Novel 11ß-hydroxysteroid dehydrogenase 1 inhibitors reduce cortisol levels in keratinocytes and improve dermal collagen content in human ex vivo skin after exposure to cortisone and UV.

Activity and selectivity assessment of new bi-aryl amide 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) inhibitors, prepared in a modular manner via Suzuki cross-coupling, are described. Several compounds inhibiting 11ß-HSD1 at nanomolar concentrations were identified. Compounds 2b, 3e, 7b and 12e were shown to selectively inhibit 11ß-HSD1 over 11ß-HSD2, 17ß-HSD1 and 17ß-HSD2. These inhibitors also potently inhibited 11ß-HSD1 activity in intact HEK-293 cells expressing the recombinant enzyme and in intact primary human keratinocytes expressing endogenous 11ß-HSD1. Moreover, compounds 2b, 3e and 12e were tested for their activity in human skin biopsies. They were able to prevent, at least in part, both the cortisone- and the UV-mediated decreases in collagen content. Thus, inhibition of 11ß-HSD1 by these compounds can be further investigated to delay or prevent UV-mediated skin damage and skin aging.

pH-tuned metal coordination and peroxidase activity of a peptide dendrimer enzyme model with a Fe(II)bipyridine at its core.

Peptide dendrimer BP1 was obtained by double thioether bond formation between 5,5'-bis(bromomethyl)-2,2'-bipyridine and two equivalents of peptide dendrimer N1 (Ac-Glu-Ser)(8)(Dap-Glu-Ala)(4)(Dap-Amb-Tyr)(2)Dap-Cys-Asp-NH(2) (Dap = branching 2,3-diaminopropanoic acid, Amb = 4-aminomethyl-benzoic acid). At pH 4.0 BP1 bound Fe(ii) to form the expected tris-coordinated complex [Fe(II)(BP1)(3)] (K(f) = 2.1 × 10(15) M(-3)). At pH 6.5 a monocoordinated complex [Fe(II)(BP1)] was formed instead (K(f) = 2.1 × 10(5) M(-1)) due to electrostatic repulsion between the polyanionic dendrimer branches, as confirmed by the behavior of three analogues where glutamates were partially or completely replaced by neutral glutamines or positive lysines. [Fe(II)(BP1)] catalyzed the oxidation of o-phenylenediamine with H(2)O(2) with enzyme-like kinetics (k(cat) = 1.0 min(-1), K(M) = 1.5 mM, k(cat)/k(uncat) = 90 000) and multiple turnover, while Fe(2+) or [Fe(bipy)(3)](2+) were inactive. The labile coordination positions allowing coordination to H(2)O(2) and to the substrate are likely responsible for the enhanced peroxidase activity of the metallopeptide dendrimer.

Replacement of Ala by Aib improves structuration and biological stability in thymine-based alpha-nucleopeptides.

Three thymine-based nucleo-heptapeptides, each containing two nucleo-amino acids and zero, one or four Aib residues, respectively, have been synthesized. A single Aib residue is enough to promote the adoption of a helical structure in our nucleopeptides and to increase significantly their resistance towards enzymatic degradation. The insertion of four Aib residues, out of seven residues in the sequence, affords a rigid, 3(10)-helical nucleopeptide that is substantially unaffected by serum enzymes and is not cytotoxic.

Conformationally controlled, thymine-based alpha-nucleopeptides.

Rigid peptide backbones and backbone-to-side chain H-bonds permit the design of alpha-nucleopeptides with known 3D-structure; thymine-thymine base pairing is also observed.

Functional Biosupramolecular Systems.

This year, the CUSO Summer School in Organic Chemistry celebrated its 40th anniversary. With a coinciding 450th anniversary, it was organized by the University of Geneva. The focus was on large molecules and supramolecules that are synthesized from scratch, have interesting functions, and address lessons from nature.

Design and synthesis of intrinsically cell-penetrating nucleopeptides.

Nucleopeptides, which are constituted of alpha-amino acids bearing nucleobases at their side chains, are able to penetrate into cells and to reach the nucleus without cytotoxic effects.