Ferric bleomycin catalyzed reduction of 10-hydroperoxy-8,12-octadecadienoic acid: evidence for homolytic O-O bond scission.
Ferric bleomycin catalyzed reduction of 10-hydroperoxy-8,12-octadecadienoic acid: evidence for homolytic O-O bond scission.
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博莱霉素铁催化 10-氢过氧-8,12-十八碳二烯酸还原：均裂 O-O 键断裂的证据。
DOI：
10.1021/bi00420a039
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发表时间：
1988
期刊：
影响因子：
2.9
通讯作者：
Marnett,LJ
中科院分区：
文献类型：
--
作者：
Padbury,G;Sligar,SG;Labeque,R;Marnett,LJ
密歇根州底特律韦恩州立大学化学系，48202收到1988年4月22日；修订稿件收到1988年6月17日摘要：10-羟基-8，12-十八碳二烯酸(1)在水溶液和甲醇溶液中被博莱霉素铁还原得到10-氧代-8-癸烯酸(2)作为主要产物(80%-90%)。还检测到了微量的10-氧代-8，12-十八碳二烯酸(3)(5-10%)和10-羟基-8，12-十八碳二烯酸(4)(5-10%)。在有或无还原底物苯酚的情况下，在pH 6.5-8.5范围内，在30-S孵育1h内，在一系列铁药物浓度范围内，还原产物比率保持相对恒定。在苯酚存在下，博莱霉素铁和1，2‘-二苯酚反应生成2，2’-联苯酚和4，4‘-联苯酚作为氧化产物。在用药物的生物底物DNA取代苯酚的反应中，发现1支持博莱霉素铁介导的DNA降解。从这些分析中还发现，2是氧化剂的主要还原产物，存在微量的3和4。对照实验表明，该反应依赖于1和博莱霉素铁。还原产物2和3以前已被证明来自过氧基0-0键均解形成的瞬时烷氧基。产物4为过氧基0-0键的异解产物[Labeque，R.，&Marnett，L.J.(1987)J.Am化学。SoC。109,2828-2829]，研究结果表明，博莱霉素铁几乎只催化1的0-0键的均质裂解，同时支持各种氧化反应。博莱霉素是一类独特的具有抗肿瘤活性的低分子糖肽抗生素家族(Sikic等人，1985年)。这些抗肿瘤药物的疗效被认为与它们降解DNA的能力有关，在这个过程中，亚铁离子的螯合和分子氧的还原激活发挥了重要的机制作用(Burger等人，1986；Ajmera等人，1986；Rabow等人，1986；Sugiyama等人，1985；Wu等人，1985a，b)。
Department of Chemistry, Wayne State University, Detroit, Michigan 48202 Received April 22, 1988; Revised Manuscript Received June 17, 1988 abstract: 10-Hydroperoxy-8, 12-octadecadienoic acid (1) is reduced by ferric bleomycin in aqueous and methanol solutions to yield 10-oxo-8-decenoic acid (2) as the major product (80-90%). Trace amounts of 10-oxo-8, 12-octadecadienoic acid (3)(5-10%) and 10-hydroxy-8, 12-octadecadienoic acid (4)(5-10%) were also detected. The reduction product ratios remained relatively constant in the presence or absence of the reducing substrate phenol, over the pH range 6.5-8.5, in incubationsfrom 30 s to 1 h, and over a series of ferric drug concentrations. In the presence of phenol, incubations of ferric bleomycin and 1 yielded2, 2'-biphenol and 4, 4'-biphenol as oxidation products. In reactions where phenol was replaced with the drug’s biological substrate DNA, 1 was found to support ferric bleomycin mediated DNA degradation. Extracts from these assays also found 2 to be the major reduction product derived from the oxidant, with trace quantities of 3 and 4 present. Control experiments demonstrated the reactionsto be dependent on both 1 and ferric bleomycin. The reductionproducts 2 and 3 have previously been shown to originate from transient alkoxyl radicals formed by homolysis of the peroxy 0-0 bond. Product 4 results from heterolysis of the peroxy 0-0 bond [Labeque, R., & Marnett, L. J.(1987) J. Am. Chem. Soc. 109, 2828-2829], The results of this investigation indicate that ferric bleomycin catalyzes the homolytic cleavage of the 0-0 bond of1 almost exclusively while supporting various oxidative reactions. e bleomycins constitute a unique family of low molecular weight glycopeptide antibiotics with demonstrated antitumor activity (Sikic et al., 1985). The therapeutic efficacy of these antineoplastic agents is presumed to be related to their ability to degrade DNA, a process for whichferrous iron chelation and reductiveactivation of molecular dioxygen play an important mechanistic role (Burger et al., 1986; Ajmera et al., 1986; Rabow et al., 1986; Sugiyama et al., 1985; Wu et al., 1985a, b).