An Improved Route to (+)‐Tedanolide and Analysis of Its Subtle Effects Controlling Conformation and Biological Behaviour

Abstract

The improved synthesis of the antitumor compound (+)-tedanolide is described through an aldol coupling of bis-ketone 7. This modification shortens the synthetic steps in the endgame and provides rapid access to this biologically important natural product. Additionally, it serves as a probe in order to unravel the conformational effects that impede or enable its successful synthesis. Having this way access to des-epoxy-tedanolide, its biological characterization surprisingly unravelled the mode of action to resemble candidaspongiolide rather than deoxytedanolide.

Investigations on the mode of action of gephyronic acid, an inhibitor of eukaryotic protein translation from myxobacteria

“…DARTS results suggest that it possibly binds to eEF2 kinase [ 24 ]. Desepoxy-tedanolide was shown to induce a phosphorylation of eEF2 and of eIF2α, but the primary target is not yet known [ 25 , 26 ].…”

The Synthesis of Desepoxy‐Isotedanolide – A Potential Biosynthetic Precursor of Tedanolide

“…Dissection of the lactone linkage leads to linear fragment 13 , which could be generated from diketo fragment 14 and aldehyde fragment 15 (Scheme ). Diketone 14 , an advanced intermediate of Roush's synthesis of tedanolides with the C(5) ketone installed was synthesized earlier by our group and would be employed in the synthesis of desepoxy‐isotedanolide ( 11 ) 13…”

The Synthesis and Biological Evaluation of Desepoxyisotedanolide and a Comparison with Desepoxytedanolide

“…With 7 , we have already shown that the mode of action resembles that of the candidaspongiolides rather than 13‐deoxytedanolide 12. As seen with candidaspongiolide,4a desepoxytedanolide ( 7 ) induces the phosphorylation of the eukaryotic initiation factor eIF2α and as a consequence the cap‐dependent initiation of translation should be inhibited.…”

“…[12] As seen with candidaspongiolide, [4a] desepoxytedanolide (7)i nduces the phosphorylation of the eukaryotic initiation factor eIF2a and as ac onsequence the cap-dependent initiation of translation should be inhibited.…”

“…With 7,w eh ave already shown that the mode of action resembles that of the candidaspongiolides rather than 13deoxytedanolide. [12] As seen with candidaspongiolide, [4a] desepoxytedanolide (7)i nduces the phosphorylation of the eukaryotic initiation factor eIF2a and as ac onsequence the cap-dependent initiation of translation should be inhibited. To confirm this hypothesis,abicistronic system, which consisted of firefly luciferase translated by ac ap-dependant system and Renilla luciferase translated by acap-independent cricket paralysis virus (CrPV) Internal Ribosome Entry Site (IRES) system, was used.…”