Total Synthesis and Target Identification of the Curcusone Diterpenes.
Total Synthesis and Target Identification of the Curcusone Diterpenes.
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DOI：
10.1021/jacs.1c00557
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发表时间：
2021-03-24
影响因子：
15
通讯作者：
Dai M
中科院分区：
文献类型：
--
作者：
Cui C;Dwyer BG;Liu C;Abegg D;Cai ZJ;Hoch DG;Yin X;Qiu N;Liu JQ;Adibekian A;Dai M
curcusone天然产物是具有类似于daphnane和tigliane二萜的特征[6-7-5]三环碳骨架的复合二萜。其中，莪术酮a - d对多种人类癌细胞具有较强的抗肿瘤活性。在这项研究之前，没有完全合成的库库酮被实现和他们的抗癌作用模式仍然未知。在此，我们报告了我们对莪术酮二萜的合成和化学蛋白质组学研究，最终首次合成了几种莪术酮天然产物，并鉴定了brca1相关的ATM激活因子1 （BRAT1）作为细胞靶点。我们的高效合成具有高度收敛性，以廉价和丰富的起始材料为基础，采用热[3,3]-信号重排和新颖的fecl3 -促进级联反应快速构建弯库酮的关键环七烯酮核心，并使我们完成了首个弯库酮a和B的全合成仅需9步，C和D仅需10步，二聚库酮a仅需12步。从莪术酮C和D化学合成二聚脲A为Diels-Alder二聚化和亲电消除生物合成途径提供了直接证据。使用炔标记的探针分子，BRAT1，一个重要的但以前“不可药物”的癌蛋白，通过化学蛋白质组学被确定为关键的细胞靶标。我们首次进一步证明，curcusone D可以抑制BRAT1，导致DNA损伤反应受损，癌细胞迁移减少，DNA损伤药物etoposide活性增强，以及其他类似BRAT1敲低的表型。
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 that 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.
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影响因子：
15
作者：
Davis, Dexter C.;Hoch, Dominic G.;Dai, Mingji
通讯作者：
Dai, Mingji
影响因子：
1.8
作者：
NAENGCHOMNONG, W;THEBTARANONTH, Y;CLARDY, J
通讯作者：
CLARDY, J
影响因子：
16.6
作者：
Nicolaou, K. C.
通讯作者：
Nicolaou, K. C.
影响因子：
13.5
作者：
Chen, Chian-Feng;Hsu, En-Chi;Jou, Yuh-Shan
通讯作者：
Jou, Yuh-Shan
Dimericursones A 和 B：来自麻风树根皮的两种前所未有的六环二聚二萜类化合物。
影响因子：
3.2
作者：
Liu, Jie-Qing;Xu, Ying;Wang, Cui-Fang
通讯作者：
Wang, Cui-Fang