Design and synthesis of bioisosteres of ultrapotent protein kinase C (PKC) ligand, 5-acetoxymethyl-5-hydroxymethyl-3-alkylidene tetrahydro-2-furanone.
Three compounds, 5-(acetoxymethyl)-5-(hydroxymethyl)-3-tetradecyl-2,5-dihydro-2-furanone (3), 5-(acetoxymethyl)-5-(hydroxymethyl)-3,3-dihexyltetrahydro-2-furano ne (4) and 5-(acetoxymethyl)-5-(hydroxymethyl)-3,3-dioctyltetrahydro-2-furano ne (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-alpha (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 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 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-alpha in terms of the direction of the long alkyl chain connected to the 3-position.
Lee
J
J
College of Pharmacy, Seoul National University, Korea.
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D018716:Molecular Mimicry; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*
C117318:5-(acetoxymethyl)-5-(hydroxymethyl)-3,3-dihexyltetrahydro-2-furanone; C117317:5-(acetoxymethyl)-5-(hydroxymethyl)-3-tetradecyl-2,5-dihydro-2-furanone; C117319:5-(acetoxymethyl)-5--(hydroxymethyl)-3,3-dioctyltetrahydro-2-furanone; D005663:Furans; D008024:Ligands; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D015107:4-Butyrolactone