Metabolic inactivation of the antitumor antibiotic bleomycin is believed to be mediated exclusively via the action of bleomycin hydrolase, a cysteine proteinase that is widely distributed in nature. While the spectrum of antitumor activity exhibited by the bleomycins is believed to reflect the anatomical distribution of bleomycin hydrolase within the host, little has been done to characterize the product of the putative inactivation at a chemical or biochemical level. The present report describes the synthesis of deamidobleomycin demethyl A(2) (3) and deamido bleomycin A(2) (4), as well as the respective aglycones. These compounds were all accessible via the key intermediate N(alpha)-Boc-N(beta)-[1-amino-3(S)-(4-amino-6-carboxy-5-methylpyrimidin-2-yl)propion-3-yl]-(S)-beta-aminoalanine tert-butyl ester (16). Synthetic deamido bleomycin A(2) was shown to be identical to the product formed by treatment of bleomycin A(2) with human bleomycin hydrolase, as judged by reversed-phase HPLC analysis and (1)H NMR spectroscopy. Deamido bleomycin A(2) was found to retain significant DNA cleavage activity in DNA plasmid relaxation assays and had the same sequence selectivity of DNA cleavage as bleomycin A(2). The most significant alteration of function noted in this study was a reduction in the ability of deamido bleomycin A(2) to mediate double-strand DNA cleavage, relative to that produced by BLM A(2).

中文翻译：

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Deamido Bleomycin A2 的全合成，抗肿瘤剂博来霉素的主要分解物

抗肿瘤抗生素博来霉素的代谢失活被认为仅通过博来霉素水解酶的作用介导，博来霉素水解酶是一种在自然界中广泛分布的半胱氨酸蛋白酶。虽然博来霉素表现出的抗肿瘤活性谱被认为反映了博来霉素水解酶在宿主体内的解剖分布，但很少有人在化学或生化水平上表征推定失活的产物。本报告描述了 deamidobleomycin demethyl A(2) (3) 和 deamido bleomycin A(2) (4) 的合成，以及各自的苷元。这些化合物都可以通过关键中间体 N(alpha)-Boc-N(beta)-[1-amino-3(S)-(4-amino-6-carboxy-5-methylpyrimidin-2-yl)propion- 3-基]-(S)-β-氨基丙氨酸叔丁酯(16)。合成 deamido 博来霉素 A(2) 显示与博来霉素 A(2) 与人博来霉素水解酶处理形成的产品相同，如反相 HPLC 分析和 (1) H 核磁共振光谱所判断。发现脱酰胺博来霉素 A(2) 在 DNA 质粒松弛试验中保留显着的 DNA 裂解活性，并且与博来霉素 A(2) 具有相同的 DNA 裂解序列选择性。本研究中最显着的功能改变是脱酰胺博来霉素 A(2) 介导双链 DNA 切割的能力降低，相对于 BLM A(2) 产生的。发现脱酰胺博来霉素 A(2) 在 DNA 质粒松弛试验中保留显着的 DNA 裂解活性，并且与博来霉素 A(2) 具有相同的 DNA 裂解序列选择性。本研究中最显着的功能改变是脱酰胺博来霉素 A(2) 介导双链 DNA 切割的能力降低，相对于 BLM A(2) 产生的。发现脱酰胺博来霉素 A(2) 在 DNA 质粒松弛试验中保留显着的 DNA 裂解活性，并且与博来霉素 A(2) 具有相同的 DNA 裂解序列选择性。本研究中最显着的功能改变是脱酰胺博来霉素 A(2) 介导双链 DNA 切割的能力降低，相对于 BLM A(2) 产生的。