Functionality‐Independent DNA Encoding of Complex Natural Products

DNA encoded chemical libraries (DELs) link the powers of genetics and chemical synthesis via combinatorial optimization. Through combinatorial chemistry, DELs can grow to the unprecedented size of billions to trillions. To take full advantage of the DEL approach, linking the power of genetics directly to chemical structures would offer even greater diversity in a finite chemical world. Natural products have evolved an incredible structural diversity along with their biological evolution. Herein, we used traditional Chinese medicines (TCMs) as examples in a late‐stage modification toolbox approach to annotate these complex organic compounds with amplifiable DNA barcodes, which could be easily incorporated into a DEL. The method of end‐products labeling also generates a cluster of isomers with a single DNA tag at different sites. These isomers provide an additional spatial diversity for multiple accessible pockets of targeted proteins. Notably, a novel PARP1 inhibitor from TCM has been identified from the natural products enriched DEL (nDEL).     

Second-generation DNA-encoded multiple display on a constant macrocyclic scaffold enabled by an orthogonal protecting group strategy

DNA-encoded chemical library(DEL) represents an emerging drug discovery technology to construct compound libraries with abundant chemical combinations. While drug-like small molecule DELs facilitate the discovery of binders against targets with defined pockets, macrocyclic DELs harboring extended scaffolds enable targeting of the protein–protein interaction(PPI) interface. We previously demonstrated the design of the first-generation DNA-encoded multiple display based on a constant macrocyclic s...     

In-solution direct oxidative coupling for the integration of sulfur/selenium into DNA-encoded chemical libraries

Sulfur/selenium-containing electron-rich arenes (ERAs) exist in a wide range of both approved and investigational drugs with diverse pharmacological activities. These unique chemical structures and bioactive properties, if combined with the emerging DNA-encoded chemical library (DEL) technique, would facilitate drug and chemical probe discovery. However, it remains challenging, as there is no general DNA-compatible synthetic methodology available for the formation of C–S and C–Se bonds in aqueous solution. Herein, an in-solution direct oxidative coupling procedure that could efficiently integrate sulfur/selenium into the ERA under mild conditions is presented. This method features simple DNA-conjugated electron-rich arenes with a broad substrate scope and a transition-metal free process. Furthermore, this synthetic methodology, examined by a scale-up reaction test and late-stage precise modification in a mock peptide-like DEL synthesis, will enable its utility for the synthesis of sulfur/selenium-containing DNA-encoded libraries and the discovery of bioactive agents.

DNA-compatible direct oxidative coupling using various sulfur/selenium sources has been achieved, featuring pre-functionalization-free substrates and transition metal-free condition.     

Merging C(sp3)–H activation with DNA-encoding

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C–H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development of DNA-encoded C(sp³)–H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp³)–H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs. Furthermore, the C–H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp³) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.

DNA-compatible C(sp³)–H activation reactions of aliphatic carboxylic acids, amides, and ketones were developed for efficient access to DEL synthesis.     

Highly efficient on-DNA amide couplings promoted by micelle forming surfactants for the synthesis of DNA encoded libraries

DNA encoded libraries (DELs) represent powerful new technology for finding small molecule ligands for proteins and are increasingly being applied to hit finding in medicinal chemistry. Crucial to the synthesis of high quality DELs is the identification of chemical reactions for their assembly that proceed with very high conversion across a range of different substrates, under conditions compatible with DNA-tagged substrates. Many current chemistries used in DEL synthesis do not meet this requirement, resulting in libraries of low fidelity. Amide couplings are the most commonly used reaction in synthesis of screening libraries and also in DELs. The ability to carry out highly efficient, widely applicable amide couplings in DEL synthesis would therefore be highly desirable. We report a method for amide coupling using micelle forming surfactants, promoted by a modified linker, that is broadly applicable across a wide range of substrates. Most significantly, this works exceptionally well for coupling of DNA-conjugated carboxylic acids (N-to-C) with amines in solution, a procedure that is currently very inefficient. The optimisation of separate procedures for coupling of DNA-conjugated acids and amines by reagent screening and statistically driven optimisation is described. The generality of the method is illustrated by the application to a wide range of examples with unprecedented levels of conversion. The utility of the (N-to-C) coupling of DNA-conjugated acids in DEL synthesis is illustrated by the three cycle synthesis of a fully DNA-encoded compound by two cycles of coupling of an aminoester, with intermediate ester hydrolysis, followed by capping with an amine. This methodology will be of great utility in the synthesis of high fidelity DELs.

