Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines
Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines
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DOI：
10.1016/j.ejmech.2015.08.047
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发表时间：
2015-10-20
影响因子：
6.7
通讯作者：
Kornienko, Alexander
中科院分区：
文献类型：
--
作者：
Dasari, Ramesh;De Carvalho, Annelise;Kornienko, Alexander
许多类型的癌症，包括神经胶质瘤、黑素瘤、非小细胞肺癌（NSCLC）等，对促凋亡刺激具有抗性，因此对基于诱导癌细胞凋亡的当前疗法的响应性差。本研究描述了从水辣蓼中分离的一种倍半萜二醛--蓼二醛的独特C12-Wittig衍生物的合成和抗癌评价。德拉布尔发现这些化合物在化学模型系统中与伯胺发生了前所未有的吡咯形成反应，该反应可能与生物环境相关，并导致目标蛋白中赖氨酸残基的吡咯化。这些化合物的抗癌评价揭示了它们对表现出各种形式的耐药性（包括对促凋亡剂的耐药性）的癌细胞的有希望的活性。机制研究表明，与母体polygodial相比，其显示出对人细胞的固定性一般细胞毒性作用，C12-Wittig衍生物主要通过细胞生长抑制作用发挥其抗增殖作用，解释了其对抗肿瘤细胞的活性。通过新的吡咯形成反应对蛋白质进行有趣的共价修饰的可能性，以及对耐药癌细胞的有用活性，使所述的远志醛衍生的化学支架成为一种有趣的新化学类型，需要进行彻底的研究。(C)2015年Elsevier Masson SAS。All rights reserved.
Many types of cancer, including glioma, melanoma, non-small cell lung cancer (NSCLC), among others, are resistant to proapoptotic stimuli and thus poorly responsive to current therapies based on the induction of apoptosis in cancer cells. The current investigation describes the synthesis and anticancer evaluation of unique C12-Wittig derivatives of polygodial, a sesquiterpenoid dialdehyde isolated from Persicaria hydropiper (L.) Delabre. These compounds were found to undergo an unprecedented pyrrole formation with primary amines in a chemical model system, a reaction that could be relevant in the biological environment and lead to the pyrrolation of lysine residues in the target proteins. The anticancer evaluation of these compounds revealed their promising activity against cancer cells displaying various forms of drug resistance, including resistance to proapoptotic agents. Mechanistic studies indicated that compared to the parent polygodial, which displays fixative general cytotoxic action against human cells, the C12-Wittig derivatives exerted their antiproliferative action mainly through cytostatic effects explaining their activity against apoptosis-resistant cancer cells. The possibility for an intriguing covalent modification of proteins through a novel pyrrole formation reaction, as well as useful activities against drug resistant cancer cells, make the described polygodial-derived chemical scaffold an interesting new chemotype warranting thorough investigation. (C) 2015 Elsevier Masson SAS. All rights reserved.