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题名: A designer bleomycin with significantly improved DNA cleavage activity
作者: null(黄胜雄) ; Feng Zhiyang ; Wang Liyan ; Galm Ute ; Wendt-Pienkowski Evelyn ; Yang Dong ; Tao Meifeng ; Coughlin Jane M ; Duan Yanwen ; Shen Ben*
刊名: J. Am. Chem. Soc
英文摘要: The bleomycins (BLMs) are used clinically in combination with a number of other agents for the treatment of several types of tumors, and the BLM, etoposide, and cisplatin treatment regimen cures 90−95% of metastatic testicular cancer patients. BLM-induced pneumonitis is the most feared, doselimiting side effect of BLM in chemotherapy, which can progress into lung fibrosis and affect up to 46% of the total patient population. There have been continued efforts to develop new BLM analogues in the search for anticancer drugs with better clinical efficacy and lower lung toxicity. We have previously cloned and characterized the biosynthetic gene clusters for BLMs from Streptomyces verticillus ATCC15003, tallysomycins from Streptoalloteichus hindustanus E465-94 ATCC31158, and zorbamycin (ZBM) from Streptomyces f lavoviridis SB9001. Comparative analysis of the three biosynthetic machineries provided the molecular basis for the formulation of hypotheses to engineer novel analogues. We now report engineered production of three new analogues, 6′-hydroxy-ZBM, BLM Z, and 6′-deoxy-BLM Z and the evaluation of their DNA cleavage activities as a measurement for their potential anticancer activity. Our findings unveiled: (i) the disaccharide moiety plays an important role in the DNA cleavage activity of BLMs and ZBMs, (ii) the ZBM disaccharide significantly enhances the potency of BLM, and (iii) 6′-deoxy-BLM Z represents the most potent BLM analogue known to date. The fact that 6′-deoxy-BLM Z can be produced in reasonable quantities by microbial fermentation should greatly facilitate follow-up mechanistic and preclinical studies to
potentially advance this analogue into a clinical drug.
出版日期: 2012
期号: 134, 页码:13501-13509
收录类别: SCI
内容类型: 期刊论文
URI标识: http://ir.kib.ac.cn/handle/151853/18016
Appears in Collections:植物化学与西部植物资源持续利用国家重点实验室_期刊论文

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