Solid-Phase Synthesis and Biological Evaluation of a Teleocidin Library—Discovery of a Selective PKC Down Regulator

Abstract

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.

Principles, implementation, and application of biology-oriented synthesis (BIOS)

“…Among the nitrogen heterocycles, indolactams are known modulators of protein kinase C and the chemical space around this scaffold was successfully explored via combinatorial synthesis (Meseguer et al, 1999(Meseguer et al, , 2000.…”

Biology-inspired synthesis of compound libraries

“…Moreover, it allows a correlation of different scaffold classes as performed during BIOS (see the BIOS section for more details). Based on this tree, Waldmann and coworkers synthesized libraries featuring spiroketal [32 -34], a,b-unsaturated lactone [35 -40], tetrahydropyrane [41,42], indolactam [43,44], decaline [45 -48], indole scaffolds [49,50] and indoloquinolizidine [27,51], and proved their biological activity in various screening campaigns, thereby validating the scaffold tree approach as a powerful method for generating libraries with high contents of biologically active molecules. For example, two cell-based screens of a library consisting of only 50 a,b-unsaturated d-lactones yielded small molecule modulators of cell cycle progression (Fig.…”

Syntheses and Cellular Investigations of 173-, 152-, and 131-Amino Acid Derivatives of Chlorin e6

“…The 13 1− carboxylic acid of chlorin ( 6 ) was activated using HOBt/TBTU under basic conditions 38 and coupled with L-aspartic di(tert)butyl ester. With DCC/DMAP a lower yield was obtained for the coupling reaction.…”