Asymmetric synthesis of isobenzofuranone derivatives and their unique character as protein kinase Cα (PKCα) activators

Efficient enantio-selective synthesis of conformationally constrained diacylglycerol analogues, 7-substituted isobenzofuranone derivatives, originally developed by us as PKCα ligands, was achieved by asymmetric dihydroxylation and γ-lactone formation via ortho-lithiation and carboxylation. A series...

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Bibliographic Details
Published inTetrahedron letters Vol. 50; no. 26; pp. 3609 - 3612
Main Authors Hirai, Go, Ogoshi, Yosuke, Ohkubo, Megumi, Tamura, Yuki, Watanabe, Toru, Shimizu, Tadashi, Sodeoka, Mikiko
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier Ltd 01.07.2009
Elsevier
Subjects
Asymmetric dihydroxylation
Bleb-forming assay
Chemistry
Chemistry, Organic
Isobenzofuranone
Physical Sciences
Protein kinase Cα
Science & Technology
Asymmetric dihydroxylation
Bleb-forming assay
Protein kinase Cα
Isobenzofuranone
PROMOTING PHORBOL ESTERS
BRYOSTATIN
CONFORMATIONALLY CONSTRAINED ANALOGS
TUMOR PROMOTERS
LIGANDS
LACTONES
Protein kinase C alpha
THERAPEUTIC TARGET
HIGH BINDING-AFFINITY
DIACYLGLYCEROL DAG
REVEALS
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Summary:Efficient enantio-selective synthesis of conformationally constrained diacylglycerol analogues, 7-substituted isobenzofuranone derivatives, originally developed by us as PKCα ligands, was achieved by asymmetric dihydroxylation and γ-lactone formation via ortho-lithiation and carboxylation. A series of derivatives having straight and/or branched side chains were synthesized and evaluated, and low-nanomolar-concentration affinity ligands and highly potent PKCα activators were found among them. These potent ligands induced phenotypic change of K562 cells, which is characteristic of PKC activators.
ISSN:0040-4039
1873-3581
DOI:10.1016/j.tetlet.2009.03.069