Wang Fuyi, Xu Jingjing, Habtemariam Abraha, Bella Juraj, Sadler Peter J
School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.
J Am Chem Soc. 2005 Dec 21;127(50):17734-43. doi: 10.1021/ja053387k.
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.
有机金属抗癌配合物[(η6 - 联苯)钌(乙二胺)氯]+（1；联苯 = 联苯，乙二胺 = 乙二胺）选择性地与DNA的鸟嘌呤（N7）碱基结合（诺瓦科娃，O.；陈，H.；弗拉纳，O.；罗杰，A.；萨德勒，P. J.；布拉贝克，V.《生物化学》2003年，42卷，11544 - 11554页）。在这项工作中，使用高效液相色谱、液相色谱 - 质谱和1H、15N核磁共振光谱研究了三肽谷胱甘肽（γ - L - 谷氨酰胺 - L - 半胱氨酸 - 甘氨酸；GSH）和鸟嘌呤（作为鸟苷3'，5' - 环一磷酸，cGMP）与配合物1之间的竞争。在未缓冲的溶液（pH约为3）中，1与GSH的反应在早期阶段（<6小时）产生了三种中间体：一种S结合的硫醇盐加合物[(η6 - 联苯)钌(乙二胺)(GS - S)]（4）和两种羧酸盐结合的谷胱甘肽产物[(η6 - 联苯)钌(乙二胺)(GSH - O)]+（5，6），随后乙二胺被取代并形成三GS桥联的双核Ru(II)配合物[((η6 - 联苯)钌)2(GS - μ - S)3]2 -（7）。在生理相关条件（微摩尔浓度的钌，pH 7，22 mM氯化钠，310 K）下，硫醇盐配合物4意外地容易被氧气氧化为亚磺酸盐配合物[(η6 - 联苯)钌(乙二胺)(GS(O) - S)]（8），而不是形成双核配合物7。在这些条件下，配合物1与GSH和cGMP的竞争反应产生了cGMP加合物[(η6 - 联苯)钌(乙二胺)(cGMP - N7)]+（10）作为主要产物，即使在存在250倍摩尔过量的GSH的情况下，72小时后约占总钌的62%。硫醇盐配合物4中配位谷胱甘肽氧化为8中的亚磺酸盐似乎为G N7取代S结合的谷胱甘肽提供了一条便捷途径。因此，这些Ru(II)芳烃抗癌配合物的半胱氨酸加合物的氧化还原反应可能在其生物活性中起重要作用。
