Total Synthesis, Biological Evaluation, and Target Identification of Rare Abies Sesquiterpenoids

Dexter C. Davis, Dominic G. Hoch, Li Wu, Daniel Abegg, Brandon S. Martin, Zhong-Yin Zhang, Alexander Adibekian, Mingji Dai

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Abiespiroside A (1), beshanzuenone C (2), and beshanzuenone D (3) belong to the Abies sesquiterpenoid family. Beshanzuenones C (2) and D (3) are isolated from the critically endangered Chinese fir tree species Abies beshanzuensis and demonstrated weak inhibiting activity against protein tyrosine phosphatase 1B (PTP1B). We describe herein the first total syntheses of these Abies sesquiterpenoids relying on the sustainable and inexpensive chiral pool molecule (+)-carvone. The syntheses feature a palladium-catalyzed hydrocarbonylative lactonization to install the 6,6-fused bicyclic ring system and a Dreiding-Schmidt reaction to build the oxaspirolactone moiety of these target molecules. Our chemical total syntheses of these Abies sesquiterpenoids have enabled (i) the validation of beshanzuenone C's weak PTP1B inhibiting potency, (ii) identification of new synthetic analogs with promising and selective protein tyrosine phosphatase SHP2 inhibiting potency, and (iii) preparation of azide-tagged probe molecules for target identification via a chemoproteomic approach. The latter has resulted in the identification and evaluation of DNA polymerase epsilon subunit 3 (POLE3) as one of the novel cellular targets of these Abies sesquiterpenoids and their analogs. More importantly, via POLE3 inactivation by probe molecule 29 and knockdown experiment, we further demonstrated that targeting POLE3 with small molecules may be a novel strategy for chemosensitization to DNA damaging drugs such as etoposide in cancer.

Original languageEnglish (US)
Pages (from-to)17465-17473
Number of pages9
JournalJournal of the American Chemical Society
Volume140
Issue number50
DOIs
StatePublished - Dec 19 2018
Externally publishedYes

Fingerprint

Abies
Phosphatases
Molecules
Non-Receptor Type 1 Protein Tyrosine Phosphatase
Proteins
DNA
DNA Polymerase II
Cunninghamia
Protein Tyrosine Phosphatases
Azides
Palladium
Etoposide
Pharmaceutical Preparations
Experiments
Neoplasms

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Total Synthesis, Biological Evaluation, and Target Identification of Rare Abies Sesquiterpenoids. / Davis, Dexter C.; Hoch, Dominic G.; Wu, Li; Abegg, Daniel; Martin, Brandon S.; Zhang, Zhong-Yin; Adibekian, Alexander; Dai, Mingji.

In: Journal of the American Chemical Society, Vol. 140, No. 50, 19.12.2018, p. 17465-17473.

Research output: Contribution to journalArticle

Davis, Dexter C. ; Hoch, Dominic G. ; Wu, Li ; Abegg, Daniel ; Martin, Brandon S. ; Zhang, Zhong-Yin ; Adibekian, Alexander ; Dai, Mingji. / Total Synthesis, Biological Evaluation, and Target Identification of Rare Abies Sesquiterpenoids. In: Journal of the American Chemical Society. 2018 ; Vol. 140, No. 50. pp. 17465-17473.
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