New activation mechanism for half-sandwich organometallic anticancer complexes.
New activation mechanism for half-sandwich organometallic anticancer complexes.
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DOI：
10.1039/c7sc05058e
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发表时间：
2018-03-28
期刊：
影响因子：
8.4
通讯作者：
Sadler PJ
中科院分区：
文献类型：
--
作者：
Banerjee S;Soldevila-Barreda JJ;Wolny JA;Wootton CA;Habtemariam A;Romero-Canelón I;Chen F;Clarkson GJ;Prokes I;Song L;O'Connor PB;Schünemann V;Sadler PJ
具有活化的CP*环的半夹心RhIII抗癌化合物不仅进行顺序的CH3H-D交换，而且在室温下与生物双烯反应，在水介质中生成RHI Diels-Alder加合物。某些有机金属RhIII半夹心抗癌配合物[(η5-Cpx)Rh(N，N‘)Cl]+中的CpxC-H质子，其中Cpx=Cp*、苯基或联苯-Me4Cp，N，N’=联吡啶、二甲基联吡啶或邻菲咯啉，在水相介质中，15个Cp*甲基质子在常温下都能发生快速顺序的氢化反应.密度泛函计算提出了一种机制，涉及Rh-羟基络合物提取Cp*质子，随后进行H/D交换，Cp*环的行为类似于动态分子‘扭曲’。计算结果揭示了N，N‘-螯合配体的p-π轨道在稳定去质子化的环氧氯丙烷配体中的关键作用，以及富烯中间体的可及性。它们还提供了为什么[(Cp*)RhIII(En)Cl]+和[(Cp*)IrIII(Bpy)Cl]+等生物活性不活跃的配合物没有活性的Cp*环的见解。硫醇三肽谷胱甘肽(γ-L-Glu-L-Cys-Gly，GSH)和活化的N-甲基马来酰亚胺(N-甲基马来酰亚胺，N-甲基马来酰亚胺)虽然能够控制Cp*的氢化程度，但不与所提出的RHI-富烯发生加成反应。我们很容易通过Diels-Alder[4+2]与天然生物异戊二烯和共轭(9Z，11E)-亚油酸在水溶液中的Diels-Alder环加成反应捕获和表征RHI-富烯中间体，这是首次报道金属结合的富烯在水溶液中的Diels-Alder反应。这些发现将为具有新作用机制的有机金属CP*抗癌配合物的设计带来新的概念。
Half-sandwich RhIII anticancer complexes with activated Cp* rings not only undergo sequential CH3 H–D exchange, but also react with biological dienes, generating RhI Diels–Alder adducts in aqueous media at ambient temperature. The Cpx C–H protons in certain organometallic RhIII half-sandwich anticancer complexes [(η5-Cpx)Rh(N,N′)Cl]+, where Cpx = Cp*, phenyl or biphenyl-Me4Cp, and N,N′ = bipyridine, dimethylbipyridine, or phenanthroline, can undergo rapid sequential deuteration of all 15 Cp* methyl protons in aqueous media at ambient temperature. DFT calculations suggest a mechanism involving abstraction of a Cp* proton by the Rh–hydroxido complex, followed by sequential H/D exchange, with the Cp* rings behaving like dynamic molecular ‘twisters’. The calculations reveal the crucial role of pπ orbitals of N,N′-chelated ligands in stabilizing deprotonated Cpx ligands, and also the accessibility of RhI–fulvene intermediates. They also provide insight into why biologically-inactive complexes such as [(Cp*)RhIII(en)Cl]+ and [(Cp*)IrIII(bpy)Cl]+ do not have activated Cp* rings. The thiol tripeptide glutathione (γ-l-Glu-l-Cys-Gly, GSH) and the activated dienophile N-methylmaleimide, (NMM) did not undergo addition reactions with the proposed RhI–fulvene, although they were able to control the extent of Cp* deuteration. We readily trapped and characterized RhI–fulvene intermediates by Diels–Alder [4+2] cyclo-addition reactions with the natural biological dienes isoprene and conjugated (9Z,11E)-linoleic acid in aqueous media, including cell culture medium, the first report of a Diels–Alder reaction of a metal-bound fulvene in aqueous solution. These findings will introduce new concepts into the design of organometallic Cp* anticancer complexes with novel mechanisms of action.
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