Boosting the Impact of EFMC Young Scientists Network Through the Creation of Working Groups.

The establishment of the Young Scientists Network (YSN) by the European Federation for Medicinal Chemistry (EFMC) served as a proactive response to the evolving landscape of the scientific community. The YSN aims to assist early-career medicinal chemists and chemical biologists by responding to emerging themes, such as the influence of social media, shifts in gender balance within the scientific population, and evolving educational opportunities. The YSN also ensures that the upcoming generation of scientists actively contributes to shape the EFMC's strategic direction while addressing their specific needs.

Identification and Validation of New Interleukin-2 Ligands Using DNA-Encoded Libraries.

Interleukin-2 (IL2) is a pro-inflammatory cytokine that plays a crucial role in immunity, which is increasingly being used for therapeutic applications. There is growing interest in developing IL2-based therapeutics which do not interact with the alpha subunit of the IL2 receptor (CD25) as this protein is primarily found on immunosuppressive regulatory T cells (T). Screenings of a new DNA-encoded library, comprising 669,240 members, provided a novel series of IL2 ligands, subsequently optimized by medicinal chemistry.

DNA-Encoded Chemical Libraries: A Comprehensive Review with Succesful Stories and Future Challenges.

DNA-encoded chemical libraries (DELs) represent a versatile and powerful technology platform for the discovery of small-molecule ligands to protein targets of biological and pharmaceutical interest. DELs are collections of molecules, individually coupled to distinctive DNA tags serving as amplifiable identification barcodes. Thanks to advances in DNA-compatible reactions, selection methodologies, next-generation sequencing, and data analysis, DEL technology allows the construction and screening of libraries of unprecedented size, which has led to the discovery of highly potent ligands, some of which have progressed to clinical trials.

An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications.

We describe the development of OncoFAP, an ultra-high-affinity ligand of fibroblast activation protein (FAP) for targeting applications with pan-tumoral potential. OncoFAP binds to human FAP with affinity in the subnanomolar concentration range and cross-reacts with the murine isoform of the protein. We generated various fluorescent and radiolabeled derivatives of OncoFAP in order to study biodistribution properties and tumor-targeting performance in preclinical models.

On-DNA hit validation methodologies for ligands identified from DNA-encoded chemical libraries.

DNA-encoded chemical libraries (DECLs) are large compound collections attached to DNA fragments, serving as amplifiable barcodes, which can be screened on target proteins of pharmaceutical interest. In DECL selections, ligands are identified by high-throughput DNA sequencing, by comparing their frequency before and after the affinity capture step. Hits identified using this procedure need to be validated by resynthesis and by performing affinity measurements.

Critical Evaluation of Photo-cross-linking Parameters for the Implementation of Efficient DNA-Encoded Chemical Library Selections.

The growing importance of DNA-encoded chemical libraries (DECLs) as tools for the discovery of protein binders has sparked an interest for the development of efficient screening methodologies, capable of discriminating between high- and medium-affinity ligands. Here, we present a systematic investigation of selection methodologies, featuring a library displayed on single-stranded DNA, which could be hybridized to a complementary oligonucleotide carrying a diazirine photoreactive group. Model experiments, performed using ligands of different affinity to carbonic anhydrase IX, revealed a recovery of preferential binders up to 10%, which was mainly limited by the highly reactive nature of carbene intermediates generated during the photo-cross-linking process.

DNA-Compatible Diazo-Transfer Reaction in Aqueous Media Suitable for DNA-Encoded Chemical Library Synthesis.

DNA-encoded chemical libraries (DECLs) are increasingly employed in hit discovery toward proteins of pharmaceutical interest. Protected amino acids are the most commonly used building blocks for the construction of DECLs; therefore, the expansion of reaction scope with the subsequent free amine is highly desired. Here, we developed a robust DNA-compatible diazo-transfer reaction using imidazole-1-sulfonyl azide tetrafluoroborate salt converting a wide range of primary amines into their corresponding azides in good to excellent yields.

Quantitative Assessment of Affinity Selection Performance by Using DNA-Encoded Chemical Libraries.

DNA-encoded chemical libraries are often used for the discovery of ligands against protein targets of interest. These large collections of DNA-barcoded chemical compounds are typically screened by using affinity capture methodologies followed by PCR amplification and DNA sequencing procedures. However, the performance of individual steps in the selection procedures has been scarcely investigated, so far.

