Total synthesis and structure-activity relationship study of the potent cAMP signaling agonist (-)-alotaketal A

Jinhua Huang, Jessica R. Yang, Jin Zhang, Jiong Yang

Research output: Contribution to journalArticle

Abstract

A detailed account of the first total synthesis of alotaketal A, a tricyclic spiroketal sesterterpenoid that potently activates the cAMP signaling pathway, is provided. The synthesis employs both intra- and intermolecular reductive allylation of esters for assembling one of the fragments and their coupling. A Hg(OAc)2-mediated allylic mercuration is used to introduce the C22-hydroxyl group. The subtle influence of substituents over the course of the spiroketalization process is revealed. The synthesis confirms the relative and absolute stereochemistry of (-)-alotaketal A and allows verification of alotaketal A's effect over cAMP signaling using reporter-based FRET imaging assays with HEK 293T cells. Our studies also revealed alotaketal A's unique activity in selectively targeting nuclear PKA signaling in living cells.

Original languageEnglish (US)
Pages (from-to)3212-3222
Number of pages11
JournalOrganic and Biomolecular Chemistry
Volume11
Issue number19
DOIs
StatePublished - 2013
Externally publishedYes

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Biochemistry

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