Anacolosins A-F and Corymbulosins X and Y, Clerodane Diterpenes from Anacolosa clarkii Exhibiting Cytotoxicity toward Pediatric Cancer Cell Lines.
Anacolosins A-F and Corymbulosins X and Y, Clerodane Diterpenes from Anacolosa clarkii Exhibiting Cytotoxicity toward Pediatric Cancer Cell Lines.
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DOI：
10.1021/acs.jnatprod.8b01015
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发表时间：
2019-04-26
影响因子：
5.1
通讯作者：
Cichewicz RH
中科院分区：
文献类型：
--
作者：
Cai S;Risinger AL;Petersen CL;Grkovic T;O'Keefe BR;Mooberry SL;Cichewicz RH
从NCI Natural Products Repository获得了植物Anacolosa clarkii的提取物，并且其对几种类型的儿科实体瘤细胞系显示出细胞毒性活性。生物测定引导的分级分离导致八个新的clerodane二萜[anacolosins A-F（1-6）和伞房菌素X和Y（7和8）]和两个已知的含有异zuelanin骨架的化合物（9和10）的纯化。新的天然产物的结构确定使用1D和2D NMR和HRESIMS数据，而化合物的相对和绝对构型进行了评估，使用1H NMR耦合常数数据，ROESY实验，ECD（电子圆二色性）和VCD（振动圆二色性）光谱，化学方法（包括Mosher和2-naphthacyl酯化），和手性HPLC分析的组合。纯化的天然产物对代表四种儿科癌症类型的细胞系（即，横纹肌肉瘤、尤文肉瘤、髓母细胞瘤和肝母细胞瘤），总生长抑制（TGI）值范围为0.2-4.1 μM。横纹肌肉瘤和髓母细胞瘤细胞系显示出对化合物1-4的更高的敏感性，化合物1-4是报道的第一个含有异泽兰素骨架并在C-6位具有酮羰基的化合物。相比之下，肝母细胞瘤细胞系对7-10（其含有C-6羟基基团部分）适度更敏感。
An extract of the plant Anacolosa clarkii was obtained from the NCI Natural Products Repository, and it showed cytotoxic activity toward several types of pediatric solid tumor cell lines. Bioassay-guided fractionation led to the purification of eight new clerodane diterpenes [anacolosins A–F (1–6) and corymbulosins X and Y (7 and 8)] and two known compounds (9 and 10) that contained an isozuelanin skeleton. The structures of the new natural products were determined using 1D and 2D NMR and HRESIMS data, while the relative and absolute configurations of the compounds were assessed using a combination of 1H NMR coupling constant data, ROESY experiments, ECD (electronic circular dichroism) and VCD (vibrational circular dichroism) spectroscopy, chemical methods (including Mosher and 2-naphthacyl esterification), and chiral HPLC analyses. The purified natural products exhibited a range of cytotoxic activities against cell lines representing four pediatric cancer types (i.e., rhabdomyosarcoma, Ewing sarcoma, medulloblastoma, and hepatoblastoma) with total growth inhibitory (TGI) values in the range 0.2–4.1 μM. The rhabdomyosarcoma and medulloblastoma cell lines showed higher sensitivity to compounds 1–4, which are the first compounds reported to contain an isozuelanin skeleton and feature keto carbonyl groups at the C-6 positions. In contrast, the hepatoblastoma cell line was modestly more sensitive to 7–10, which contained a C-6 hydroxy group moiety.
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