Innovative On-DNA Synthesis of Sulfides and Sulfoximines: Enriching the DEL Synthesis Toolbox.

DNA-encoded library (DEL) technologies enable the fast exploration of gigantic chemical space to identify ligands for the target protein of interest and have become a powerful hit finding tool for drug discovery projects. However, amenable DEL chemistry is restricted to a handful of reactions, limiting the creativity of drug hunters. Here, we describe a new on-DNA synthetic pathway to access sulfides and sulfoximines. These moieties, usually contemplated as challenging to achieve through alkylation and oxidation, can now be leveraged in routine DEL selection campaigns.

Development of on-DNA Formation of Benzofuran for DNA-Encoded Library Synthesis.

Using a novel homologation-heterocyclization cascade, the on-DNA synthesis of benzofurans from aldehydes has been developed. The methodology, based on an innovative use of the Seyferth-Gilbert homologation, followed by a high yielding Sonogashira coupling in situ intramolecular cyclization one-pot, two-step reaction, provides a powerful and unique pathway for DNA-encoded library (DEL) synthesis of a wide array of pharmaceutically relevant benzofuran-based scaffolds.

Simple and Practical DNA Quantification Method for DNA-Encoded Library Synthesis.

Over the past three decades, DNA-encoded library (DEL) technologies have become one of the most relevant strategies for hit-finding. Recent advances in synthetic methodologies for DNA-encoded libraries rendered the increased chemical space available, but it is unknown how every variety of chemistry affects DNA's integrity. Available assays to quantify DNA damage are restricted to electrophoresis, ligation efficiency, and mostly qPCR quantification and sequencing, which may contain predisposition and inconsistency. We developed an external standard method through LC-MS analysis to accurately quantify DNA damage throughout the chemical transformations. An assessment was conducted on on-DNA chemical reactions that are frequently employed in DEL synthesis, and these results were compared to traditional qPCR measurements. Our study provides a simple, practicable, and accurate measurement for DNA degradation during DEL synthesis. Our finding reveals substantial disagreement among the usual DNA-damaging assessment methods, which have been largely neglected so far.

Constructive on-DNA Thiol Aerial Oxidization for DNA-Encoded Library Synthesis.

A novel on-DNA oxidative disulfide formation method has been developed. Under ambient conditions, the methodology showcased wide applicability and swift implementation in routine DNA-encoded library synthesis to access pharmaceutically relevant motifs.

On-DNA Morita-Baylis-Hillman Reaction: Accessing Targeted Covalent Inhibitor Motifs in DNA-Encoded Libraries.

We herein present the first application of the on-DNA Morita-Baylis-Hillman (MBH) reaction for the creation of pharmaceutically relevant targeted covalent inhibitors (TCIs) with an α-hydroxyl Michael acceptor motif. Adapting a DNA-compatible organocatalytic process, this MBH reaction for covalent selection-capable DNA encoded library (DEL) synthesis grants access to densely functionalized and versatile precursors to explore novel chemical space for molecule recognition in drug discovery. Most importantly, this methodology sheds light on potentially unexpected reaction outcomes of the MBH reaction.

Development of On-DNA Cyclic Imide Synthesis for DNA Encoded Library Construction.

Here, we describe a novel method for the on-DNA synthesis of cyclic imides, an important class of molecules that includes several well-known medications. Significantly, the new method enabled on-DNA synthesis under mild conditions with high conversions and a broad functional group tolerance, utilizing ubiquitous bifunctional amines and bis-carboxylic acid, or alkyl halides, and therefore served as the linchpin for DNA encoded library (DEL) synthesis. The mechanism study of off-DNA and on-DNA chemical transformations revealed unique insights in contrast to conventional chemical transformation.

Constructive On-DNA Abramov Reaction and Pudovik Reaction for DEL Synthesis.

Organophosphonic compounds are distinctive among natural products in terms of stability and mimicry. Numerous synthetic organophosphonic compounds, including pamidronic acid, fosmidromycin, and zoledronic acid, are approved drugs. DNA encoded library technology (DELT) is a well-established platform for identifying small molecule recognition to target protein of interest (POI). Therefore, it is imperative to create an efficient procedure for the on-DNA synthesis of α-hydroxy phosphonates for DEL builds.

Development of the Inverse Sonogashira Reaction for DEL Synthesis.

