Total Synthesis, Biological Evaluation, and Target Identification of Rare Abies Sesquiterpenoids
Total Synthesis, Biological Evaluation, and Target Identification of Rare Abies Sesquiterpenoids
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DOI：
10.1021/jacs.8b07652
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发表时间：
2018-12-19
影响因子：
15
通讯作者：
Dai, Mingji
中科院分区：
文献类型：
--
作者：
Davis, Dexter C.;Hoch, Dominic G.;Dai, Mingji
Abiespiroside A(1)、Beshanzuenone C(2)和Beshanzuenone D(3)属于冷杉倍半萜类化合物。贝山祖酮C(2)和D(3)是从极度濒危的杉木中分离得到的两个化合物，对蛋白酪氨酸磷酸酶1B(PTP1B)有较弱的抑制活性。在这里，我们描述了这些冷杉倍半萜类化合物的首次全合成，依赖于可持续和廉价的手性池分子(+)-香芹酮。这些合成的特点是钯催化的烷基化内酯反应安装6，6-稠合双环体系，以及德雷丁-施密特反应建立这些目标分子的草内酯部分。我们对这些冷杉倍半萜类化合物的化学全合成使得：(I)验证了贝山祖酮C微弱的PTP1B抑制活性，(Ii)鉴定了具有潜在和选择性蛋白酪氨酸磷酸酶SHP2抑制活性的新的合成类似物，以及(Iii)制备了叠氮标记的探针分子，用于通过化学蛋白质组学方法进行靶标识别。后者导致了DNA聚合酶epsilon亚基3(POLE3)作为这些冷杉倍半萜及其类似物的新的细胞靶标的鉴定和评估。更重要的是，通过探针分子29灭活POLE3和击倒实验，我们进一步证明了以小分子靶向POLE3可能是一种新的肿瘤对DNA损伤药物如依托泊苷的化学增敏策略。
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.