Biomedical subjects
Publications and source records attributed to Sijbren Otto.
This perspective describes how kinetic studies of organic reactions can be used to increase our understanding of hydrophobic interactions. In turn, our understanding of hydrophobic interactions can be used as a tool to influence chemical reactions.
A dynamic combinatorial library of potential anion receptors was generated from a cyclic peptide disulfide dimer and a series of dithiol spacers. Exposing the library to KI or K2SO4 led to the amplification of two new neutral receptors that bind anions through hydrogen bonding with up to micromolar affinity in aqueous solution. Thermodynamic studies suggest that these second-generation receptors outclass the previously described first-generation receptor, largely as a result of a more favorable enthalpy of binding. These results demonstrate that dynamic combinatorial optimization of designed hosts can be a powerful strategy, bringing synthetic receptors that approach the efficiencies of proteins one step closer.
Three building blocks of general structure (MeO)2 CH-aromatic linker-Pro-amino acid-NHNH2 have been prepared and tested in acid-catalysed dynamic combinatorial libraries. Exposure of these libraries to LiI and NaI led to the amplification of three macrocyclic pseudopeptide receptors. The receptors were isolated and their interactions with LiI and NaI were analysed using NMR, IR and ITC. Binding of the metal ions to the receptors is invariably entropy-driven. Nevertheless, all receptors were found to be flexible with substantial conformational rearrangements accompanying guest binding. This type of receptor is extremely difficult to access through rational design and the fact that dynamic combinatorial chemistry allows facile access to these challenging molecules underlines the power of the dynamic approach.
The coordination of diphenyl(phenylacetenyl)phosphine (DPAP, 1) to (X)Rh(III)TPP (X = I (2) or Me (3); TPP = tetraphenyl porphyrin) was studied in solution and in the solid state. The iodide is readily displaced by the phosphine, leading to the bis-phosphine complex [(DPAP)(2)Rh(TPP)](I) (4). The methylide on rhodium in 3 is not displaced, leading selectively to the mono-phosphine complex (DPAP)(Me)Rh(TPP) (5). The first and second association constants, as determined by isothermal titration calorimetry and UV-vis titrations, are in the range 10(4)-10(7) M(-1) (in CH(2)Cl(2)). Using LDI-TOF mass spectrometry, the mono-phosphine complexes can be detected but not the bis-phosphine complexes. The electronic spectrum of 4 is similar to those previously reported with other tertiary phosphine ligands, whereas (DPAP)(I)Rh(TPP) (6) displays a low energy B-band absorption and a high energy Q-band absorption. In contrast to earlier reports, displacement of the methylide on rhodium in 5 could not be observed at any concentration, and the electronic spectra of 4 and 5 are almost identical. Isothermal titration calorimetry experiments showed that all binding events are exothermic, and all are enthalpy driven. The largest values of DeltaG degrees are found for 6. The thermodynamic and UV-vis data reveal that the methylide and the phosphine ligand have an almost identical electronic trans-influence on the sixth ligand.
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In a dynamic combinatorial library, all compounds are in thermodynamic equilibrium, allowing the library composition to adapt to external influences. Thus, non-covalent forces between a ligand and its receptor can be used to select, stabilize and, thereby, amplify the best receptor in the library. Ligand-induced amplification can be a means of receptor synthesis. Dynamic combinatorial chemistry facilitates access to new receptors, including highly flexible induced-fit receptors and structurally complex capsule-like receptors that are difficult to access using traditional methods. Recently, dynamic combinatorial chemistry has also been used to identify and prepare catalytically active receptors.
We have discovered two receptors for two different guests from a single dynamic combinatorial library. Each of the two guests amplifies the formation of a tightly binding host at the expense of unfit library members. Small differences in host-guest binding translate into useful differences in amplification. The selected hosts could be readily synthesized using biased dynamic libraries that contain only the right ratio of those building blocks that were selected by the guests. These results establish dynamic combinatorial chemistry as a practical method not only for the discovery but also for the synthesis of new receptors.
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A combinatorial library that responds to its target by increasing the concentration of strong binders at the expense of weak binders sounds ideal. Dynamic combinatorial chemistry has the potential to achieve exactly this. In this review, we will highlight the unique features that distinguish dynamic combinatorial chemistry from traditional combinatorial chemistry, and that could make a useful addition to the set of combinatorial techniques used in drug discovery.
Generating combinatorial libraries under equilibrium conditions has the important advantage that the libraries are adaptive (i.e. they can respond to exterior influences in the form of molecular recognition events). Thus, a ligand will direct and amplify the formation of its ideal receptor and vice versa. Proof of principle of this approach has been established using small libraries showing highly efficient amplification of selected receptors. The approach has recently been extended to address folding of macromolecules, including peptides.