Chen Jon K, Yang Dong, Shen Ben, Neilan Brett A, Murray Vincent
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Bioorg Med Chem. 2016 Nov 15;24(22):6094-6101. doi: 10.1016/j.bmc.2016.09.072. Epub 2016 Sep 30.
Bleomycin (BLM) is used clinically in combination with a number of other agents for the treatment of several types of tumours. Members of the BLM family of drugs include zorbamycin (ZBM), phleomycin D1, BLM A2 and BLM B2. By manipulating the BLM biosynthetic machinery, we have produced two new BLM analogues, BLM Z and 6'-deoxy-BLM Z, with the latter exhibiting significantly improved DNA cleavage activity. Here we determined the DNA sequence specificity of BLM Z, 6'-deoxy-BLM Z and ZBM, in comparison with BLM, with high precision using purified plasmid DNA and our recently developed technique. It was found that ZBM had a different DNA sequence specificity compared with BLM and the BLM analogues. While BLM and the BLM analogues showed a similar DNA sequence specificity, with TGTA sequences as the main site of cleavage, ZBM exhibited a distinct DNA sequence specificity, with both TGTA and TGTG as the predominant cleavage sites. These differences in DNA sequence specificity are discussed in relation to the structures of ZBM, BLM and the BLM analogues. Our findings support the strategy of manipulating the BLM biosynthetic machinery for the production of novel BLM analogues, difficult to prepare by total synthesis; some of which could have beneficial cancer chemotherapeutic properties.
博来霉素（BLM）在临床上与多种其他药物联合使用，用于治疗多种类型的肿瘤。博来霉素类药物成员包括佐尔巴霉素（ZBM）、争光霉素D1、博来霉素A2和博来霉素B2。通过操纵博来霉素生物合成机制，我们制备了两种新的博来霉素类似物，即博来霉素Z和6'-脱氧博来霉素Z，后者表现出显著提高的DNA切割活性。在此，我们使用纯化的质粒DNA和我们最近开发的技术，高精度地测定了博来霉素Z、6'-脱氧博来霉素Z和佐尔巴霉素与博来霉素相比的DNA序列特异性。结果发现，与博来霉素和博来霉素类似物相比，佐尔巴霉素具有不同的DNA序列特异性。虽然博来霉素和博来霉素类似物表现出相似的DNA序列特异性，以TGTA序列作为主要切割位点，但佐尔巴霉素表现出独特的DNA序列特异性，以TGTA和TGTG作为主要切割位点。结合佐尔巴霉素、博来霉素和博来霉素类似物的结构，讨论了这些DNA序列特异性的差异。我们的研究结果支持通过操纵博来霉素生物合成机制来生产新型博来霉素类似物的策略，这些类似物难以通过全合成制备；其中一些可能具有有益的癌症化疗特性。
