Conformationally Constrained Analogues of Bleomycin A5

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• 作者：Michael J. Rishel ; Craig J. Thomas ; Zhi-Fu Tao ; Corine Vialas ; Christopher J. Leitheiser ; and Sidney M. Hecht
• 刊名：Journal of the American Chemical Society
• 出版年：2003
• 出版时间：August 27, 2003
• 年：2003
• 卷：125
• 期：34
• 页码：10194 - 10205
• 全文大小：287K
• 年卷期：v.125,no.34(August 27, 2003)
• ISSN：1520-5126

文摘

The bleomycin (BLM) group antitumor antibiotics are glycopeptide-derived natural products shownto cause sequence selective lesions in DNA. Prior studies have indicated that the linker region, composedof the methylvalerate and threonine residues, may be responsible for a conformational bend in the agentrequired for efficient DNA cleavage. We have synthesized a number of conformationally constrainedmethylvalerate analogues and incorporated them into deglycobleomycin A₅ congeners using our recentlyreported procedure for the solid phase construction of (deglyco)bleomycin and its analogues. Theseanalogues were designed to probe the effects of conformational constraint of the native valerate moiety.Initial experiments indicated that the constrained molecules, none of which mimic the conformation proposedfor the natural valerate linker, possessed DNA cleavage activity, albeit with potencies less than that of(deglyco)BLM and lacking sequence selectivity. Further experiments demonstrated that these analoguesfailed to produce alkali-labile lesions in DNA or sequence selective oxidative damage in RNA. However,two of the conformationally constrained deglycoBLM analogues were shown to mediate RNA cleavage inthe absence of added Fe²⁺. The ability of the analogues to mediate the oxygenation of small moleculeswas also assayed, and it was shown that they were as competent in the transfer of oxygen to low molecularweight substrates as the parent compound.