Synthesis and reactivity of the aquation product of the antitumor complex trans-[RuIIICl4(indazole)2]-
Synthesis and reactivity of the aquation product of the antitumor complex trans-[RuIIICl4(indazole)2]-
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DOI：
10.1021/ic800506g
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发表时间：
2008-07-21
影响因子：
4.6
通讯作者：
Keppler, Bernhard K.
中科院分区：
文献类型：
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作者：
Cebrian-Losantos, Berta;Reisner, Erwin;Keppler, Bernhard K.
d 研究抗癌药物反式-[(RuCl4)-Cl-III(Hind)(2)](-) (1, KP1019) 的水化导致形成mer,反式-[(RuCl3)-Cl-III(Hind)(2)(H2O)] (2)，并以高产率 (85%) 分离并表征。通过光谱方法和X射线晶体学。 2 在丙酮中溶解，导致其二聚成 [Ru-2(III)(mu-Cl)(2)Cl-4(Hind)(4)]中心点 2(Me)(2)CO (3)，产率 79%，并释放出两个水分子。配合物 2 在室温下通过替换水配体而容易地与亲核有机分子（即甲醇或二甲硫醚）反应，生成 mer,trans[(RuCl3)-Cl-III(Hind)(2)(MeOH)] (4) 和 mer,trans-[(RuCl3)-Cl-III(Hind)(2)(Me2S)] (5)，产率分别为 58% 和 64%。通过 2 在室温下与 DMSO 或在高温下与二甲硫醚反应，分别以 64% 和 75% 的收率制备反式，反式，反式[(RuCl2)-Cl-III(Hind)(2)(Me2S)(2)] (6) 和反式，反式，反式-[(RuCl2)-Cl-II(Hind)(2)(S-DMSO)(2)] (7)。乙腈或苯甲腈产生 mer,trans-[(RuCl3)-Cl-III(Hind)(HN=C(Me)ind)] (8a)、mer,trans-[(RuCl3)-Cl-III(Hind)(HN=C(Ph)ind)] (8b) 和 trans,trans-[(RuCl2)-Cl-III(HN=C(Me)ind)(2)]Cl (9) 在金属辅助的吲唑亚氨基酰化反应中，产率分别为 67%、50% 和 23%，这对于钌(III) 来说是前所未有的。此外，复合物 2 与 DNA 模型碱基 9-甲基腺嘌呤 (9-meade) 和 N6,N6-二甲基腺嘌呤 (6-me(2)ade) 反应生成 mer,trans-[(RuCl3)-Cl-III(Hind)(2)(9-meade)] (10) 和 mer,trans-[(RuCl3)-Cl-III(Hind)(2)(6-me(2)ade)] (11) 嘌呤碱基分别通过 N7 和 N3 与 Ru(III) 中心结合。络合物 11 代表第一个钌络合物，其中嘌呤配体 N6,N6-二甲基腺嘌呤通过 N3 发生配位。此外，聚合物[Na(EtOAc)(2)Ru-III(mu-Cl)(4)(Hind)(2)](n)(12)从Na[反式-(RuCl4)-Cl-III(Hind)(2)]中心点1.5H(2)O(1a)的乙酸乙酯/乙醚溶液中结晶。所报道的配合物通过元素分析、红外和紫外-可见光谱、ESI 质谱、循环伏安法和 X 射线晶体学进行了表征。电化学研究深入了解了配合物 2 的溶剂分解行为的机制细节。2 中水配体的不稳定性表明该配合物是一种潜在的活性物质，负责反式-[(RuCl4)-Cl-III(Hind)(2)](-) 的高抗肿瘤活性。
d Aquation of the investigational anticancer drug trans-[(RuCl4)-Cl-III(Hind)(2)](-) (1, KP1019) results in the formation of mer,trans-[(RuCl3)-Cl-III(Hind)(2)(H2O)] (2), which was isolated in high yield (85%) and characterized. by spectroscopic methods and X-ray crystallography. Dissolution of 2 in acetone, led to its dimerization into [Ru-2(III)(mu-Cl)(2)Cl-4(Hind)(4)]center dot 2(Me)(2)CO (3) in 79% yield, with release of two water molecules. Complex 2 reacts readily with nucleophilic organic molecules, viz., methanol or dimethyl sulfide, at room temperature by replacement of the aqua ligand to give mer,trans[(RuCl3)-Cl-III(Hind)(2)(MeOH)] (4) and mer,trans-[(RuCl3)-Cl-III(Hind)(2)(Me2S)] (5) in 58 and 64% yield, respectively. By reaction of 2 with DMSO at room temperature or dimethyl sulfide at elevated temperatures trans,trans,trans[(RuCl2)-Cl-III(Hind)(2)(Me2S)(2)] (6) and trans,trans,trans-[(RuCl2)-Cl-II(Hind)(2)(S-DMSO)(2)] (7) were prepared in 64 and 75% yield, respectively, Dissolution of 2 in acetonitrile or benzonitrile gave rise to mer,trans-[(RuCl3)-Cl-III(Hind)(HN=C(Me)ind)] (8a), mer,trans-[(RuCl3)-Cl-III(Hind)(HN=C(Ph)ind)] (8b), and trans,trans-[(RuCl2)-Cl-III(HN=C(Me)ind)(2)]Cl (9) in 67, 50, and 23% yield, respectively, upon metal-assisted iminoacylation of indazole, which is unprecedented for ruthenium(III). Furthermore, complex 2 reacts with the DNA-model bases 9-methyladenine (9-meade) and N6,N6-dimethyladenine (6-me(2)ade) to yield mer,trans-[(RuCl3)-Cl-III(Hind)(2)(9-meade)] (10) and mer,trans-[(RuCl3)-Cl-III(Hind)(2)(6-me(2)ade)] (11) with the purine bases bound to the Ru(III) center via N7 and N3, respectively. Complex 11 represents the first ruthenium complex in which the coordination of the purine ligand N6,N6-dimethyladenine occurs via N3. In addition, the polymer [Na(EtOAc)(2)Ru-III(mu-Cl)(4)(Hind)(2)](n) (12) was crystallized from ethyl acetate/diethyl ether solutions of Na[trans-(RuCl4)-Cl-III(Hind)(2)]center dot 1.5H(2)O (1a). The reported complexes were characterized by elemental analysis, IR and UV-vis spectroscopy, ESI mass spectrometry, cyclic voltarnmetry, and X-ray crystallography. Electrochemical investigations give insight into the mechanistic details of the solvolytic behavior of complex 2. The lability of the aqua ligand in 2 suggests that this complex is a potential active species responsible for the high antitumor activity of trans-[(RuCl4)-Cl-III(Hind)(2)](-).