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KMID : 0043319980210040452
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Archives of Pharmacal Research
1998 Volume.21 No. 4 p.452 ~ p.457
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Design and Synthesis of Bioisosteres of Ultrapotent Protein Kinase C(PKC) Ligand, 5-Acetoxymethyl-5-hydroxymethyl-3-alkylidene tetrahydro-2-furanone
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Lee Jee-Woo
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Abstract
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Three compounds, 5-(acetoxymethyl)-5-(hydroxymethyl)-3-tetradecyl-2,5-dihydro-2-furanone (3), 5-(acetoxymethyl)-5-(hydroxymethyl)-3,3-dihexyltetrahydro-2-furanone (4) and 5-(acetoxymethyl)-5-(hydroxymethyl)-3,3-dioctyltetrahydro-2-furanone (5), were designed and synthesized as surrogates of the ultrapotent DAG analogue, 5-(acetoxymethyl)-5-(hydroxymethyl) 3-[(Z)-tetradecylideneltetrahydro-2-furanone (1), a compound that showed high affinity for PKC- (=35 nM) in a competition binding assay with [-20]phorbol-12,13-dibutyrate (PDBU). In an attempt to overcome the problem of generating geometrical E- and Z- isomers, as encountered with 1, the double bond was moved to an endocyclic location as in 3, or an additional alkyl chain was appended to C3 to give the corresponding 3,3-dialkyl saturated lactones (4 and 5). The lactone was constructed from glycidyl-4-methoxyphenyl ether in 5 steps. The target compounds showed reduced binding affinities for PKC-.alpha. with values of 192 nM (3), 4,829 nM (4), and 2,812 nM (5), respectively. These results indicate that constrained DAG analogues having a tetrahydro-2-furanone template are effectively discriminated by PKC-(X in terms of the direction of the long alkyl chain connected to the 3-position.n.
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KEYWORD
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Protein Kinase C, Ligand, Diacylglycerol, Phorbol ester, 5, 5-Disubstituted tetrahydro-2-furanone template, Bioisosteres
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