Solid-phase synthesis of bleomycin group antibiotics. construction of a 108-member deglycobleomycin library
Solid-phase synthesis of bleomycin group antibiotics. construction of a 108-member deglycobleomycin library
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DOI：
10.1021/ja021388w
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发表时间：
2003-07-09
影响因子：
15
通讯作者：
Hecht, SM
中科院分区：
文献类型：
--
作者：
Leitheiser, CJ;Smith, KL;Hecht, SM
博莱霉素（bleomycin, BLMs）是从轮状链霉菌（Streptomyces verticillus）中分离出来的结构相关的糖肽抗生素，介导DNA和RNA的序列选择性氧化损伤。去糖博莱霉素缺乏碳水化合物部分，它可以像博莱霉素一样切割DNA，尽管效果较差，并且已经成功地用于分析博莱霉素的功能域。虽然对博来霉素和去糖博来霉素的结构修饰已有报道，但尚未发现博来霉素或去糖博来霉素类似物具有增强DNA切割活性的研究。在固体载体上成功合成去糖博莱霉素，使得通过平行固相合成108种独特的去糖博莱霉素类似物成为可能。每一种去糖博莱霉素类似物都能高效合成；经HPLC整合测定，各粗品纯度均大于60%。去糖博莱霉素库的固相合成提供了每一种去糖博莱霉素近毫克至毫克的量，从而允许通过H-1核磁共振和高分辨率质谱进行表征。每个类似物在背景切割上方显示出超螺旋质粒DNA松弛；文库包括两个类似物，介导质粒松弛的程度比亲本去糖博霉素分子更大。
The bleomycins (BLMs) are structurally related glycopeptide antibiotics isolated from Streptomyces verticillus that mediate the sequence-selective oxidative damage of DNA and RNA. Deglycobleomycin, which lacks the carbohydrate moiety, cleaves DNA analogously to bleomycin itself, albeit less potently, and has been used successfully for analyzing the functional domains of bleomycin. Although structural modifications to bleomycin and deglycobleomycin have been reported, no bleomycin or deglycobleomycin analogue having enhanced DNA cleavage activity has yet been described. The successful synthesis of a deglycobleomycin on a solid support has permitted the facile solid-phase synthesis of 108 unique deglycobleomycin analogues through parallel solid-phase synthesis. Each of the deglycobleomycin analogues was synthesized efficiently; the purity of each crude product was greater than 60%, as determined by HPLC integration. The solid-phase synthesis of the deglycobleomycin library provided near-milligram to milligram quantities of each deglycobleomycin, thereby permitting characterization by H-1 NMR and high-resolution mass spectrometry. Each analogue demonstrated supercoiled plasmid DNA relaxation above background cleavage; the library included two analogues that mediated plasmid relaxation to a greater extent than the parent deglycobleomycin molecule.