Hetero-Diels-Alder and CuAAC Click Reactions for Fluorine-18 Labeling of Peptides: Automation and Comparative Study of the Two Methods.

Radiolabeled peptides are valuable tools for diagnosis or therapies; they are often radiofluorinated using an indirect approach based on an F-18 prosthetic group. Herein, we are reporting our results on the F-18 radiolabeling of three peptides using two different methods based on click reactions. The first one used the well-known CuAAC reaction, and the second one is based on our recently reported hetero-Diels-Alder (HDA) using a dithioesters (thia-Diels-Alder) reaction. Both methods have been automated, and the 18F-peptides were obtained in similar yields and synthesis time (37-39% decay corrected yields by both methods in 120-140 min). However, to obtain similar yields, the CuAAC needs a large amount of copper along with many additives, while the HDA is a catalyst and metal-free reaction necessitating only an appropriate ratio of water/ethanol. The HDA can therefore be considered as a minimalist method offering easy access to fluorine-18 labeled peptides and making it a valuable additional tool for the indirect and site-specific labeling of peptides or biomolecules.

Convergent access to mono-fluoroalkene-based peptidomimetics.

The convergent and selective preparation of (Z)-monofluoroalkene-based dipeptide isosteres from functionalized fluorosulfones as a cornerstone is described. In this approach, the N-terminal amino group is introduced by a conjugate addition reaction of phthalimide onto fluorinated vinylsulfones containing α-amino-acid side chains while the C-terminal motif is linked to the fluorovinylic peptide bond mimic via the Julia-Kocienski reaction between fluorosulfones and substituted aldehydes bearing α-amino-acid side chains.

Access to Fluoropyrrolidines by Intramolecular Aza-Michael Addition Reaction.

Study of the intramolecular aza-Michael addition reaction from an aminofluorovinylsulfone opens a new route for the synthesis of pyrrolidine derivatives. An unexpected diastereoselective cyclization reaction was observed, leading preferentially to the anti-N-benzylpyrrolidine sulfone. The resulting sulfone was reacted with aldehydes to access ß-substituted α-fluoroalkenyl pyrrolidines in one step.

Fluorinated hydroxypiperidines as selective ß-glucosidase inhibitors.

A new series of fluoroallylamines derived from hydroxypiperidines was prepared and evaluated against various glycosidases. The short synthesis of target molecules involved the modified Julia reaction between aldehydes and functionalized fluoroaminosulfones. Biological studies revealed good and selective ß-glucosidase inhibition in the micromolar range for two compounds, while the non-fluorinated analogue of the most active compound was selective towards α-glucosidase.

THE IMS LIBRARY: FROM IN-STOCK TO VIRTUAL.

A chemical library is a key element in the early stages of pharmaceutical research. Its design encompasses various factors, such as diversity, size, ease of synthesis, aimed at increasing the likelihood of success in drug discovery. This article explores the collaborative efforts of computational and synthetic chemists in tailoring chemical libraries for cost-effective and resource-efficient use, particularly in the context of academic research projects. It proposes chemoinformatics methodologies that address two pivotal questions: first, crafting a diverse panel of under 1000 compounds from an existing pool through synthetic efforts, leveraging the expertise of organic chemists; and second, expanding pharmacophoric diversity within this panel by creating a highly accessible virtual chemical library. Chemoinformatics tools were developed to analyse initial panel of about 10,000 compounds into two tailored libraries: eIMS and vIMS. The eIMS Library comprises 578 diverse in-stock compounds ready for screening. Its virtual counterpart, vIMS, features novel compounds guided by chemists, ensuring synthetic accessibility. vIMS offers a broader array of binding motifs and improved drug-like characteristics achieved through the addition of diverse functional groups to eIMS scaffolds followed by filtering of reactive or unusual structures. The uniqueness of vIMS is emphasized through a comparison with commercial suppliers' virtual chemical space.