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Total Synthesis, Biological Evaluation, and Target Identification of Rare Abies Sesquiterpenoids
- Dexter C. DavisDexter C. DavisDepartment of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Dexter C. Davis
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- Dominic G. HochDominic G. HochDepartment of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United StatesMore by Dominic G. Hoch
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- Li WuLi WuDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Li Wu
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- Daniel AbeggDaniel AbeggDepartment of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United StatesMore by Daniel Abegg
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- Brandon S. MartinBrandon S. MartinDepartment of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Brandon S. Martin
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- Zhong-Yin Zhang*Zhong-Yin Zhang*[email protected]Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United StatesDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Zhong-Yin Zhang
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- Alexander Adibekian*Alexander Adibekian*[email protected]Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United StatesMore by Alexander Adibekian
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- Mingji Dai*Mingji Dai*[email protected]Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Mingji Dai
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.
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