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

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Schlagwörter: 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;
 Zusammenfassung: 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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Sprache(n): eng - English
 Datum: 2000
 Publikationsstatus: Erschienen
 Seiten: 15
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Art des Abschluß: -

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Titel: CHEMISTRY-A EUROPEAN JOURNAL
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: Weinheim : WILEY-VCH
Seiten: - Band / Heft: 6 (21) Artikelnummer: - Start- / Endseite: 3943 - 3957 Identifikator: ISSN: 0947-6539