Floris P. J. T. Rutjes

Enzymatic Glycosylation of Triazole-Linked GlcNAc/Glc–Peptides: Synthesis, Stability and Anti-HIV Activity of Triazole-Linked HIV-1 gp41 Glycopeptide C34 Analogues

Long‐lasting sweet proteins: The chemoenzymatic synthesis of a triazole (T)‐linked glycosylated C34 fragment from HIV‐1 gp41 is described. The glycopeptide shows high solubility, excellent fusion inhibition, and as shown in the graph, promising protease resistance.

An Enantioselective Organocatalytic Approach to Both Enantiomers of Lasubine II

A concise stereoselective route providing access to both enantiomers of the bioactive quinolizidine alkaloid lasubine II has been developed. The enantioselectivity was introduced by taking advantage of a proline-catalyzed asymmetric Mannich reaction. Next, the bicyclic system was constructed via a diastereoselective Mannich cyclization and subsequent ring-closing metathesis as the key steps.

Synthesis and aggregation behavior of biohybrid amphiphiles composed of a tripeptidic head group and a polystyrene tail

The modular synthesis and self-assembly behavior of a set of peptide-polymer hybrid amphiphiles is described. Gly-Gly-Arg derivatives were conjugated to one of the ends of hetero-telechelic polystyrene (PS) via either the Cu-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction or conventional peptide coupling chemistry. Both conjugation strategies proved to be efficient and they were also applied sequentially to create a biohybrid ABA-type triblock copolymer, which can be considered as a macromolecular bolaamphiphile. In the synthesis of the regularly-shaped peptide-PS amphiphiles (i.e. AB-type) two polymer lengths (n = 21 and n = 49) were employed having additional variations in their end group composition. As expected, the structural variations were demonstrated not to influence the self-assembly behavior of the biohybrids in water, and comparable vesicles were formed in all cases. At the air/water interface, the structural variations had a greater impact on the self-assembly of the biohybrids, especially for the phase transition from gas to liquid because it is dominated by steric interactions between the polymer chains. In a condensed phase (which closely resembles the situation in a bilayer vesicle), the packing of various biohybrids was found to be comparable. The interfacial self-assembly behavior of the bolaamphiphile (n = 21) was also studied and this compound probably formed multi-layered structures on the water surface. In aqueous solution the bolaamphiphile formed spherical aggregates similar to the regular peptide-PS amphiphiles. Although these assemblies appeared to be vesicular, their exact nature remains unclear.

Synthesis of Hydantoins and Thiohydantoins Spiro-Fused to Pyrrolidines: Druglike Molecules Based on the 2-Arylethyl Amine Scaffold

The synthesis of a 144-compound library of hydantoins and thiohydantoins spiro-fused to pyrrolidines is described. These compounds are synthesized from beta-aryl pyrrolidines, providing products with the 2-arylethyl amine moiety, a structural feature often encountered in compounds active in the central nervous system. All possible stereoisomers of the two-stereocenter products are synthesized. The 80-membered hydantoin sublibrary was obtained with yields ranging from 58 to 100% (87% average) and purities from 51 to 100% (87% average) and the 64-membered thiohydantoin sublibrary was obtained with yields ranging from 65 to 100% (89% average) and purities from 67 to 100% (93% average).

Solution-Phase Parallel Annulation of (Thio)hydantoins to Tetrahydroisoquinolines and Tetrahydro-beta-carbolines Containing the 2-Arylethyl Amine Scaffold

The one-step solution-phase parallel synthesis of two structurally diverse libraries of pharmacologically important compounds is described. The presented compounds combine three privileged structures: the 2-arylethyl amine moiety, a tetrahydro(hetero)areno[c]pyridine, and a (thio)hydantoin. These compounds are synthesized by annulation of a hydantoin or a 2-thiohydantoin ring to tri- or tetracyclic scaffolds, containing the 2-arylethyl amine moiety and a tetrahydroisoquinoline, a tetrahydro-beta-carboline, or a tetrahydrofuro[3,2-c]pyridine. The annulation leads to pharmacologically relevant structural motifs such as imidazopyrroloisoquinolines, dioxoloimidazopyrroloisoquinolines, furoimidazopyrrolopyridines, and imidazopyrrolopyridoindoles. Both libraries were obtained with quantitative yields. The 36-membered hydantoin library was obtained with purities from 57 to 100% (90% average) and the 32-membered thiohydantoin library with purities from 73 to 100% (94% average).

Synthesis of Tetrahydro-beta-carbolines and Tetrahydroisoquinolines Fused to Pyrrolidines and Solution-Phase Parallel Acylation

A structurally diverse library of potentially pharmacologically important compounds employing classical synthesis methods is described. These compounds are synthesized from beta-aryl pyrrolidines, providing products with the 2-arylethyl amine moiety, a structural feature often encountered in compounds active in the central nervous system. Tri- and tetracyclic scaffolds were obtained using the Pictet-Spengler reaction, resulting in hexahydropyrrolo[3,4-c]isoquinolines 1-3, an octahydropyrrolo[3,4:5,6]pyrido[3,4-b]indole 4, and a hexahydrofuro[2,3-d]pyrrolo[3,4-b]pyridine 5. These scaffolds were further derivatized in parallel fashion to make a 32-membered amide library with yields from 62 to 100% (90% average) and purities from 63 to 100% (93% average).

Thrombin generation test in microfluidic systems

The thrombin generation test is one of the diagnostic tests currently in use as a universal method for measuring hemostatic disorders. We envisioned that conventional monitoring of thrombin generation could be miniaturized resulting in a time-saving, accurate, easy-to-operate, and cost-efficient test. For the translation of the conventional thrombin generation test to microfluidic devices, our focus was directed to parameters such as the detection limit, temperature, protein-surface interactions (i.e., hydrophilicity of microchannels), and mixing behavior. Scaling down to microchannels (e.g., capillaries) resulted in volume reduction and allowed us to study the effect of a microchannel surface (either hydrophilic or hydrophobic) on the thrombin activity. Finally, the use of a micromixer enabled us to perform efficient on-chip mixing, resulting in the successful measurement of a thrombin generation in a microfluidic device.