Synthesis and Biological Evaluation of the Southern Hemisphere of Spirastrellolide A and Analogues

Abstract

The synthesis and biological evaluation of truncated spirastrellolide A analogues comprised of the southern hemisphere against protein phosphatase 2A are described. A convergent synthesis was designed featuring two gold-catalyzed cyclization reactions, specifically, a dehydrative cyclization of monoallylic diols for the synthesis of the tetrahydropyran (A-ring) and a regioselective spiroketalization for the efficient generation of the [6,6]-spiroketal (B, C-ring system). The synthesis of the southern hemisphere of spirastrellolide A was achieved involving the longest linear sequence of 19 steps. A total of eight spirastrellolide A analogues were synthesized, and preliminary PP2A enzyme assay inhibition studies were performed for the first time on analogues of the southern hemisphere. Several analogues showed inhibition, which is a positive indication and perhaps suggests that the unsaturated spiroketal fragment might be crucial to induce PP2A inhibition.

C-glycosides analogues of the okadaic acid central fragment exert neuroprotection via restoration of PP2A-phosphatase activity: A rational design of potential drugs for Alzheimer's disease targeting tauopathies

“…However, these contributions merely focused on reaching the final polyketide structure and, in scarce examples, probed their PP2A inhibitory action, without realizing that small fragments lacking the C1-C15 moiety might exert an allosteric activation. Recently, Aponick and co-workers described the synthesis of Spirastrellolide A analogues with high structural similarity to OA fragments [82]. Besides the extensive synthetic work, these authors reported maximal PP2A inhibitory activities of several derivatives of about 20% when tested at concentrations as high as 30 μM.…”