyspongia sp. [326]. The relative stereochemistry of the ring junction in the upper decalin moiety of akaterpin was shown to be cis by synthesis of model compounds [327]. 

Llansola M., Monfort P., and Felipo V. (2000). Inhibitors of phospholipase C prevent glutamate neurotoxicity in primary cultures of cerebellar neurons. J. Pharmacol. Exp. Ther. 292 870-876. 

St-Gelais F., Menard C., Congar P., Tmdeau L. E., and Massicotte G. (2004). Postsynaptic injection of calcium-independent phospholipase A2 inhibitors selectively increases AMPA receptor-mediated synaptic transmission. Hippocampus 14 319-325. 

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