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首页> 外文期刊>The Journal of Antibiotics: An International Journal >Engineered production and evaluation of 6'-deoxy-tallysomycin H-1 revealing new insights into the structure-activity relationship of the anticancer drug bleomycin
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Engineered production and evaluation of 6'-deoxy-tallysomycin H-1 revealing new insights into the structure-activity relationship of the anticancer drug bleomycin

机译：6'-脱氧-Tallysomycin H-1的工程生产和评估揭示了抗癌药物博霉素结构 - 活性关系的新见解

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摘要

The bleomycins (BLMs), a family of glycopeptide antibiotics, are currently used clinically in combination with a number of other agents for the treatment of malignant tumors. Other members of the BLM family include tallysomycins (TLMs), phleomycins and zorbamycin (ZBM). We previously cloned and characterized the biosynthetic gene clusters for BLMs, TLMs and ZBM. Applications of combinatorial biosynthesis strategies to the three biosynthetic machineries enabled the engineered production of several BLM analogs with unique structural characteristics and varying DNA cleavage activities, thereby providing an outstanding opportunity to study the structure-activity relationship (SAR) for the BLM family of anticancer drugs. We now report the engineered production of a new BLM-TLM-ZBM hybrid metabolite, named 6'-deoxy-TLM H-1, which consists of the 22-desmethyl- BLM aglycone, the TLM A C-terminal amine and the ZBM disaccharide, by heterologous expression of the zbmGL genes from the ZBM biosynthetic gene cluster in the Streptoalloteichus hindustanus Delta tlmH mutant strain SB8005. Evaluation of the DNA cleavage activities of 6'-deoxy-TLM H-1 as a measurement for its potential anticancer activity, in comparison with TLM H-1 and BLM A2, reveals new insight into the SAR of BLM family of anticancer drugs.
机译：玻璃肽（BLMS）是一种糖肽抗生素，目前与许多其他药剂组合使用，用于治疗恶性肿瘤。 BLM家族的其他成员包括甲霉素（TLMS），贫霉素和ZOBMYCIN（ZBM）。我们以前克隆并表征了BLMS，TLM和ZBM的生物合成基因簇。组合生物合成策略对三种生物合成机器的应用使得具有独特的结构特征和不同的DNA切割活动的工程化生产，从而提供了研究结构 - 活动关系（SAR）为BLM系列抗癌药物的突出机会提供了杰出的机会。我们现在报告了新的BLM-TLM-ZBM杂交代谢物的工程化生产，名为6'-DEOXY-TLM H-1，其由22-去甲基-BLM糖苷酮，TLM A C末端胺和ZBM二糖组成，通过从ZBM生物合成基因簇中的ZBMGL基因的异源表达在链霉素Hindustancus delta TLMH突变菌株SB8005中。与TLM H-1和BLM A2相比，评价6'-脱氧-TLM H-1作为其潜在抗癌活性的测量的DNA切割活性揭示了对BLM系列抗癌药物SAR的新洞察力。

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    Yang Dong; Hindra; Dong Liao-Bin; Crnovcic Ivana; Shen Ben;

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    Scripps Res Inst Dept Chem 130 Scripps Way 3A1 Jupiter FL 33458 USA;

    Scripps Res Inst Dept Chem 130 Scripps Way 3A1 Jupiter FL 33458 USA;

    Scripps Res Inst Dept Chem 130 Scripps Way 3A1 Jupiter FL 33458 USA;

    Scripps Res Inst Dept Chem 130 Scripps Way 3A1 Jupiter FL 33458 USA;

    Scripps Res Inst Dept Chem 130 Scripps Way 3A1 Jupiter FL 33458 USA;

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  • 正文语种 eng
  • 中图分类 药学;
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