P-Amidites can be used in iterative couplings to selectively give mixed P(III) -P(V) anhydrides. These intermediates can be oxidized followed by a rapid removal of the two terminal fluorenylmethyl groups. An iterative synthesis (coupling, oxidation, deprotection) of nucleoside oligophosphates can be carried out in solution and on a solid support. The coupling rates and yields are high, the procedures convenient (non-dry reagents and solvents, ambient conditions, unprotected nucleotides), and the purification is very simple. The method works with all canonical nucleosides and holds promise for significant simplification of the usually cumbersome process of P-anhydride bond construction.

Phosphoanhydrides (P-anhydrides) are ubiquitously occurring modifications in nature. Nucleotides and their conjugates, for example, are among the most important building blocks and signaling molecules in cell biology. To study and manipulate their biological functions, a diverse range of analogues have been developed. Phosphate-modified analogues have been successfully applied to study proteins that depend on these abundant cellular building blocks, but very often both the preparation and purification of these molecules are challenging. This study discloses a general access to P-anhydrides, including different nucleotide probes, that greatly facilitates their preparation and isolation. The convenient and scalable synthesis of, for example, (18) O labeled nucleoside triphosphates holds promise for future applications in phosphoproteomics.

This review provides an overview and historical context to two concepts for the design of natural product-inspired compound libraries and highlights the used synthetic methodologies.

Natural product (NP) structures are a rich source of inspiration for the discovery of new biologically relevant chemical matter. In natural product inspired pseudo‐NPs, NP‐derived fragments are combined de novo in unprecedented arrangements. Described here is the design and synthesis of a 155‐member pyrroquinoline pseudo‐NP collection in which fragments characteristic of the tetrahydroquinoline and pyrrolidine NP classes are combined with eight different connectivities and regioisomeric arrangements. Cheminformatic analysis and biological evaluation of the compound collection by means of phenotyping in the morphological “cell painting” assay followed by principal component analysis revealed that the pseudo‐NP classes are chemically diverse and that bioactivity patterns differ markedly, and are dependent on connectivity and regioisomeric arrangement of the fragments.

P-Amidite kçnnen verwendet werden, um in einer iterativen Kupplung selektiv gemischte P III -P V -Anhydride herzustellen. Diese Intermediate kçnnen oxidiert und die terminalen Fluorenylmethylgruppen darauffolgend abgespalten werden. Eine iterative Synthese (Kupplung, Oxidation, Entschützung) von Nukleosidoligophosphaten kann sowohl in Lçsung als auch auf einer festen Phase durchgeführt werden. Die Geschwindigkeiten und Ausbeuten der einzelnen Schritte sind hoch, das Vorgehen einfach (keine wasserfreien Reagentien und Lçsungsmittel, atmosphärische Bedingungen, keine Schutzgruppen am Nukleotid), und die Reinigung ist sehr einfach. Die Methode kann bei allen kanonischen Nukleosiden angewendet werden und verspricht eine signifikante Vereinfachung des sonst mühsamen Prozesses der P-Anhydrid-Synthese. und Prof. J. Robinson für die anhaltende Unterstützung sowie dem NMR-Service an der UZH (O. Zerbe). Diese Studie wurde vom Fonds der Chemischen Industrie (FCI, Liebig-Stipendium an H.J.J.) und dem Schweizer Nationalfonds zur Fçrderung der wissenschaftlichen Forschung (SNF, Ambizione Grant PZ00P2_136816 an H.J.J.) unterstützt.Hintergrundinformationen zu diesem Beitrag sind im WWW unter http://dx.

Natural product (NP) structures are a rich source of inspiration for the discovery of new biologically relevant chemical matter. In natural product inspired pseudo‐NPs, NP‐derived fragments are combined de novo in unprecedented arrangements. Described here is the design and synthesis of a 155‐member pyrroquinoline pseudo‐NP collection in which fragments characteristic of the tetrahydroquinoline and pyrrolidine NP classes are combined with eight different connectivities and regioisomeric arrangements. Cheminformatic analysis and biological evaluation of the compound collection by means of phenotyping in the morphological “cell painting” assay followed by principal component analysis revealed that the pseudo‐NP classes are chemically diverse and that bioactivity patterns differ markedly, and are dependent on connectivity and regioisomeric arrangement of the fragments.