Enantioselective Catalysis Coupled with Stereodivergent Cyclization Strategies Enables Rapid Syntheses of (+)-Limaspermidine and (+)-Kopsihainanine A.

Enantioselective Pd-catalyzed allylic alkylations of dihydropyrido[1,2-a]indolone (DHPI) substrates were used to construct the C20-quaternary stereocenters of multiple monoterpene indole alkaloids. Stereodivergent Pictet-Spengler and Bischler-Napieralski cyclization/reduction cascades furnish the cis- and trans-fused azadecalin subunits present in Aspidosperma and Kopsia alkaloids, respectively, en route to highly efficient syntheses of (+)-limaspermidine and (+)-kopsihainanine A.

A Three-Step Synthesis of Tetrasubstituted NH-Pyrroles.

Buta-1,3-dienes appended with electron-withdrawing groups (EWGs), derived from the [2 + 2] cycloaddition-retroelectrocyclization (CA-RE) cascade, react with (predominately) nitrogen-based nucleophiles affording tetrasubstituted 2-amino-NH-pyrroles in moderate to excellent yields with complete regioselectivity. Penta-2,4-dien-1-ones also undergo a similar transformation, providing analogous products and greatly enhancing the substitution of the pyrrole available. Oxidation from pyrrole to pyrrolidinone affords highly colored compounds that experience a strong bathochromic shift of the longest-wavelength absorption band in the UV/vis spectrum upon protonation, with return to the original spectra following neutralization.

The [2 + 2] Cycloaddition-Retroelectrocyclization and [4 + 2] Hetero-Diels-Alder Reactions of 2-(Dicyanomethylene)indan-1,3-dione with Electron-Rich Alkynes: Influence of Lewis Acids on Reactivity.

The reaction of electrophilic 2-(dicyanomethylene)indan-1,3-dione (DCID) with substituted, electron-rich alkynes provides two classes of push-pull chromophores with interesting optoelectronic properties. The formal [2 + 2] cycloaddition-retroelectrocyclization reaction at the exocyclic double bond of DCID gives cyanobuta-1,3-dienes, and the formal [4 + 2] hetero-Diels-Alder (HDA) reaction at an enone moiety of DCID generates fused 4H-pyran heterocycles. Both products can be obtained in good yield and excellent selectivity by carefully tuning the reaction conditions; in particular, the use of Lewis acids dramatically enhances formation of the HDA adduct.

A new class of non-C2-symmetric ligands for oxidative and redox-neutral palladium-catalyzed asymmetric allylic alkylations of 1,3-diketones.

We report the discovery, synthesis, and application of a new class of non-C2-symmetric phosphoramidite ligands derived from pyroglutamic acid for use in both oxidative and redox-neutral palladium-catalyzed asymmetric allylic alkylations of 1,3-diketones. The resulting chiral products are typically obtained in high yield with good to excellent levels of enantioselectivity.

Outstanding chiroptical properties: a signature of enantiomerically pure alleno-acetylenic macrocycles and monodisperse acyclic oligomers.

A second series of shape-persistent alleno-acetylenic macrocycles and monodisperse acyclic oligomers with conformationally less flexible backbones were synthesized in enantiomerically pure form by short, high-yielding routes starting from optically active 1,3-diethynylallenes. All seven stereoisomers-two pairs of enantiomers and three achiral stereoisomers-in the macrocyclic series were separated and configurationally assigned. The electronic circular dichroism (ECD) spectra of the D2 -symmetric, (P,P,P,P)- and (M,M,M,M)-configured macrocycles display remarkably intense chiroptical responses.

Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.

A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.

Application of a catalytic asymmetric Povarov reaction using chiral ureas to the synthesis of a tetrahydroquinoline library.

A 2328-membered library of 2,3,4-trisubstituted tetrahydroquinolines was produced using a combination of solution- and solid-phase synthesis techniques. A tetrahydroquinoline (THQ) scaffold was prepared via an asymmetric Povarov reaction using cooperative catalysis to generate three contiguous stereogenic centers. A matrix of 4 stereoisomers of the THQ scaffold was prepared to enable the development of stereo/structure-activity relationships (SSAR) upon biological testing.

Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries.

The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.