Total Synthesis, Biological Evaluation, and Target Identification of Rare Abies Sesquiterpenoids
| Autor: | Dominic Gregor Hoch, Alexander Adibekian, Li Wu, Brandon S. Martin, Zhong Yin Zhang, Mingji Dai, Daniel Abegg, Dexter C. Davis |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Stereochemistry Antineoplastic Agents Protein Tyrosine Phosphatase Non-Receptor Type 11 Protein tyrosine phosphatase 010402 general chemistry Ring (chemistry) 01 natural sciences Biochemistry Article Catalysis 03 medical and health sciences Colloid and Surface Chemistry Cell Line Tumor Humans Moiety Molecule Enzyme Inhibitors DNA Polymerase III Etoposide Biological evaluation biology Bicyclic molecule Chemistry Abies beshanzuensis Total synthesis Drug Synergism General Chemistry biology.organism_classification 0104 chemical sciences DNA-Binding Proteins Nucleoproteins 030104 developmental biology Cyclization Abies Sesquiterpenes |
| Zdroj: | Journal of the American Chemical Society. 140:17465-17473 |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/jacs.8b07652 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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