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Component-Based Syntheses of Trioxacarcin A, DC-45-A1, and Structural Analogs

The trioxacarcins are polyoxygenated, structurally complex natural products that potently inhibit the growth of cultured human cancer cells. Here we describe syntheses of trioxacarcin A, DC-45-A1, and structural analogs by latestage, stereoselective glycosylation reactions of fully functionalized, d...

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Detalles Bibliográficos
Autores principales: Magauer, Thomas, Smaltz, Daniel J., Myers, Andrew G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164168/
https://www.ncbi.nlm.nih.gov/pubmed/24056347
http://dx.doi.org/10.1038/nchem.1746
Descripción
Sumario:The trioxacarcins are polyoxygenated, structurally complex natural products that potently inhibit the growth of cultured human cancer cells. Here we describe syntheses of trioxacarcin A, DC-45-A1, and structural analogs by latestage, stereoselective glycosylation reactions of fully functionalized, differentially protected aglycon substrates. Key issues addressed in this work include the identification of an appropriate means to activate and protect each of the two 2-deoxysugar components, trioxacarcinose A and trioxacarcinose B, as well as a viable sequencing of the glycosidic couplings. The convergent, component-based sequence we present allows for rapid construction of structurally diverse, synthetic analogs that would be inaccessible by any other means, in amounts required to support biological evaluation. Analogs arising from modification of four of five modular components are assembled in 11 steps or fewer. The majority of these are found to be active in antiproliferative assays using cultured human cancer cells.