Fungal metabolite ophiobolin A as a promising anti-glioma agent: In vivo evaluation, structure-activity relationship and unique pyrrolylation of primary amines.
Fungal metabolite ophiobolin A as a promising anti-glioma agent: In vivo evaluation, structure-activity relationship and unique pyrrolylation of primary amines.
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DOI：
10.1016/j.bmcl.2015.08.066
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发表时间：
2015-10-15
影响因子：
2.7
通讯作者：
Kornienko A
中科院分区：
文献类型：
--
作者：
Dasari R;Masi M;Lisy R;Ferdérin M;English LR;Cimmino A;Mathieu V;Brenner AJ;Kuhn JG;Whitten ST;Evidente A;Kiss R;Kornienko A
胶质母细胞瘤是最常见的恶性原发性脑肿瘤，其特点是对细胞凋亡具有抵抗力，这在很大程度上导致了基于癌细胞细胞凋亡诱导的经典化疗方法的低效性。此前，人们发现真菌次生代谢产物 ophiobolin A 通过诱导非凋亡细胞死亡，对抗凋亡胶质母细胞瘤细胞具有显着活性，从而为对抗此类癌症提供了一种创新策略。目前的工作描述了在体内胶质母细胞瘤模型中初步评估 ophiobolin A 的结果及其化学衍生化，以建立第一个合成生成的结构-活性关系。合成工作还发现了 ophiobolin A 与伯胺的独特反应，表明其细胞内靶蛋白上的赖氨酸残基发生吡咯化的可能性。
Glioblastoma, the most common form of malignant primary brain tumor, is characterized by resistance to apoptosis, which is largely responsible for the low effectiveness of the classical chemotherapeutic approaches based on apoptosis induction in cancer cells. Previously, a fungal secondary metabolite ophiobolin A was found to have significant activity against apoptosis-resistant glioblastoma cells through the induction of a non-apoptotic cell death, thus, offering an innovative strategy to combat this type of cancer. The current work describes the results of a preliminary evaluation of ophiobolin A in an in vivo glioblastoma model and its chemical derivatization to establish first synthetically generated structure-activity relationship. The synthetic work has also led to the discovery of a unique reaction of ophiobolin A with primary amines suggesting the possibility of pyrrolylation of lysine residues on its intracellular target protein(s).