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

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.

Emerging chemical scaffolds with potential SHP2 phosphatase inhibitory capabilities – A comprehensive review

“…In continuation to their work on Abies sesquiterpenoids isolated from the critically endangered Chinese fir tree species Abis beshanzuensis, Davis and co-workers (2019) described the synthesis of abiespiroside A (25a), beshanzuenone C (25b) and their analogs (25c-h) including azidetagged chemical probe molecules (25i) to discover novel lead molecules with potential SHP2 inhibitory activity ( Figure 13) (Davis et al, 2018). 25g was found to be more potent amongst all sesquiterpenoid analogs and has been reported as the first covalent inhibitor with selectivity for SHP2.…”

Chemoproteomic Profiling by Cysteine Fluoroalkylation Reveals the DNA Repair Protein XRCC5 as a Functional Target of Myrocin G

“…3,[7][8] Functional cysteines tend to display pronounced hyperreactivity and these reactive cysteine hot spots can be precisely mapped in complex proteomes with cysteine-reactive electrophilic probes. These probes are particularly useful for competitive chemoproteomic profiling of cysteines as targets of natural products, [9][10][11][12][13][14] libraries of covalent fragments, [15][16][17] and electrophilic metabolites. 18 Over the past decade, a broad variety of electrophilic probes for cysteine profiling have been reported.…”

Chemoproteomic Profiling by Cysteine Fluoroalkylation Reveals the DNA Repair Protein XRCC5 as a Functional Target of Myrocin G

“…3,[7][8] Functional cysteines tend to display pronounced hyperreactivity and these reactive cysteine hot spots can be precisely mapped in complex proteomes with cysteine-reactive electrophilic probes. These probes are particularly useful for competitive chemoproteomic profiling of cysteines as targets of natural products, [9][10][11][12][13][14] libraries of covalent fragments, [15][16][17] and electrophilic metabolites. 18 Over the past decade, a broad variety of electrophilic probes for cysteine profiling have been reported.…”