pH-dependent binding of guests in the cavity of a polyhedral coordination cage: reversible uptake and release of drug molecules

Cullen, William; Turega, Simon M.; Hunter, Christopher A.; Ward, Michael D.

doi:10.1039/c4sc02090a

Cited by 130 publications

(114 citation statements)

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“…13 The CH hydrogen atom of the guest that is removed in the elimination reaction is directed towards one of the windows in the cage. The guest is oriented inside the cavity, as we have seen in other structures of cage/guest complexes, 26,27 …”

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confidence: 69%

“…An important point is that at the pD of the reaction, the product 2-cyanophenolate (pKa = 6.9) is deprotonated and therefore hydrophilic and shows no sign of binding to the cage by NMR spectroscopy. 27,28 Thus, the anionic product of the reaction is expelled from the cavity, facilitating catalytic turnover and we did not observe the reaction rate decreasing with time: the reaction was not being inhibited by accumulation of product.To confirm that the reaction is indeed associated with the benzisoxazole being bound in the cage cavity, we added an excess of a strongly-binding competing guest (20 mM cycloundecanone, K = 1.2 ! 10 6 M -1 ).…”

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confidence: 81%

“…Importantly, only neutral guests bind strongly: cationic (protonated amines) or anionic (carboxylate) guests bind much more weakly as they are hydrophilic and preferentially solvated by bulk water, which means that pH can be used to control uptake and release of ionisable guests. 27,28 In the catalytic system we report here, conversion of a neutral starting material to an anionic product is the basis of product release and catalytic turnover.The reaction that is catalysed is the Kemp elimination (Fig. 2) in which benzisoxazole undergoes a ring-opening reaction with hydroxide to afford 2-cyanophenolate.…”

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confidence: 99%

“…The interior of the cage therefore provides a poorer medium than water for the reaction because of preferential solvation of the developing negative charge by water, and the weak binding of the product anion underlines this. 27,28 In these terms, binding the substrate is anti-catalytic.Secondly, what is the reason for the pD-independence of kcat? As there are no basic sites associated with the cage, the rate invariance in the pD 8.5 -11.4 range could be explained by the use of water as the base for the reaction rather than hydroxide.…”

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confidence: 99%

“…Fig. 4c), 23,24,26,27,37 which would position hydroxide close to the CH of the substrate constrained in the cavity. If these sites around the cage are saturated with hydroxide ions at pD 8.5 due to the high positive charge, increasing the pD to 11.4 will not result in an increase in the local hydroxide concentration and the rate of the reaction should therefore be independent of pD in this range.…”

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confidence: 99%

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Highly efficient catalysis of the Kemp elimination in the cavity of a cubic coordination cage

et al. 2016

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The hollow cavities of coordination cages can provide an environment for enzyme-like catalytic reactions of small-molecule guests . We report here a new example (catalysis of the Kemp elimination -reaction of benzisoxazole with hydroxide to form 2-cyanophenolate) in the cavity of a water-soluble M8L12 coordination cage, with two features of particular interest. Firstly, the rate enhancement is amongst the largest so far observed: at pD 8.3, kcat/kuncat is 2 x 10 5 , due to the accumulation of a high concentration of partially desolvated hydroxide ions around the bound guest arising from ion-pairing with the 16+ cage. Secondly, the catalysis is based on two orthogonal interactions: (i) hydrophobic binding of benzisoxazole in the cavity, and (ii) polar binding of hydroxide ions to sites on the cage surface, both of which were established by competition experiments. Hundreds of turnovers occur with no loss of activity due to expulsion of the hydrophilic, anionic product. 2Since the realisation that hollow molecular container molecules can accommodate guest molecules in their central cavities, 1-3 their ability to modify the reactivity of their bound guests has been of great interest. [4][5][6][7][8] Well known examples include Cram's stabilisation of highly-reactive cyclobutadiene; 4 Fujita's 'ship-in-a-bottle' synthesis of cyclic silanol oligomers; 5 Nitschke's stabilisation of P4 in a tetrahedral cage; 6 and the demonstration of unusual regioselectivity in a Diels-Alder reaction when the two reacting molecules are co-confined in a host cavity. 7 The ultimate expression of this behaviour is efficient catalysis of a reaction occurring in the cavity of a container molecule. 8 These synthetic systems have the potential to achieve the selectivity and catalytic rate enhancements displayed by biological systems. For example, artificial container molecules provide relatively rigid and hydrophobic central cavities that may mimic binding pockets in enzymes. These containers may be purely organic hydrogen-bonded assemblies (such as Rebek's 'softball' dimer) 9 or may be metal-ligand polyhedral coordination cages [such as Fujita's Pd6/tris(pyridyl)triazine cage]. 10 Coordination cages offer particular promise in this field because of the ease with which they can be formed by a self-assembly process from very simple component parts, using the predictable coordination geometries of metal ions to provide the three-dimensional ordering of the components which generates the necessary cavity. [1][2][3]8,11,12 In order for a container molecule to act as an efficient catalyst it needs to (i) recognise and bind the guest(s); (ii) accelerate the reaction by increasing the local concentration of reactants and/or stabilising the transition state; and (iii) expel the product to allow catalytic turnover. 8 Guest binding in cage cavities has been very well studied and is becoming a mature field, 1 to the extent that a modeling tool for quantitative prediction of guest binding has recently been reported by us. 13 For a reaction of t...

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