Highly efficient forward and reverse on-DNA amide couplings were developed exploiting hydrophobic linkers in combination with the micelle forming surfactant TPGS-750M. The method is highly effective for a wide range of substrates in the synthesis of DNA-encoded libraries.     

RASS-Enabled S/P−C and S−N Bond Formation for DEL Synthesis

DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on-DNA chemistries to incorporate medicinally relevant and C−S, C−P and N−S linkages into DELs, which are underrepresented in the canonical methods.     

The Potential of Micellar Media in the Synthesis of DNA-Encoded Libraries

DNA-encoded library (DEL) technology has become widely used in drug discovery research. The construction of DELs requires robust organic transformations that proceed in aqueous media under mild conditions. Unfortunately, the application of water as reaction medium for organic synthesis is not evident due to the generally limited solubility of organic reagents. However, the use of surfactants can offer a solution to this issue. Oil-in-water microemulsions formed by surfactant micelles are able to localize hydrophobic reagents inside them, resulting in high local concentrations of the organic substances in an otherwise poorly solvated environment. This review provides a conceptual and critical summary of micellar synthesis possibilities that are well suited to DEL synthesis. Existing examples of micellar DEL approaches, together with a selection of micellar organic transformations fundamentally suitable for DEL are discussed.     

RASS‐Enabled S/P−C and S−N Bond Formation for DEL Synthesis

DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on‐DNA chemistries to incorporate medicinally relevant and C?S, C?P and N?S linkages into DELs, which are underrepresented in the canonical methods.     

Antimony salt-promoted cyclization facilitating on-DNA syntheses of dihydroquinazolinone derivatives and its applications

DNA-encoded chemical libraries technology has become a novel approach to finding hit compounds in early drug discovery. The chemical space in a DEL would be expanded to realize its full potential, especially when integrating privileged scaffold dihydroquinazoline that has demonstrated a variety of diverse bioactivities. Driven by the requirement of parallel combinatorial synthesis, we here report a facile synthesis of on-DNA dihydroquinazolinone from aldehyde and anthranilamide. This DNA-compatible reaction was promoted by antimony trichloride, which has been proven to accelerate the reaction and improve conversions. Notably, the broad substrate scope of aldehydes and anthranilamides was explored under the mild reaction condition to achieve moderate-to-excellent conversion yields. We further applied the reaction into on-DNA macrocyclization, obtaining macrocycles embedded dihydroquinazolinone scaffold in synthetically useful conversion yields.     

Hierarchical Microtubular Covalent Organic Frameworks Achieved by COF-to-COF Transformation

Pore environment and aggregated structure play a vital role in determining the properties of porous materials, especially regarding the mass transfer. Reticular chemistry imparts covalent organic frameworks (COFs) with well-aligned micro/mesopores, yet constructing hierarchical architectures remains a great challenge. Herein, we reported a COF-to-COF transformation methodology to prepare microtubular COFs. In this process, the C₃-symmetric guanidine units decomposed into C₂-symmetric hydrazine units, leading to the crystal transformation of COFs. Moreover, the aggregated structure and conversion degree varied with the reaction time, where the hollow tubular aggregates composed of mixed COF crystals could be obtained. Such hierarchical architecture leads to enhanced mass transfer properties, as proved by the adsorption measurement and chemical catalytic reactions. This self-template strategy was successfully applied to another four COFs with different building units.     

N,N-dimethylformamide: a multipurpose building block

Often used as a common solvent for chemical reations and utilized widely in industry as a reagent, N,N-dimethylformamide (DMF) has played an important role in organic synthesis for a long time. Numerous highly useful articles and reviews discussing its utilizations have been published. With a focus on the performance of DMF as a multipurpose precursor for various units in numerous reactions, this Minireview summarizes recent developments in the employment of DMF in the fields of formylation, aminocarbonylation, amination, amidation, and cyanation, as well as its reaction with arynes.     

