Higginsianins A and B, Two Diterpenoid α-Pyrones Produced by Colletotrichum higginsianum, with in Vitro Cytostatic Activity.
Higginsianins A and B, Two Diterpenoid α-Pyrones Produced by Colletotrichum higginsianum, with in Vitro Cytostatic Activity.
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DOI：
10.1021/acs.jnatprod.5b00779
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发表时间：
2016-01-22
影响因子：
5.1
通讯作者：
Evidente A
中科院分区：
文献类型：
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作者：
Cimmino A;Mathieu V;Masi M;Baroncelli R;Boari A;Pescitelli G;Ferderin M;Lisy R;Evidente M;Tuzi A;Zonno MC;Kornienko A;Kiss R;Evidente A
从液体培养条件下生长的真菌Colletotrichum higginsianum的菌丝体中分离得到两个新的二萜类α-吡喃酮化合物，命名为higginsianins A（1）和B（2）。通过NMR、HRESIMS和化学方法分别表征了它们为3-[5 a，9 b-二甲基-7-亚甲基-2-（2-甲基丙烯基）十二氢萘并[2，1-B]呋喃-6-基甲基]-4-羟基-5，6-二甲基吡喃-2-酮和4-羟基-3-[6-羟基-5，8 a-二甲基-2-亚甲基-5-（4-甲基-3-烯基）十氢萘-1-基甲基]-5，6-二甲基吡喃-2-酮。通过X射线衍射分析确定了Higginsianin A（1）的结构和相对构型，通过电子圆二色性（ECD）实验和固体ECD/TDDFT方法计算确定了其绝对构型。用核磁共振分析和电子捕获检测法测定了不适于X射线分析的Higginsianin B（2）的相对和绝对构型，并与Higginsianin A进行了比较。1和2分别是辛二醇A和二萜BR-050的C-8差向异构体。1和2对一组六种癌细胞系的抗增殖活性的评价显示，用报道对促凋亡刺激敏感的细胞获得的IC 50值比它们的抗凋亡对应物低1个数量级以上（1 vs >80 μM）。最后，三个半合成衍生物1制备和抗增殖活性进行了评价。其中两种具有与1相似的IC 50值和微分敏感性曲线。
Two new diterpenoid α-pyrones, named higginsianins A (1) and B (2), were isolated from the mycelium of the fungus Colletotrichum higginsianum grown in liquid culture. They were characterized as 3-[5a,9b-dimethyl-7-methylene-2-(2-methylpropenyl)dodecahydronaphtho[2,1-b]-furan-6-ylmethyl]-4-hydroxy-5,6-dimethylpyran-2-one and 4-hydroxy-3-[6-hydroxy-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-enyl)decahydronaphthalen-1-ylmethyl]-5,6-dimethylpyran-2-one, respectively, by using NMR, HRESIMS, and chemical methods. The structure and relative configuration of higginsianin A (1) were confirmed by X-ray diffractometric analysis, while its absolute configuration was assigned by electronic circular dichroism (ECD) experiments and calculations using a solid-state ECD/TDDFT method. The relative and absolute configuration of higginsianin B (2), which did not afford crystals suitable for X-ray analysis, were determined by NMR analysis and by ECD in comparison with higginsianin A. 1 and 2 were the C-8 epimers of subglutinol A and diterpenoid BR-050, respectively. The evaluation of 1 and 2 for antiproliferative activity against a panel of six cancer cell lines revealed that the IC50 values, obtained with cells reported to be sensitive to proapoptotic stimuli, are by more than 1 order of magnitude lower than their apoptosis-resistant counterparts (1 vs >80 μM). Finally, three hemisynthetic derivatives of 1 were prepared and evaluated for antiproliferative activity. Two of these possessed IC50 values and differential sensitivity profiles similar to those of 1.