title: Total synthesis and structure-activity relationship study of the potent cAMP signaling agonist (-)-alotaketal A.
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.
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Huang
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Yang
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Jiong
authors.initials: J
authors.lastname: Yang
mesh_terms: D000242:Cyclic AMP / Q000819:agonists* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D054830:Sesterterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D054830:Sesterterpenes; C546269:alotaketal A; D000242:Cyclic AMP