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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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Abstract

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)-tetradecylidene] tetrahydro-2-furanone (1), a compound that showed high affinity for PKC-α (Ki=35 nM) in a competition binding assay with [3H-20]phorbol-12, 13-dibutyrate (PDBU). In an attempt to overcome the problem of generating geometrical E- and Z-isomers, as encountered with1, the double bond was moved to an endocyclic location as in3, or an additional alkyl chain was appended to C3 to give the corresponding 3,3-dialkyl saturated lactones (4 and5). The lactone was constructed from glycidyl-4-methoxyphenyl ether in 5 steps. The target compounds showed reduced binding affinities for PKC-α with Ki 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-α in terms of the direction of the long alkyl chain connected to the 3-position.

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  1. College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, 151-742, Seoul, Korea

    Jeewoo Lee

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  1. Jeewoo Lee
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Lee, J. Design and synthesis of bioisosteres of ultrapotent protein kinase C (PKC) ligand, 5-Acetoxymethyl-5-hydroxymethyl-3-alkylidene tetrahydro-2-furanone. Arch. Pharm. Res. 21, 452–457 (1998). https://doi.org/10.1007/BF02974642

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  • DOI: https://doi.org/10.1007/BF02974642

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