888009-83-4Relevant articles and documents
Synthesis and structure-activity correlation of natural-product inspired cyclodepsipeptides stabilizing F-actin
Tannert, Rene,Milroy, Lech-Gustav,Ellinger, Bernhard,Hu, Tai-Shan,Arndt, Hans-Dieter,Waldmann, Herbert
supporting information; experimental part, p. 3063 - 3077 (2010/05/15)
The fundamental role played by actin In the regulation of eukaryotic cell maintenance and motility renders it a primary target for small-molecule intervention. in this arena, a class of potent cytotoxic cyclodepsipeptide natural products has emerged over the last quarter-century to stimulate the fields of biology and chemistry with their unique actin-stabilizing properties and complex peptide-polyketide hybrid structures. Despite considerable research effort, a structural basis for the activity of these secondary metabolites remains elusive, not least for the lack of high-resolution structural data and a reliable synthetic route to diverse compound libraries. in response to this, an efficient solid-phase approach has been developed and successfully applied to the total synthesis of Jasplakinolide and chondramide C and diverse analogues. The key macrocylization step was realized using ruthenium-catalyzed ring-closing metathesis (RCM) that in the course of a library synthesis produced discernible trends in metathesis reactivity and E/Z-selectivity, After optimization, the RCM step could be operated under mild conditions, a result that promises to facilitate the synthesis of more extensive analogue libraries for structure-function studies. The growth inhibitory effects of the synthesized compounds were quantified and structure-activity correlations established which appear to be in good alignment with relevant biological data from natural products. in this way a number of potent unnatural and simplified analogues have been found. Furthermore, potentially important stereochemical and structural components of a common pharmacophore have been identified and rationalized using molecular modeling. These data will guide in-depth mode-of-action studies, especially into the relationship between the cytotoxicity of these compounds and their actin-perturbing properties, and should inform the future design of simplified and functionalized actln stabilizers as well.
Total synthesis of chondramide C and its binding mode to F-actin
Waldmann, Herbert,Hu, Tai-Shan,Renner, Steffen,Menninger, Sascha,Tannert, Rene,Oda, Toshiro,Arndt, Hans-Dieter
supporting information; scheme or table, p. 6473 - 6477 (2009/03/11)
(Chemical Equation Presented) Actin glue: An E-selective ring-closing metathesis as the key step allowed the solid-phase-based total synthesis of the F-actin stabilizer chondramide C as well as the establishment of its hitherto unknown stereochemistry. A strong influence of the polyketide configuration was revealed in cellular assays. Docking studies on the F-actin filament structure led to a detailed model of the binding site.
