Robert Martin Grotzfeld

Reversible Encapsulation of Disc-Shaped Guests by a Synthetic, Self-Assembled Host

Here, the synthesis of a bowl-shaped molecule is described and evidence of its reversible dimerization by means of hydrogen bonds is presented. The dimer features a flattened spherical cavity of peculiar symmetry and acts as a host for the encapsulation of guest molecules of complementary shape. Encapsulation of aromatic guests in chloroform solution and of cyclohexane in p-xylene solution was demonstrated by nuclear magnetic resonance experiments. The passage of guests into and out of the cavity is slow and occurs on a time scale of hours. The system was used to explore the effects of size, shape, and solvation on molecular recognition coupled with assembly.

Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay.

Allosteric inhibitors of Bcr-Abl have emerged as a novel therapeutic option for the treatment of CML. Using fragment-based screening, a search for novel Abl inhibitors that bind to the myristate pocket was carried out. Here we show that not all myristate ligands are functional inhibitors, but that the conformational state of C-terminal helix_I is a structural determinant for functional activity. We present an NMR-based conformational assay to monitor the conformation of this crucial helix_I and show that myristate ligands that bend helix_I are functional antagonists, whereas ligands that bind to the myristate pocket but do not induce this conformational change are kinase agonists. Activation of c-Abl by allosteric agonists has been confirmed in a biochemical assay.

Control of Self-Assembly by Acid-Base Chemistry

Recent progress in the field of molecular recognition has led to the introduction of self- assembling systems of varying complexity. A simple system in which two identical subunits are held together by hydrogen bonds has previously been developed.[1] Since then, two similar capsule-forming compounds have been synthesized (figure 1).[2] These are based on p-N,N-dimethylaminophenyl- or carbethoxysubstituted glycolurils which are readily available from the corresponding benzil and dihydroxytartaric acid (disodium salt) respectively by condensation with urea. By using other alcohols for the esterification such as isoamyl alcohol or cyclohexanol, soluble glycolurils (e.g. in pyridine or dioxane) are obtained which are promising candidates for the synthesis of more complex self-assembling systems. Alkylation of the glycolurils la and lb with 1,2,4,5-tetrakisbromomethylbenzene gave the new self-complementary compounds 2a and 2b, both showing enhanced solubility in organic solvents. As expected, both compounds can encapsulate methane, ethane, and ethylene as evidenced by 1H-NMR.