An efficient approach for aryl acetylene DNA-encoded library (DEL) synthesis was developed in this study by transition-metal-mediated inverse Sonogashira reaction of 1-iodoalkyne with boronic acid under ambient conditions, with moderate to excellent conversions and broad substrate adaptability for the first time. Compared to palladium-phosphine, copper iodide performed better in the on-DNA inverse Sonogashira reaction. Interestingly, substrate diversity can be enhanced by first interrogating coupling reagents under copper-promoted conditions, and then revalidating them under palladium-facilitated conditions for those reagents which failed under the former. This complementary validation strategy is particularly well-fitted to any DEL validation studies.

On-DNA Alkyne Iodination and Acetylenic Coupling as a Useful Tool for DEL Synthesis.

1-Iodoalkynes and 1,3-diynes are versatile chemical intermediates and pharmaceutically valuable ingredients. In this study, copper mediated on-DNA alkyne iodination and Cadiot-Chodkiewicz coupling are developed for the first time. This generates diverse, systematic, and unprecedented topographic structural features, which could be invaluable as molecular recognition agents for drug discovery in DEL screening.

Kinugasa Reaction for DNA-Encoded ß-Lactam Library Synthesis.

ß-Lactam antibiotics are one of the most important antibacterial drug classes worldwide. This work will present the first prototype on-DNA ß-lactam combinatorial library with novel structures and chemical space properties that would be significant for phenotypic screening to identify the next generation of antibiotics to combat the pervasive problem of bacterial resistance.

DNA Compatible Oxidization and Amidation of Terminal Alkynes.

Through a modified Kinugasa reaction, a novel method of amidation on terminal oligo alkyne conjugates by copper-promoted oxidation with nitrones has been developed. Unprotected bifunctional carboxylic acid-amine reagents can be transformed directly to the respective amide products under these edited Kinugasa reaction conditions. 3-Cycle DNA-encoded libraries (DELs) can be built in three steps of chemical conversion.

N-Alkyl Linkers for DNA-Encoded Chemical Libraries.

A series of novel N-alkyl linkers that connect small-molecule library members with their encoding DNA oligonucleotides has been developed. In comparison with the standard amide linker (usually constructed with oligo-AOP-NH2 ), the N-alkyl linker is not only more chemically stable, but also provides better structural diversity at the linkage point. Chemical variety in the vicinity of the polyglycol terminus, in particular, could affect binding interactions with the target protein. It could have been neglected in previous DNA-encoded chemical library (DEL) synthesis and screening studies due to the limited linkage alternatives. With these linkers, one can produce versatile key intermediates as Cycle 1 products directly amenable to Cycle 2 chemistry without the use of protecting groups. As a result, a DEL synthesis process that uses the fewest chemical conversions, such as 3-step, 3-cycle DELs, can achieve higher synthetic efficiency while creating less DNA tag degradation, resulting in higher quality DELs.

Discovery of a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine and a 1-aryloxyisoquinoline series of TRPA1 antagonists.

A series of TRPA1 antagonists is described having a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine or a 1-aryloxyisoquinoline scaffold. These compounds have high ligand efficiency and favorable physical properties and may thus serve as scaffolds for further optimization.

Discovery of P2X3 selective antagonists for the treatment of chronic pain.

Purinergic receptor P2X3 has been linked to analgesia in a number of pre-clinical models of pain, and is expressed in the human pain perception pathway. Only few P2X3-selective antagonists have been reported to date. This Letter describes the SAR and in vivo analgesic profile of a novel scaffold of selective P2X3 antagonists.

Development of 2,4-diaminopyrimidine derivatives as novel SNSR4 antagonists.

2,4-Diaminopyrimidines derivatives were developed as a novel class of SNSR4 antagonists. Structure activity relationship of the diamino pyrimidine core was explored and a tool compound suitable for target validation was identified.

Formal Synthesis of 3-Deoxy-D-manno-2-Octulosonic Acid (KDO) via a Highly Double-Stereoselective Hetero Diels-Alder Reaction Directed by a (Salen)Co(II) Catalyst and Chiral Diene.

This paper presents a formal total synthesis of 3-deoxy-D-manno-2-octulosonic acid (KDO) based on a highly double-stereoselective hetero Diels-Alder reaction between an electron-rich diene and ethyl glyoxylate catalyzed by (Salen)Co(II) complex, a new catalyst for Diels-Alder reactions. A facial specific hydroboration followed by oxidative workup leads to a diol system with the trans-diequatorial arrangement of hydroxyl groups at the C-4 and C-5. Inversion of the configuration of the C-5 hydroxyl group in 12 and then ketal formation afford the desired target diisopropylidene-2-deoxy-KDO methyl ester (18), which can be converted to KDO according to the literature procedure.