TOTAL SYNTHESIS OF BLEOMYCIN-A(2) AND RELATED AGENTS .3. SYNTHESIS AND COMPARATIVE-EVALUATION OF DEGLYCOBLEOMYCIN-A(2), EPIDEGLYCOBLEOMYCIN-A(2), DEGLYCOBLEOMYCIN-A(1), AND DESACETAMIDODEGLYCOBLEOMYCIN, DESCARBOXAMIDODEGLYCOBLEOMYCIN, DESMETHYLDEGLYCOBLEOMYCIN, AND DESIMIDAZOLYLDEGLYCOBLEOMYCIN-A(2)
TOTAL SYNTHESIS OF BLEOMYCIN-A(2) AND RELATED AGENTS .3. SYNTHESIS AND COMPARATIVE-EVALUATION OF DEGLYCOBLEOMYCIN-A(2), EPIDEGLYCOBLEOMYCIN-A(2), DEGLYCOBLEOMYCIN-A(1), AND DESACETAMIDODEGLYCOBLEOMYCIN, DESCARBOXAMIDODEGLYCOBLEOMYCIN, DESMETHYLDEGLYCOBLEOMYCIN, AND DESIMIDAZOLYLDEGLYCOBLEOMYCIN-A(2)
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DOI：
10.1021/ja00092a013
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发表时间：
1994-06-29
影响因子：
15
通讯作者：
COLLETTI, SL
中科院分区：
文献类型：
--
作者：
BOGER, DL;HONDA, T;COLLETTI, SL
本文提供了两种天然存在的博莱霉素的海藻素，即去糖博莱霉素A(2)(2)和去糖博莱霉素A(1)(3)的全合成完成的全部细节。将研究扩展到制备表皮糖霉素A(2)(4)、去乙酰氨基去糖霉素A(2)(5)、去羧氨基去糖霉素A(2)(6)、去甲基去糖霉素A(2)(7)和去咪唑基去糖霉素A(2)(8)。药物4-8是无法通过天然产物本身的结构修饰获得的，它们构成了关键的亚结构类似物，在金属螯合亚基中包含了深层和机械相关的结构修饰。将研究扩展到GABA， gly -去糖苷博莱霉素A(2)（43）和GABA， gly -去乙酰氨基去糖苷博莱霉素A(2)（45）的制备，证实了在2与4和5的初步比较中检测到的C2乙酰氨基侧链的微妙而重要的作用，并提供了对四肽S骨架取代基的作用的初步评估（43与2,45与5）。对1-8和43,45的Fe（II）或Fe（III）配合物的DNA切割特性进行了比较研究，并评估了四个特性，包括超螺旋Phi X174 DNA的相对DNA切割效率和双链与单链DNA断裂的比率，以及与5'端标记的w794/w836双链DNA的相对DNA切割效率和DNA切割选择性。相对DNA切割研究和双链到单链DNA切割事件的评估结果表明，末端的磺胺盐和嘧啶双链乙酰氨基侧链具有重要的生产作用，C2侧链β -氨基- l -丙氨酸羧胺具有更微妙但可察觉的作用，嘧啶C5甲基没有作用，组氨酸咪唑具有预期的重要作用。同样，在43和45中缺失的四肽S骨干取代基被确定为在不改变DNA结合亲和力或特征DNA切割选择性的情况下显著但不显着降低DNA切割效率。与博莱霉素A(2)金属结合域内的结构变化对DNA相对切割效率的相对影响相反，除了8的重要例外，它们对观察到的DNA切割选择性，5'-GC, 5/-GT > 5'-GA没有明显的影响。同样，去糖博莱霉素A(1)缺乏c端磺酸盐，43和45缺乏所有四肽S主取代基，表现出相同的特征5'-GC, 5'-GT > 5'-GA 1和2的DNA切割选择性，表明它们影响DNA的切割效率而不影响切割选择性。只有8，缺乏必需的咪唑，被发现表现出一种改变的和非选择性的DNA切割模式，可能是通过产生可扩散的氧化剂来产生双工DNA的氧化切割。
Full details of the completion of the total synthesis of deglycobleomyein A(2) (2) and deglycobleomycin A(1) (3), the algycones of two naturally occurring bleomycins, are provided. Extensions of the studies to the preparation of epideglycobleomycin A(2) (4), desacetamidodeglycobleomycin A(2) (5), descarboxamidodeglycobleomycin A(2) (6), desmethyldeglycobleomycin A(2) (7), and desimidazolyldeglycobleomycin A(2) (8) are described. The agents 4-8, which are not accessible through structural modification of the natural products themselves, constitute key substructure analogs incorporating deep-seated and mechanistically relevant structural modifications in the metal chelation subunit. Extensions of the studies to the preparation of GABA,Gly-deglycobleomycin A(2) (43) and GABA,Gly-desacetamidodeglycobleomycin A(2) (45) are detailed in efforts that confirm a subtle and significant role for the C2 acetamido side chain detected in the initial comparisons of 2 with 4 and 5 and additionally provide an initial assessment of the role of the tetrapeptide S backbone substituents (43 versus 2, 45 versus 5). The comparative examination of the DNA cleavage properties of the Fe(II) or Fe(III) complexes of 1-8 and 43, 45 has been conducted, and four properties have been assessed including the relative DNA cleavage efficiency and ratio of double- to single-strand DNA breaks with supercoiled Phi X174 DNA as well as the relative DNA cleavage efficiency and the DNA cleavage selectivity with 5'-end-labeled w794/w836 duplex DNA. The results of the relative DNA cleavage studies and the assessment of double- to single-strand DNA cleavage events demonstrate important, productive roles for the terminal sulfonium salt, and the pyrimidoblamic acid C2 acetamido side chain, a more subtle but perceptible role for the C2 side chain beta-amino-L-alanine carboxamide, no role for the pyrimidine C5 methyl group, and an expected essential role for the histidine imidazole. Similarly, the tetrapeptide S backbone substituents absent in 43 and 45 were determined to substantially but not dramatically diminish DNA cleavage efficiency without altering DNA binding affinity or the characteristic DNA cleavage selectivity. In contrast to the relative impact that the structural changes within the bleomycin A(2) metal binding domain had on the relative DNA cleavage efficiencies and with the important exception of 8, they had no perceptible impact on the observed selectivity of DNA cleavage, 5'-GC, 5/-GT > 5'-GA. Similarly, deglycobleomycin A(1), lacking the C-terminal sulfonium salt, or 43 and 45, lacking all the tetrapeptide S backbone substituents, exhibited the identical and characteristic 5'-GC, 5'-GT > 5'-GA DNA cleavage selectivity of 1 and 2, indicating that they affect DNA cleavage efficiency but not cleavage selectivity. Only 8, lacking the essential imidazole, was found to exhibit an altered and nonselective DNA cleavage pattern presumably derived from oxidative cleavage of duplex DNA via generation of a diffusable oxidant.