Natural Product Synthesis on Polymeric Supports—Synthesis and Biological Evaluation of an Indolactam Library

Abstract

Potent activators of protein kinase C in fibroblasts: This property was determined for several indolactam V analogues (1) with a new cell-based assay system. This tumor-promoting indole alkaloid and analogues thereof can be synthesized efficiently on the solid phase. The key steps of the combinatorial approach are a regioselective amination of the indole ring and an enantioselective enzymatic reaction.

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.…”

Natural Product‐Like Combinatorial Libraries

“…180,183 Based on known structural requirements of indolactams to their binding ability to PKC, these authors have prepared a 31-membered library of analogues (166) with diversified substituents at C-12, C-7 and N-13 ( Figure 44). 21,182 The formation of the nine membered lactam ring and the introduction of three substituents at C-12 was methylated polystyrene beads through a THP-based linker, was achieved by reductive amination of N-13 and Sonogashira coupling at C-7, respectively. Eleven library members were further assayed for PKC activation on Swiss 3T3 cells.…”

“…21,178 A similar solidphase approach has been described for the synthesis of demethoxyfumitremorgin (158a), the most active of this series of alkaloids, allowing the use of a larger variety of aldehydes for the Pictet-Spengler condensation with Nacyliminium species. 179 With the aim to generate libraries of potential activators and/or inhibitors of protein kinase C (PKC), 180,181 Waldmann and co-workers 182 established a methodology for the solidphase synthesis of analogues of (-)-indolactam V (163), a metabolite that possess the core structure of the tumor promoting teleocidins and has been recognised as a PKC activator. 180,183 Based on known structural requirements of indolactams to their binding ability to PKC, these authors have prepared a 31-membered library of analogues (166) with diversified substituents at C-12, C-7 and N-13 ( Figure 44).…”