Chiral polymers by iterative tandem catalysis

Racemic omega-substituted caprolactones can be completely converted into chiral polyesters of remarkable MW and high ee by combining lipase-catalyzed ring-opening polymerization with Ru-catalyzed racemization.     

Development of proneurogenic, neuroprotective small molecules

Degeneration of the hippocampus is associated with Alzheimer's disease and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apoptotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile, and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive toward increases in activity and regions subject to modification. We have discovered compounds that are orally available, nontoxic, stable in mice, rats, and cell culture, and capable of penetrating the blood-brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photo-cross-linking.     

The effect of irradiation by ultraviolet light on ureido‐pyrimidinone based biomaterials

Supramolecular polymers based on ureido‐pyrimidinone (UPy) represent a promising class of biocompatible materials for medical applications. Here, the chemical modification effect of UV irradiation, used to sterilize these materials, is studied. Besides anticipated crosslinking effects, UV irradiation causes telechelic UPy‐polymers to become fluorescent. UPy‐model compounds confirm a relation between UV‐induced changes and the UPy‐moiety. UV‐induced fluorescence and IR‐spectral changes are (partially) reversible by heat and/or solvent treatment. The results indicate the presence of at least two distinct UV‐induced molecular species. UPy‐model compounds with specific tautomeric forms directly relate fluorescence to UPy‐enol tautomers. Photo‐enolization is hypothesized to occur via an excited‐state intermolecular double proton transfer. Changes in UPy‐tautomeric equilibrium and crosslinking are factors that influence the dynamics of UPy‐based materials. Identification and understanding of such factors will aid in the successful application of these materials, for example as biomaterial in tissue engineering applications. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 81–90     

Synthesis and stability of oligonucleotides containing acyclic achiral nucleoside analogues with two base moieties

[structure: see text] Nucleotide building blocks with two base moieties were synthesized and incorporated into oligonucleotides. One of the two bases is involved in base pairing within the double helix, while the other base is sticking out of the minor groove. This system may be used for presenting sequence information at the outside of the helix.     

Switching from S- to R-selectivity in the Candida antarctica lipase B-catalyzed ring-opening of omega-methylated lactones: tuning polymerizations by ring size

Novozym 435-catalyzed ring-opening of a range of omega-methylated lactones demonstrates fascinating differences in rate of reaction and enantioselectivity. A switch from S- to R-selectivity was observed upon going from small (ring sizes or=8). This was attributed to the transition from a cisoid to a transoid conformational preference of the ester bond on going from small to large lactones. The S-selectivity of the ring-opening of the small, cisoid lactones was low to moderate, while the R-selectivity of the ring-opening of the large transoid lactones was surprisingly high. The S-selectivity of the ring-opening of the small, cisoid lactones combined with the established R-selectivity of the transesterification of (aliphatic) secondary alcohols prevented polymerization from taking place. Ring-opening of the large, transoid lactones was R-selective with high enantioselectivity. As a result, these lactones could be polymerized, without exception, by straightforward kinetic resolution polymerization, yielding the enantiopure R-polyester with excellent enantiomeric excess (>99%).     

Tuning the stacking properties of C3-symmetrical molecules by modifying a dipeptide motif

C3-symmetrical molecules are described which consists of a 1,3,5-benzenetricarboxamide core extended with dipeptide fragments bearing peripheral mesogenic groups. Small structural modifications in the dipeptide fragment have been performed to demonstrate their influence on the stability of the stacks and on the order within the self-assemblies formed. Seven C3-symmetrical discs have been investigated, all with different combinations of glycine, L- and/or D-phenylalanine in the dipeptide fragments. Characterization of these discotics in the neat state using differential scanning calorimetry (DSC), X-ray diffraction (XRD) and polarized optical microscopy (POM) and in solution with circular dichroism (CD), UV-visible spectroscopy, low-concentration proton nuclear magnetic resonance and IR spectroscopy reveals that there is a clear trend in the stack stability, going from the glycine-phenylalanine motifs to the phenylalanine-phenylalanine ones. The combination of a larger hydrophobic core, more confinement of space and the possibility of additional pi-pi interactions leads to more stable stacks. Surprisingly, the weakest stacks consist of discotics of which the center is extended with L-phenylalanyl-glycines and not of discotics of which the center is extended with the glycyl-L-phenylalanine sequences. Furthermore, the XRD investigations show that it is difficult to form well-ordered self-assemblies in the neat state. And, CD measurements point out that some of the discs have a very complex energy landscape in solution. These observations suggest that small differences in the balance between the secondary interactions originating from the benzenetricarboxamide core and the dipeptide fragments, have a strong influence on the order within the stack. From these results it can be concluded that subtle modifications in the peptide fragments of the discs cause significant changes in the stacking properties, stressing the importance of understanding the self-assembly mechanism of each discotic in order to clarify its self-assembly behavior.