Glycosylated derivatives of steffimycin:: Insights into the role of the sugar moieties for the biological activity
Glycosylated derivatives of steffimycin:: Insights into the role of the sugar moieties for the biological activity
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DOI：
10.1002/cbic.200700610
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发表时间：
2008-03-03
期刊：
影响因子：
3.2
通讯作者：
Salas, Jose A.
中科院分区：
文献类型：
--
作者：
Olano, Carlos;Abdelfattah, Mohamed S.;Salas, Jose A.
与指导不同的中性和支链脱氧己糖的生物合成的质粒相结合的Steffimycin基因簇在甜菊糖中的表达导致了在四环核心中具有不同程度的装饰的12种新的糖基化的Steffimycin衍生物的鉴定。这些实验证明了L-鼠李糖基转移酶StfG识别各种D-和L-脱氧己糖的灵活性，其具有不同程度的脱氧，如2-脱氧己糖、2，6-脱氧己糖和2，3，6-脱氧己糖，以及它们与8-去甲氧基-10-脱氧斯替霉素酮的连接。此外，来自链霉菌属的3 '-O-甲基转移酶OleY对连接到斯替菲霉素糖苷配基上的脱氧己糖的甲基化的灵活性通过在斯替菲堡链霉菌中表达oleY而显示，导致3'-O-甲基斯替菲霉素的分离。分析这些化合物对三种人肿瘤细胞系-乳腺癌、非小细胞肺癌和结肠腺癌-的生物活性，发现其中两种，3 ′-O-甲基斯替霉素和D-洋地黄糖基-8-去甲氧基-10-脱氧斯替霉素酮，具有改善的抗肿瘤活性，显示GI（50）值低于1.0 μ M，而steffimycin的GI（50）值在2.61 - 6.79 μ M之间波动，这取决于所用的细胞系。抗肿瘤活性数据提供了新的斯替菲霉素衍生物的结构-活性关系的一些见解，与糖部分的C-3'和C-4'位置以及四环核心的C-8和C-10位置处的羟基构型有关。
Expression of the steffimycin gene cluster in Steptomyces albus in combination with plasmids directing the biosynthesis of different neutral and branched-chain deoxyhexoses led to the identification of twelve new glycosylated derivatives of steffimycin with different degrees of decoration in the tetracyclic core. These experiments demonstrate the flexibility of L-rhamnosyltransferase StfG for recognition of a variety of D- and L-deoxyhexoses, harboring different degrees of deoxygenotion as 2-deoxyhexoses, 2,6-deoxyhexoses, and 2,3,6-deoxyhexoses, and their attachment to 8-demethoxy-10-deoxysteffimycinone. In addition, the flexibility of 3'-O-methyltransferase OleY, from Streptomyces, for the methylation of deoxyhexoses attached to the steffimycin aglycone is shown by expression of oleY in Streptomyces steffisburgensis, leading to the isolation of 3'-O-methylsteffimycin. Analysis of the biological activities of these compounds against three human tumor cell lines-breast adenocarcinoma, non-small cell lung cancer, and colon adenocarcinoma-revealed two of them, 3'-O-methylsteffimycin and D-digitoxosyl-8-demethoxy-10-deoxysteffimycinone, to possess improved antitumor activities, showing Gl(50) values below 1.0 mu M, while steffimycin's Gl(50) values fluctuate between 2.61 to 6.79 mu M depending upon the cell line used. The antitumor activity data provide some insights into the structure-activity relationships of the new steffimycin derivatives, in relation to the configuration of hydroxy groups at positions C-3' and C-4' of the sugar moiety and positions C-8 and C-10 of the tetracyclic core.