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  Solid-phase synthesis and biological evaluation of a teleocidin library - discovery of a selective PKC delta down regulator

Meseguer, B., Alonso-Diaz, D., Griebenow, N., Herget, T., & Waldmann, H. (2000). Solid-phase synthesis and biological evaluation of a teleocidin library - discovery of a selective PKC delta down regulator. CHEMISTRY-A EUROPEAN JOURNAL, 6(21), 3943-3957. doi:10.1002/1521-3765(20001103)6:21<3943:AID-CHEM3943>3.3.CO;2-K.

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 Creators:
Meseguer, B1, Author
Alonso-Diaz, D1, Author
Griebenow, N1, Author
Herget, T1, Author
Waldmann, Herbert2, Author           
Affiliations:
1external, ou_persistent22              
2Abt. IV: Chemische Biologie, Max Planck Institute of Molecular Physiology, Max Planck Society, ou_1753290              

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Free keywords: PROTEIN-KINASE-C; ACTIVATOR-BINDING DOMAIN; SWISS 3T3 CELLS; TUMOR PROMOTERS; AMINO-ACIDS; INDOLACTAM CONGENERS; PHORBOL ESTER; STEREOCHEMISTRY; SUBSTRATE; (-)-INDOLACTAM-V Chemistry; alkaloids; combinatorial chemistry; enzyme catalysis; lactams; protein kinase C; signal transduction;
 Abstract: Protein kinase C (PKC) is linked to the signal-induced modulation of a wide variety of cellular processes, such as growth, differentiation, secretion, apoptosis, and tumor development. The design and synthesis of small molecules that regulate these different cellular signaling systems is at the forefront of modern drug design. Herein we report a) an efficient method for the synthesis of indolactam V (6), a PKC activator, and its N-13-des(methyl) analogues (19) using a regioselective organometallic transformation, a convenient aminomalonate derivative (10) to introduce the appropriate functionality and an enantiospecific enzymic hydrolysis as key steps; b) the use of this method in the first solid-phase synthesis of a teleocidin library modifying the N-13, C-12 and C-7 alkyl chains, and, therefore, producing a library of potential activators and/or inhibitors of PKC of the general structure (32); c) the activation of PKC by selected members of the library using a MARCKS translocation in vivo assay system; d) the observation that some of these analogues are nearly as effective as the natural PKC activators phorbol dibutyrate and (-)-indolactam V (6), and e) the observation that some of these analogues have different potential to induce down-regulation of members of the PKC gene family after chronic stimulation.

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Language(s): eng - English
 Dates: 2000
 Publication Status: Issued
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Degree: -

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Title: CHEMISTRY-A EUROPEAN JOURNAL
Source Genre: Journal
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Publ. Info: Weinheim : WILEY-VCH
Pages: - Volume / Issue: 6 (21) Sequence Number: - Start / End Page: 3943 - 3957 Identifier: ISSN: 0947-6539