Total Synthesis and Target Identification of the Curcusone Diterpenes.

Abstract

The curcusone natural products are complex diterpenes featuring a characteristic [6-7-5] tricyclic carbon skeleton similar to the daphnane and tigliane diterpenes. Among them, curcusones A-D demonstrated potent anticancer activity against a broad spectrum of human cancer cell lines. Prior to this study, no total synthesis of the curcusones was achieved and their anticancer mode of action remained unknown. Herein, we report our synthetic and chemoproteomics studies of the curcusone diterpenes which culminate in the first total synthesis of several curcusone natural products and identification of BRCA1-associated ATM activator 1 (BRAT1) as a cellular target. Our efficient synthesis is highly convergent, builds upon cheap and abundant starting materials, features a thermal [3,3]-sigmatropic rearrangement and a novel FeCl3-promoted cascade reaction to rapidly construct the critical cycloheptadienone core of the curcusones, and led us to complete the first total synthesis of curcusones A and B in only 9 steps, C and D in 10 steps, and dimericursone A in 12 steps. The chemical synthesis of dimericursone A from curcusones C and D provided direct evidence to support the proposed Diels-Alder dimerization and cheletropic elimination biosynthetic pathway. Using an alkyne-tagged probe molecule, BRAT1, an important but previously "undruggable" oncoprotein, was identified as a key cellular target via chemoproteomics. We further demonstrate for the first time that BRAT1 can be inhibited by curcusone D, resulting in impaired DNA damage response, reduced cancer cell migration, potentiated activity of the DNA damaging drug etoposide, and other phenotypes similar to BRAT1 knockdown.

• Authors: Chengsen Cui, Brendan G Dwyer, Chang Liu, Daniel Abegg, Zhong-Jian Cai, Dominic G Hoch, Xianglin Yin, Nan Qiu, Jie-Qing Liu, Alexander Adibekian, Mingji Dai
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 143 Issue 11 Pg. 4379-4386 (03 24 2021) ISSN: 1520-5126 [Electronic] United States
• PMID: 33705657 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• BRAT1 protein, human
• Biological Products
• Diterpenes
• Nuclear Proteins
• curcusone B
• curcusone D

Topics

• Biological Products (chemical synthesis, chemistry)
• Diterpenes (chemical synthesis, chemistry)
• Humans
• Molecular Conformation
• Nuclear Proteins (analysis)
• Stereoisomerism