Search

DNA encoded library (DEL) synthesis represents a convenient means to produce, annotate and store large collections of compounds in a small volume. While DELs are well suited for drug discovery campaigns, the chemistry used in their production must be compatible with the DNA tag, which can limit compound class accessibility. As a result, most DELs are heavily populated with peptidomimetic and sp2‐rich molecules. Herein, we show that sp3‐rich mono‐ and bicyclic heterocycles can be made on DNA from ketochlorohydrin aldol products through a reductive amination and cyclization process. The resulting hydroxypyrrolidines possess structural features that are desirable for DELs and target a distinct region of pharmaceutically relevant chemical space. [ABSTRACT FROM AUTHOR]

Herein we report the automation and scale-up of a photofluorination process key to the production of branched-chain aliphatic radiotracers such as (S)-5-[18F]fluorohomoleucine ((S)-5-[18F]]FHL). (S)-5-[18F]FHL is a leucine analogue that is primarily taken up by the L-type amino acid transporter (LAT or System L). LAT1 expression levels correlate closely with tumor proliferation, angiogenesis, and treatment outcomes, making it an attractive target for molecular imaging of cancer. We have previously synthesized (S)-5-[18F]FHL and tested this tracer in mice bearing PC3 (prostate) or U87 (glioma) xenografts in order to establish its feasibility for detecting and monitoring treatment for a broad range of cancers. In this study, the radiosynthesis of 5-[18F]FHL is demonstrated on an automated DT-PhotoFluor module with a radiochemical yield of 20.1 ± 4.8% (n = 3), radiochemical purity of 94.5 ± 4.9% (n = 3), and a synthesis time of ~ 75 min. The reported DT-PhotoFluor module will allow for higher molar activity, better reproducibility, and reduced radiation exposure for upcoming first-in-human studies. [ABSTRACT FROM AUTHOR]

A short enantioselective total synthesis of 1-deoxygalactonojirimycin (migalastat) has been achieved that does not rely on chiral pool starting materials or biocatalysis. Instead, this synthesis exploits a one-pot proline-catalyzed [alpha]-chlorination and aldol reaction of a commercially available aldehyde to assemble the entire carbon skeleton in a single step. The key role played by a nitrogen protecting group in the final epoxide opening reaction is highlighted as is the amenability to access structural analogues using this route. Key words: 1-deoxygalactonojirimycin, iminosugar, organocatalysis, chlorohydrin, total synthesis, natural product. Nous avons realise une courte synthese totale enantioselective de la 1 desoxygalactonojirimycine (migalastat) sans faire appel a des produits de depart issus du bassin chiral ou a la biocatalyse. Cette synthese, realisee en recipient unique, exploite plutot une [alpha]-chloration catalysee par la proline et une aldolisation a partir d'un aldehyde commercial, et permet d'assembler tout le squelette carbone en une seule etape. Nous soulignons le role cle que joue le groupe protecteur de l'azote dans la reaction finale d'ouverture d'epoxyde ainsi que la possibilite d'acceder a des analogues structuraux par cette voie. [Traduit par la Redaction] Mots-cles : 1-desoxygalactonojirimycine, iminosucre, organocatalyse, chlorhydrine, synthese totale, produit naturel., Polyhydroxylated piperidines, or iminosugars, have received much attention as biological tools and drug leads with potential applications in the treatment of cancer, viral infections, diabetes, and lysosomal storage disorders. (1-3) [...]

We have recently shown that the aggregation pheromone of the common bed bug, Cimex lectularius, comprises a six-component blend of dimethyl disulfide (DMDS), dimethyl trisulfide (DMTS), (E)-2-hexenal, (E)-2-octenal, 2-hexanone, and histamine. Here, we tested the hypothesis that bed bugs biosynthesize some pheromone components from amino acid precursors in human blood, namely DMDS and DMTS from L-methionine and histamine from histidine. We tested this hypothesis by (i) allowing bed bugs to feed on and metabolize sheep blood enriched with [.sup.13]C-labelled histidine or [.sup.2]H-labelled methionine, (ii) extracting bed bug feces (a source of the aggregation pheromone), and (iii) analyzing feces extracts by GC-MS, HPLC-MS and NMR spectroscopy. The analyses revealed that bed bugs converted [.sup.2]H-methionine to [.sup.2]H-DMDS and [.sup.2]H-DMTS, and [.sup.13]C-histidine to [.sup.13]C-histamine. There is not enough histidine in human blood to account for the amount of histamine that bed bugs produce and excrete with their feces, and only a small proportion of the available [.sup.13]C-histidine was converted to [.sup.13]C-histamine in our study. Therefore, it is likely that bed bugs biosynthesize histamine, and possibly also DMDS and DMTS, primarily de novo. Key words: pheromone biosynthesis, L-methionine, histidine, histamine, dimethyl disulfide, dimethyl trisulfide. Nous avons recemment montre que la pheromone d'agregation chez la puce de lit commune, Cimex lectularius, est constitutee d'un melange de six composants : le dimethyldisulfure (DMDS), dimethyltrisulfure (DMTS), le (E)-2-hexenal, le (E)-2-octenal, la 2-hexanone et l'histamine. Dans le cadre des presents travaux, nous avons voulu verifier l'hypothese selon laquelle les puces de lit biosynthetisent certains composants de la pheromone a partir d'acides amines provenant du sang humain, a savoir le DMDS et le DMTS a partir de la L-methionine et l'histamine a partir de l'histidine. Nous avons mis a l'epreuve cette hypothese (i) en laissant les puces de lit se nourrir de sang de mouton enrichi d'histidine marquee au [.sup.13]C ou de methionine marquee au [.sup.2]H qu'elles ont metabolise, (ii) en extrayant les excrements des puces de lit (une source de la pheromone d'agregation) et (iii) en analysant les extraits d'excrements par GC-MS, HPLC-MS et RMN. Les analyses ont revele que les puces de lit transformaient la [[.sup.2]H]methionine en [[.sup.2]H]DMDS et en [[.sup.2]H]DMTS, et la [[.sup.13]C]histidine en [[.sup.13]C]histamine. Le sang humain ne renferme pas assez d'histidine pour justifier la quantite d'histamine produite par les puces de lit et excretee dans leurs excrements. De plus, dans le cadre de notre etude, seule une faible proportion de la [[.sup.13]C]histidine disponible a ete transformee en [[.sup.13]C]histamine. Par consequent, il est probable que les puces de lit biosynthetisent l'histamine, et possiblement aussi le DMDS et le DMTS, essentiellement de toutes pieces. [Traduit par la Redaction] Mots-cles: biosynthese des pheromones, L-methionine, histidine, histamine, dimethyldisulfure, dimethyltrisulfure., Introduction Over the last two decades, common bed bugs, Cimex lectularius (Hemiptera: Cimicidae), have become a global epidemic. (1) Bed bug infestations have multiple adverse effects on the human host, [...]