Component-based syntheses of trioxacarcin A, DC-45-A1 and structural analogues.
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 analogues by late-stage 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 analogues that would be inaccessible by any other means, in amounts required to support biological evaluation. Analogues that arise from the 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.
1] Harvard Department of Chemistry and Chemical Biology, 12 Oxford Street, Cambridge, Massachusetts 02138, USA [2].
Thomas
T
Magauer
Daniel J
DJ
Smaltz
Andrew G
AG
Myers
D000617:Aminoglycosides / Q000138:chemical synthesis* / Q000737:chemistry*; D001688:Biological Products / Q000138:chemical synthesis; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry; D006031:Glycosylation; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism
D000617:Aminoglycosides; D001688:Biological Products; C584358:DC-45-A1 compound; D006027:Glycosides; C033790:trioxacarcin