Practical synthesis of the therapeutic leads tigilanol tiglate and its analogues.

Autor: Wender PA; Department of Chemistry, Stanford University, Stanford, CA, USA. wenderp@stanford.edu.; Department of Systems and Chemical Biology, Stanford University, Stanford, CA, USA. wenderp@stanford.edu., Gentry ZO; Department of Chemistry, Stanford University, Stanford, CA, USA., Fanelli DJ; Department of Chemistry, Stanford University, Stanford, CA, USA., Luu-Nguyen QH; Department of Chemistry, Stanford University, Stanford, CA, USA., McAteer OD; Department of Chemistry, Stanford University, Stanford, CA, USA., Njoo E; Department of Chemistry, Stanford University, Stanford, CA, USA.
Jazyk: angličtina
Zdroj: Nature chemistry [Nat Chem] 2022 Dec; Vol. 14 (12), pp. 1421-1426. Date of Electronic Publication: 2022 Oct 03.
DOI: 10.1038/s41557-022-01048-2
Abstrakt: Tigilanol tiglate is a natural product diterpenoid in clinical trials for the treatment of a broad range of cancers. Its unprecedented protein kinase C isoform selectivity make it and its analogues exceptional leads for PKC-related clinical indications, which include human immunodeficiency virus and AIDS eradication, antigen-enhanced cancer immunotherapy, Alzheimer's disease and multiple sclerosis. Currently, the only source of tigilanol tiglate is a rain forest tree, Fontainea picrosperma, whose limited number and restricted distribution (northeastern Australia) has prompted consideration of designed tree plantations to address supply needs. Here we report a practical laboratory synthesis of tigilanol tiglate that proceeds in 12 steps (12% overall yield, >80% average yield per step) and can be used to sustainably supply tigilanol tiglate and its analogues, the latter otherwise inaccessible from the natural source. The success of this synthesis is based on a unique strategy for the installation of an oxidation pattern common to many biologically active tiglianes, daphnanes and their analogues.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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