Competition between glutathione and guanine for a ruthenium(II) arene anticancer complex: detection of a sulfenato intermediate.
Competition between glutathione and guanine for a ruthenium(II) arene anticancer complex: detection of a sulfenato intermediate.
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DOI：
10.1021/ja053387k
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发表时间：
2005-11
影响因子：
15
通讯作者：
Fuyi Wang;Jingjing Xu;A. Habtemariam;J. Bella;P. Sadler
中科院分区：
文献类型：
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作者：
Fuyi Wang;Jingjing Xu;A. Habtemariam;J. Bella;P. Sadler
有机金属抗癌复合物 [(eta6-bip)Ru(en)Cl]+ (1; bip = 联苯，en = 乙二胺) 选择性结合 DNA 的鸟嘌呤 (N7) 碱基 (Novakova, O.; Chen, H.; Vrana, O.; Rodger, A.; Sadler, P. J.; Brabec, V. Biochemistry 2003, 42, 11544-11554）。在这项工作中，使用 HPLC、LC-MS 和 1H,15N NMR 光谱研究了三肽谷胱甘肽（γ-L-Glu-L-Cys-Gly；GSH）和鸟嘌呤（鸟苷 3',5'-环单磷酸，cGMP）之间对复合物 1 的竞争。在无缓冲溶液（pH 约 3）中，1 与 GSH 的反应产生三种中间体：在早期阶段（<6 小时），一种 S 结合的硫醇加合物 [(eta6-bip)Ru(en)(GS-S)] (4) 和两种羧酸结合的谷胱甘肽产物 [(eta6-bip)Ru(en)(GSH-O)]+ (5, 6)，随后发生 en 置换并形成 三-GS-桥联双核Ru(II)络合物[((eta6-bip)Ru)2(GS-mu-S)3]2- (7)。在生理相关条件下（微摩尔 Ru 浓度，pH 7，22 mM NaCl，310 K），硫醇络合物 4 出乎意料地容易被双氧氧化成亚磺络合物 [(eta6-bip)Ru(en)(GS(O)-S)] (8)，而不是形成双核络合物 7。在这些条件下，络合物 1 与 GSH 和 cGMP 的竞争反应产生 cGMP加合物[(eta6-bip)Ru(en)(cGMP-N7)]+ (10)为主要产物，约占10%。 72 小时后，即使存在 250 倍摩尔过量的 GSH，仍占总 Ru 的 62%。硫代复合物 4 中的配位谷胱甘肽氧化为 8 中的次磺酸盐似乎为 G N7 置换 S-结合谷胱甘肽提供了一条简便的途径。因此，这些 Ru(II) 芳烃抗癌复合物的半胱氨酰加合物的氧化还原反应可能在其生物活性中发挥重要作用。
The organometallic anticancer complex [(eta6-bip)Ru(en)Cl]+ (1; bip = biphenyl, en = ethylenediamine) selectively binds to guanine (N7) bases of DNA (Novakova, O.; Chen, H.; Vrana, O.; Rodger, A.; Sadler, P. J.; Brabec, V. Biochemistry 2003, 42, 11544-11554). In this work, competition between the tripeptide glutathione (gamma-L-Glu-L-Cys-Gly; GSH) and guanine (as guanosine 3',5'-cyclic monophosphate, cGMP) for complex 1 was investigated using HPLC, LC-MS and 1H,15N NMR spectroscopy. In unbuffered solution (pH ca. 3), the reaction of 1 with GSH gave rise to three intermediates: an S-bound thiolato adduct [(eta6-bip)Ru(en)(GS-S)] (4) and two carboxylate-bound glutathione products [(eta6-bip)Ru(en)(GSH-O)]+ (5, 6) during the early stages (<6 h), followed by en displacement and formation of a tri-GS-bridged dinuclear Ru(II) complex [((eta6-bip)Ru)2(GS-mu-S)3]2- (7). Under physiologically relevant conditions (micromolar Ru concentrations, pH 7, 22 mM NaCl, 310 K), the thiolato complex 4 was unexpectedly readily oxidized by dioxygen to the sulfenato complex [(eta6-bip)Ru(en)(GS(O)-S)] (8) instead of forming the dinuclear complex 7. Under these conditions, competitive reaction of complex 1 with GSH and cGMP gave rise to the cGMP adduct [(eta6-bip)Ru(en)(cGMP-N7)]+ (10) as the major product, accounting for ca. 62% of total Ru after 72 h, even in the presence of a 250-fold molar excess of GSH. The oxidation of coordinated glutathione in the thiolato complex 4 to the sulfenate in 8 appears to provide a facile route for displacement of S-bound glutathione by G N7. Redox reactions of cysteinyl adducts of these Ru(II) arene anticancer complexes could therefore play a significant role in their biological activity.