- Synthesis and structure-activity correlation of natural-product inspired cyclodepsipeptides stabilizing F-actin
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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.
- Tannert, Rene,Milroy, Lech-Gustav,Ellinger, Bernhard,Hu, Tai-Shan,Arndt, Hans-Dieter,Waldmann, Herbert
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supporting information; experimental part
p. 3063 - 3077
(2010/05/15)
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- Solid-phase based total synthesis of Jasplakinolide by ring-closing metathesis
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The study of classical ring-closing metathesis and relay ring-closing metathesis in a total synthesis of Jasplakinolide and its desbromo analog is described.
- Tannert, René,Hu, Tai-Shan,Arndt, Hans-Dieter,Waldmann, Herbert
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supporting information; experimental part
p. 1493 - 1495
(2009/09/06)
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- Enantioselective total synthesis of (+)-jasplakinolide
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An enantioselective total synthesis of (+)-jasplakinolide is described. The synthesis of the polyketide template utilized a diastereoselective syn-aldol, ortho-ester Claisen rearrangement followed by efficient conversion to a cyanide. The β-amino acid uni
- Ghosh Deuk Kyu Moon, Arun K.
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p. 2425 - 2427
(2008/02/07)
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- A synthesis of Jaspamide based on 1,2-metallate rearrangements of α-heteroalkenylmetal derivatives
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Jaspamide (Jasplakinolide), a marine cyclodepsipeptide, was synthesised from tripeptide fragment 4 and (2S,4E,6R,8S)-8-benzoyloxy-2,4,6-trimethylnon-4-enoic acid (3). The tripeptide fragment was prepared from β-tyrosine derivative 6, Boc-2-bromoabrine (8)
- Ashworth,Broadbelt,Jankowski,Kocienski,Pimm,Bell
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p. 199 - 206
(2007/10/02)
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- Studies on the Novel Cyclodepsipeptides. A Total Synthesis of (+)-Jasplakinolide (Jaspamide)
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Diastereocontrolled total synthesis of (+)-jasplakinolide (1) has been accomplished via coupling of the tetrapropionate-derived segment (9) with the tripeptide (10) followed by trichlorobenzoyl chloride-mediated macrolactonization.
- Hirai, Yoshiro,Yokota, Katsuyuki,Momose, Takefumi
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p. 603 - 612
(2007/10/02)
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- Studies on cyclodepsipeptides - Part II : The total synthesis of jaspamide and geodiamolide-D
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The total synthesis of cyclodepsipeptides jaspamide and geodiamolide D have been presented.
- Rama Rao,Gurjar, Mukund K.,Nallaganchu, Bhaskara Rao,Bhandari, Ashok
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p. 7085 - 7088
(2007/10/02)
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