Solid-phase synthesis and biological evaluation of a teleocidin library--discovery of a selective PKCdelta down regulator.
Protein kinaseC (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 indolactamV (6), a PKC activator, and its N13-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.
Meseguer
B
B
Max-Planck-Institut für Molekulare Physiologie, Dortmund, Germany.
Alonso-Díaz
D
D
Griebenow
N
N
Herget
T
T
Waldmann
H
H
D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D020650:Combinatorial Chemistry Techniques; D015536:Down-Regulation; D004789:Enzyme Activation; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008235:Lyngbya Toxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins; D051379:Mice; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051745:Protein Kinase C-delta; D011506:Proteins / Q000378:metabolism; D013237:Stereoisomerism; D014364:Tryptophan / Q000031:analogs & derivatives / Q000737:chemistry
D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D007769:Lactams; D008235:Lyngbya Toxins; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C022176:teleocidins; D014364:Tryptophan; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta