表硫代二酮哌嗪生物碱的合成及其抗癌活性
Synthesis and Anticancer Activity of Epipolythiodiketopiperazine Alkaloids.
作者信息
Boyer Nicolas, Morrison Karen C, Kim Justin, Hergenrother Paul J, Movassaghi Mohammad
机构信息
Massachusetts Institute of Technology, Department of Chemistry, Cambridge, Massachusetts 02139, USA.
出版信息
Chem Sci. 2013 Apr 1;4(4):1646-1657. doi: 10.1039/C3SC50174D.
Abstract
The epipolythiodiketopiperazine (ETP) alkaloids are a highly complex class of natural products with potent anticancer activity. Herein, we report the application of a flexible and scalable synthesis, allowing the construction of dozens of ETP derivatives. The evaluation of these compounds against cancer cell lines in culture allows for the first expansive structure-activity relationship (SAR) to be defined for monomeric and dimeric ETP-containing natural products and their synthetic cognates. Many ETP derivatives demonstrate potent anticancer activity across a broad range of cancer cell lines, and kill cancer cellsviainduction of apoptosis. Several traits thatbode well for the translational potential of the ETP class of natural products includeconcise and efficient synthetic access, potent induction of apoptotic cell death, activity against a wide range of cancer types, and a broad tolerance for modifications at multiple sitesthat should facilitate small-molecule drug development, mechanistic studies, and evaluation .
摘要
表硫代二酮哌嗪（ETP）生物碱是一类具有强大抗癌活性的高度复杂的天然产物。在此，我们报道了一种灵活且可扩展的合成方法的应用，该方法能够构建数十种ETP衍生物。对这些化合物在培养的癌细胞系中的评估，使得首次能够为含单体和二聚体ETP的天然产物及其合成类似物定义广泛的构效关系（SAR）。许多ETP衍生物在广泛的癌细胞系中均表现出强大的抗癌活性，并通过诱导凋亡来杀死癌细胞。对ETP类天然产物的转化潜力来说预示良好的几个特性包括简洁高效的合成途径、对凋亡性细胞死亡的有效诱导、对多种癌症类型的活性以及对多个位点修饰的广泛耐受性，这应有助于小分子药物开发、机理研究和评估。
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本文引用的文献
1
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Chem Biol Drug Des. 2013 Jan;81(1):113-21. doi: 10.1111/cbdd.12085.
2
The promise of antibody-drug conjugates.抗体药物偶联物的前景。
N Engl J Med. 2012 Nov 8;367(19):1847-8. doi: 10.1056/NEJMe1211736.
3
Concise Total Synthesis of (+)-Gliocladins B and C.(+)-Gliocladins B和C的简洁全合成
Chem Sci. 2012 Jan 1;3(6):1798-1803. doi: 10.1039/C2SC20270K. Epub 2012 Mar 30.
4
Cytotoxic metabolites from the antarctic psychrophilic fungus Oidiodendron truncatum.南极嗜冷真菌 Oidiodendron truncatum 的细胞毒性代谢产物。
J Nat Prod. 2012 May 25;75(5):920-7. doi: 10.1021/np3000443. Epub 2012 May 14.
5
Inhibition of histone H3K9 methyltransferases by gliotoxin and related epipolythiodioxopiperazines.Gliotoxin及相关环硫二酮哌嗪对组蛋白H3K9甲基转移酶的抑制作用。
J Antibiot (Tokyo). 2012 May;65(5):263-5. doi: 10.1038/ja.2012.6. Epub 2012 Feb 15.
6
The anticancer effects of chaetocin are independent of programmed cell death and hypoxia, and are associated with inhibition of endothelial cell proliferation.沙烯菌素的抗癌作用不依赖于程序性细胞死亡和缺氧，而是与抑制内皮细胞增殖有关。
Br J Cancer. 2012 Jan 17;106(2):314-23. doi: 10.1038/bjc.2011.522. Epub 2011 Dec 20.
7
Thiolation of symmetrical and unsymmetrical diketopiperazines.二酮哌嗪的硫醇化反应。（对称和不对称二酮哌嗪的硫醇化反应。）
Org Biomol Chem. 2012 Feb 7;10(5):935-40. doi: 10.1039/c2ob06663g. Epub 2011 Dec 20.
8
Disulfide- and multisulfide-containing metabolites from marine organisms.来自海洋生物的含二硫键和多硫键的代谢产物。
Chem Rev. 2012 Apr 11;112(4):2179-207. doi: 10.1021/cr200173z. Epub 2011 Dec 16.
9
A practical sulfenylation of 2,5-diketopiperazines.2,5-二酮哌嗪的实用亚磺酰化反应。
Angew Chem Int Ed Engl. 2012 Jan 16;51(3):728-32. doi: 10.1002/anie.201107623. Epub 2011 Dec 7.
10
Enantioselective total synthesis of (-)-acetylaranotin, a dihydrooxepine epidithiodiketopiperazine.（-）-乙酰阿罗他汀的对映选择性全合成，一种二氢氧杂环庚二酮硫代二肽。
J Am Chem Soc. 2012 Feb 1;134(4):1930-3. doi: 10.1021/ja209354e. Epub 2011 Oct 28.
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