Thailandepsins: Bacterial Products with Potent Histone Deacetylase Inhibitory Activities and Broad-Spectrum Antiproliferative Activities
Thailandepsins: Bacterial Products with Potent Histone Deacetylase Inhibitory Activities and Broad-Spectrum Antiproliferative Activities
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DOI：
10.1021/np200324x
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发表时间：
2011-10-01
影响因子：
5.1
通讯作者：
Cheng, Yi-Qiang
中科院分区：
文献类型：
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作者：
Wang, Cheng;Henkes, Leonhard M.;Cheng, Yi-Qiang
组蛋白去乙酰化酶（HDAC）抑制剂已经作为一类新的抗癌药物出现，其中一种合成化合物SAHA（伏立诺他，Zolinza; 1）和一种天然产物FK 228（缩酚酸肽，罗米地辛，Istodax; 2）被FDA批准用于临床使用。我们对紫色色杆菌968中FK 228生物合成的研究导致在泰国伯克霍尔德氏菌E264基因组中鉴定出一个隐藏的生物合成基因簇。对该基因簇的基因组挖掘和遗传操作进一步导致了两种新产物的发现，thailandepsin A（6）和thailandepsin B（7）。HDAC抑制试验表明，泰国地辛具有与FK 228不同的选择性抑制特征，对人HDAC 1、HDAC 2、HDAC 3、HDAC 6、HDAC 7和HDAC 9的抑制活性与FK 228相当，但对HDAC 4和HDAC 8的抑制活性弱于FK 228，后者可能是有益的。NCI-60抗癌筛选试验表明，thailandepsins具有广谱抗增殖活性，GI（50）超过90%的测试细胞系在低纳摩尔浓度和有效的细胞毒活性对某些类型的细胞系，特别是那些来自结肠癌，黑色素瘤，卵巢癌，肾癌。因此，Thailandepsins代表了新的天然产生的HDAC抑制剂，有希望用于抗癌药物开发。
Histone deacetylase (HDAC) inhibitors have emerged as a new class of anticancer drugs, with one synthetic compound, SAHA (vorinostat, Zolinza; 1), and one natural product, FK228 (depsipeptide, romidepsin, Istodax; 2), approved by FDA for clinical use. Our studies of FK228 biosynthesis in Chromobacterium violaceum no. 968 led to the identification of a cryptic biosynthetic gene cluster in the genome of Burkholderia thailandensis E264. Genome mining and genetic manipulation of this gene cluster further led to the discovery of two new products, thailandepsin A (6) and thailandepsin B (7). HDAC inhibition assays showed that thailandepsins have selective inhibition profiles different from that of FK228, with comparable inhibitory activities to those of FK228 toward human HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, and HDAC9 but weaker inhibitory activities than FK228 toward HDAC4 and HDAC8, the latter of which could be beneficial. NCI-60 anticancer screening assays showed that thailandepsins possess broad-spectrum antiproliferative activities with GI(50) for over 90% of the tested cell lines at low nanomolar concentrations and potent cytotoxic activities toward certain types of cell lines, particularly for those derived from colon, melanoma, ovarian, and renal cancers. Thailandepsins thus represent new naturally produced HDAC inhibitors that are promising for anticancer drug development.