The role of hydroxo-bridged dinuclear species and the influence of “innocent” buffers in the reactivity of cis-[CoIII(cyclen)(H2O)2]3+ and [CoIII(tren)(H2O)2]3+ complexes with biologically relevant ligands at physiological pH

Abstract

In view of the relevance of the reactivity of inert tetraamine Co(III) complexes having two substitutionally active cis positions capable of interact with biologically relevant ligands, the study of the reaction of cis-[Co(cyclen)(H2O)2](3+) and [Co(tren)(H2O)2](3+) with chlorides, inorganic phosphate and 5'-CMP (5'-cytidinemonophosphate) has been pursued at physiological pH. The results indicate that, in addition to the actuation of the expected labilising conjugate-base mechanism, the formation of mono and inert bis hydroxo-bridged species is relevant for understanding their speciation and reactivity. The reactivity pattern observed also indicates the key role played by the "innocent" buffers frequently used in most in vitro studies, which can make the results unreliable in many cases. The differences between the reactivity of inorganic and biologically relevant phosphates has also been found to be remarkable, with outer-sphere hydrogen bonding interactions being a dominant factor for the process. While for the inorganic phosphate substitution process the formation of μ-η(2)-OPO2O represents the termination of the reactivity monitored, for 5'-CMP only the formation of η(1)-OPO3 species is observed, which evolve with time to the final dead-end bis hydroxo-bridged complexes. The promoted hydrolysis of the 5'-CMP phosphate has not been observed in any of the processes studied.

Kinetico-mechanistic studies of substitution reactions on cross-bridged cyclen CoIIIcomplexes with nucleosides and nucleotides

“…29,36 At the same time-scale, for the parent cyclen derivative, the presence of very acidic equatorial NH groups, 29 induce fast polymerization reactions. 9 As found for the previously studied related systems, the absorbance changes increase significantly with increasing pH, but can be reversed in a fast process by addition of HClO 4 to acidic pH. At pH > 7.5 the changes associated with the second process become very important and are related to the lack of reactivity observed with the variety of ligands studied (see the following section).…”

“…S1 †), and show the two-step sequence indicated above. The time-scale of these processes (10 plus 70 minutes at 17 °C) is clearly intermediate between those observed for the parent cyclen 9 and those found for the fully substituted {(Me) 2 (μ-ET)-cyclen} 22 analogous derivatives. This trend is in line with the residual presence of two slightly acidic NH axial groups attached to the Co III centre in the present compound, still capable of induced base-catalysed substitution reactivity.…”

“…Summarising, the behaviour of the [Co{(μ-ET)cyclen}-(H 2 O) 2 ] 3+ system has intermediate features between those of the parent cyclen 9 and {(Me) 2 (μ-ET)cyclen} 22 derivatives. The polymerisation equilibria indicated in Scheme 2 are at pH values higher than 7.5 (after 30 minutes at room temperature, see below) significantly displaced to the formation of a dimeric dead-end bis-hydroxo [(Co{(μ-ET)cyclen}) 2 (μ-OH) 2 ] 4+ complex.…”

“…In this respect, hydrogen bonding and stabilization of supramolecular interactions have dramatic consequences in many processes expected to be rather simple. 9 Another important aspect relates to the effect of temperature on the activity of these coordination compounds, 10 which underlines the importance of determining activation parameters for these simple substitution reactivities, a point normally not considered.…”

“…18 Even some Co alkyne complexes have shown promising activity associated with their capability to target specific enzymes. 19,20 The use of complexes of type cis-[Co(N) 4 (H 2 O) 2 ] 3+ , with (N) 4 being tren, cyclen or fully alkylated {(Me) 2 (μ-ET)cyclen} has already been explored by us 9,21,22 by studying their substitution processes with some nucleosides and nucleotides at physiological pH. In this respect there has been an important increase in the use of cross-bridged cyclen and cyclam ligands, both for their promising properties and the robustness of their structure containing five-and six-membered macrocyclic full encapsulation.…”