The carmaphycins: new proteasome inhibitors exhibiting an α,β-epoxyketone warhead from a marine cyanobacterium.
The carmaphycins: new proteasome inhibitors exhibiting an α,β-epoxyketone warhead from a marine cyanobacterium.
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DOI：
10.1002/cbic.201200007
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发表时间：
2012-04-16
期刊：
影响因子：
3.2
通讯作者：
Gerwick, William H.
中科院分区：
文献类型：
--
作者：
Pereira, Alban R.;Kale, Andrew J.;Fenley, Andrew T.;Byrum, Tara;Debonsi, Hosana M.;Gilson, Michael K.;Valeriote, Frederick A.;Moore, Bradley S.;Gerwick, William H.
两个新的肽类蛋白酶体抑制剂被分离为微量成分从库拉索收集Symploca属海洋蓝藻。卡马菲辛A（1）和卡马菲辛B（2）的特征是亮氨酸衍生的α，β -环氧酮弹头直接连接到甲硫氨酸亚砜或甲硫氨酸砜上。通过NMR/MS分析和全合成确证了化合物的结构，为进一步的生物活性评价提供了材料。发现纯的卡马霉素A和B抑制S.酿酒酵母20 S蛋白酶体在低纳摩尔范围内。此外，它们对肺癌和结肠癌细胞系表现出强烈的细胞毒性，以及在NCI 60细胞系组中的精致抗增殖作用。这些测定结果以及初步结构生物学研究表明，这些新抑制剂具有独特的结合模式。
Two new peptidic proteasome inhibitors were isolated as trace components from a Curaçao collection of Symploca sp. marine cyanobacteria. Carmaphycin A (1) and carmaphycin B (2) feature a leucine-derived α, β -epoxyketone warhead directly connected to either methionine sulfoxide or methionine sulfone. Their structures were elucidated on the basis of extensive NMR/MS analyses and confirmed by total synthesis, which in turn provided more material for further biological evaluations. Pure carmaphycins A and B were found to inhibit the β5 subunit (chymotrypsin-like activity) of the S. cerevisiae 20S proteasome in the low nanomolar range. Additionally, they exhibited strong cytotoxicity to lung and colon cancer cell lines, as well as exquisite antiproliferative effects in the NCI60 cell line panel. These assay results as well as initial structural biology studies suggest a distinctive binding mode for these new inhibitors.
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