Total synthesis of griseusins and elucidation of the griseusin mechanism of action

Yinan Zhang, Qing Ye, Larissa V. Ponomareva, Yanan Cao, Yang Liu, Zheng Cui, Steven G. Van Lanen, S. Randal Voss, Qing Bai She, Jon S. Thorson

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

A divergent modular strategy for the enantioselective total synthesis of 12 naturally-occurring griseusin type pyranonaphthoquinones and 8 structurally-similar analogues is described. Key synthetic highlights include Cu-catalyzed enantioselective boration-hydroxylation and hydroxyl-directed C-H olefination to afford the central pharmacophore followed by epoxidation-cyclization and maturation via diastereoselective reduction and regioselective acetylation. Structural revision of griseusin D and absolute structural assignment of 2a,8a-epoxy-epi-4′-deacetyl griseusin B are also reported. Subsequent mechanistic studies establish, for the first time, griseusins as potent inhibitors of peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3). Biological evaluation, including comparative cancer cell line cytotoxicity and axolotl embryo tail inhibition studies, highlights the potential of griseusins as potent molecular probes and/or early stage leads in cancer and regenerative biology.

Original languageEnglish
Pages (from-to)7641-7648
Number of pages8
JournalChemical Science
Volume10
Issue number32
DOIs
StatePublished - 2019

Bibliographical note

Publisher Copyright:
© 2019 The Royal Society of Chemistry.

ASJC Scopus subject areas

  • General Chemistry

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