title: A designer bleomycin with significantly improved DNA cleavage activity.
abstract: 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, dose-limiting 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 flavoviridis 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.
authors: Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors: Sheng-Xiong
authors: SX
authors: Huang
authors: Zhiyang
authors: Z
authors: Feng
authors: Liyan
authors: L
authors: Wang
authors: Ute
authors: U
authors: Galm
authors: Evelyn
authors: E
authors: Wendt-Pienkowski
authors: Dong
authors: D
authors: Yang
authors: Meifeng
authors: M
authors: Tao
authors: Jane M
authors: JM
authors: Coughlin
authors: Yanwen
authors: Y
authors: Duan
authors: Ben
authors: B
authors: Shen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001761:Bleomycin / Q000737:chemistry* / Q000494:pharmacology; D053837:DNA Cleavage / Q000187:drug effects*; D006020:Glycopeptides / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000235:genetics; D013302:Streptomyces / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D006020:Glycopeptides; D011994:Recombinant Proteins; D001761:Bleomycin; C003787:zorbamycin