681830-15-9Relevant academic research and scientific papers
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 syntheses of amphidinolides B1, B4, G1, H1 and structure revision of amphidinolide H2
Fuerstner, Alois,Bouchez, Laure C.,Morency, Louis,Funel, Jaques-Alexis,Liepins, Vilnis,Poree, Francois-Hugues,Gilmour, Ryan,Laurich, Daniel,Beaufils, Florent,Tamiya, Minoru
scheme or table, p. 3983 - 4010 (2009/12/22)
Dinoflagellates of the genus Amphidinium produce a "library" of closely related secondary metabolites of mixed polyketide origin, which are extremely scarce but highly promising owing to the exceptional cytotoxicity against various cancer cell lines. Because of the dense array of sensitive functionalities on their largely conserved macrocyclic frame, however, these amphidinolides of the B, D, G and H types elapsed many previous attempts at their synthesis. Described herein is a robust, convergent and hence general blueprint which allowed not only to conquest five prototype members of these series, but also holds the promise of making "non-natural" analogues available by diverted total synthesis. This notion transpires for a synthesis-driven structure revision of amphidinolide H2. The successful route hinges upon a highly productive Stille-Migita cross-coupling reaction at the congested and chemically labile 1,3-diene site present in all such targets, which required the development of a modified chloride- and fluoride-free protocol. The macrocyclic ring could be formed with high efficiency and selectivity by ring-closing metathesis (RCM) engaging a vinyl epoxide unit as one of the reaction partners. Because of the sensitivity of the targets to oxidizing and reducing conditions as well as to pH changes, the proper adjustment of the protecting group pattern for the peripheral -OH functions also constitutes a critical aspect, which has to converge to silyl groups only once the diene is in place. Tris(dime-thylamino)sulfomum difluorotrimethyl-silicate (TASF) turned out to be a sufficiently mild fluoride source to allow for the final deprotection without damaging the precious macrolides.
