Dynamic Combinatorial Systems
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Carbonic anhydrase-encoded dynamic constitutional libraries
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Bioorg. Med. Chem. Lett. 2009, 19, 6014–6017.
J. Med. Chem, 2009, 42, 4853-4859.
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Constitutional dynamic libraries (CDL) have been studied by using the amino-carbonyl/imine interconversion as reversible chemistry, combined with non-covalent bonding within the active site of the metalloenzyme carbonic anhydrase-CA. Considering the pharmacological importance to find isoform-selective inhibitors, human hCAI and hCA II, have been subjected to a parallel screening of the same CDL. We demonstrate that the high specificity of inhibiting the hCA I and hCA II isozymes may be used to describe a complex constitutional behavior through component selection, driven by the selective binding to the specific active site. These results also point to the possibility of modulating the drug discovery methods by constitutional recomposition induced by a specific enzymatic target.
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Elaboration of the DCL of inhibitorsfor Carbonic anhydrase: Inhibition constants KI and the amplification of the constitutional dynamic library (CDL) against catalytically active human hCA I and hCA II cytosolic isosymes.
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Constitutional crystallization.
Science, 2010,329, 299-302. Chem. Eur J. 2011, 17, 10021-10028.
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Single–crystal X-ray structure of 1,3-dimethylcyclobutadiene by confinement in a crystalline matrix: Cyclobutadiene (CBD), the smallest cyclic hydrocarbon bearing double bonds, has long intrigued chemists on account of its strained geometry and electronic instability, but the parent compound and its unperturbed derivatives have eluded crystallographic characterization. Here we imobilize a precursor, 4,6-dimethyl-α-pyrone, in a guanidinium-sulfonate-calixarene G4C crystalline network that confines the guest through a combination of CH-π and hydrogen-bond interactions.
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Ultraviolet irradiation of the crystals transforms the entrapped 4,6-dimethyl-α-pyrone into a 4,6-dimethyl-β-lactone Dewar intermediate that is sufficiently stable under the confined conditions at 175 Kelvin to allow a conventional structure determination by X-ray diffraction. Further irradiation pushes the reaction to completion, enabling the structure determination of 1,3-dimethylcyclobutadiene Me2CBD. The data support experimental observation of square-planar, Me2CBDS and rectangular-bent Me2CBDR geometries in the G4C host matrix. The hydrogen-bonded CO2 dissociated molecule is stronger interacting with Me2CBDS than Me2CBDR.
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Self-sorting of metallosupramolecular DCLs
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Chem. Commun, 2009, 2192-2194.
Chem. Commun, 2009, 2667-2669
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The generation of metallosupramolecular DCLs results in the formation of interexchanging equilibrating mixture of subcomponents of different stoichiometries which converts into unique solid state species via crystallization. The solid-state organization is promoted by constitutional affinity between monuclear complexes. The internal robustness of the crystal-packing is mainly responsible for the transmission of the supramolecular order, which is then constitutionally transmitted at the next hierarchical level, producing a crystallization selection process. Considering the simplicity of this strategy, possible applications on the synthesis of more complex heteroarchitectures might to be very effective, reaching close to full conversion via crystallization process with no need of further purification.
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