Expanding the scope of native chemical ligation – templated small molecule drug synthesis via benzanilide formation

We describe a reaction system that enables the synthesis of Bcr–Abl tyrosine kinase inhibitors (TKI) via benzanilide formation in water. The reaction is based on native chemical ligation (NCL). In contrast to previous applications, we used the NCL chemistry to establish aromatic rather than aliphatic amide bonds in coupling reactions between benzoyl and o-mercaptoaniline fragments. The method was applied for the synthesis of thiolated ponatinib and GZD824 derivatives. Acid treatment provided benzothiazole structures, which opens opportunities for diversification. Thiolation affected the affinity for Abl1 kinase only moderately. Of note, a ponatinib-derived benzothiazole also showed nanomolar affinity. NCL-enabled benzanilide formation may prove useful for fragment-based drug discovery. To show that benzanilide synthesis can be put under the control of a template, we connected the benzoyl and o-mercaptoaniline fragments to DNA and peptide nucleic acid (PNA) oligomers. Complementary RNA templates enabled adjacent binding of reactive conjugates triggering a rapid benzoyl transfer from a thioester-linked DNA conjugate to an o-mercaptoaniline-DNA or -PNA conjugate. We evaluated the influence of linker length and unpaired spacer nucleotides within the RNA template on the product yield. The data suggest that nucleic acid-templated benzanilide formation could find application in the establishment of DNA-encoded combinatorial libraries (DEL).

The templated native chemical ligation between benzoyl thioesters and o-mercaptoaniline fragments proceeds in water and provides benzanilides that have nanomolar affinity for Abl1 kinase.     

Study of the reactivity of α‐acylenaminoketones. Synthesis of pyrazoles

The reactions of 4‐(methylamino)‐3‐penten‐2‐one with diazoketones yielded the α‐acylenaminoketones 1–3 in good yields. Preparation of the α‐acylenaminoketone 4 was carried out by treatment of 4‐(t‐butyl‐amino)‐3‐penten‐2‐one with benzoyl chloride being followed by reaction of transamination with methyl‐amine. The reactions were carried out in five different solvents and were submitted to gas chromatogra‐phy/mass spectrometry analysis, with the goal of obtaining substituted pyrazoles and determining which of the carbonyls would preferentially be attacked by the nucleophile. The reactions of compounds 1–4 with hydrazine reagents led to the formation of the pyrazoles 5–7a‐q . Small amounts of 4‐methylamino‐2‐pentenones 10a‐q , amides 11a‐q and pyrazoles 12a‐q were also obtained in these reactions. The unexpected formation of pyrazoles 15d,h,q was detected when methanol and N,N‐dimethylformamide were used as solvents in the reactions of α‐acylenaminoketone 4 with hydrazine reagents.     

Diversified strategy for the synthesis of DNA-encoded oxindole libraries

DNA-encoded library technology (DELT) employs DNA as a barcode to track the sequence of chemical reactions and enables the design and synthesis of libraries with billions of small molecules through combinatorial expansion. This powerful technology platform has been successfully demonstrated for hit identification and target validation for many types of diseases. As a highly integrated technology platform, DEL is capable of accelerating the translation of synthetic chemistry by using on-DNA compatible reactions or off-DNA scaffold synthesis. Herein, we report the development of a series of novel on-DNA transformations based on oxindole scaffolds for the design and synthesis of diversity-oriented DNA-encoded libraries for screening. Specifically, we have developed 1,3-dipolar cyclizations, cyclopropanations, ring-opening of reactions of aziridines and Claisen–Schmidt condensations to construct diverse oxindole derivatives. The majority of these transformations enable a diversity-oriented synthesis of DNA-encoded oxindole libraries which have been used in the successful hit identification for three protein targets. We have demonstrated that a diversified strategy for DEL synthesis could accelerate the application of synthetic chemistry for drug discovery.

Constructing DNA-encoded oxindole libraries by a diversified strategy.     

Chemical Investigation on Various Aromatic Compounds Polymerization in Low Pressure Helium Plasma

Remarkable properties of plasma polymer films are greatly dependent not only on the chemical structure of precursor but also on the reactor design and the deposition conditions. In many industrial applications it is a challenge to control the plasma polymer structure. In this paper we investigate the chemical transformation of various aromatic compounds, such as activation and fragmentation of substituent-part, aromatic ring opening, during plasma polymerization process. Polymerized films are deposited in a low-frequency capacitively coupled plasma-enhanced chemical vapour deposition reactor, working at low pressure. The chemical composition of plasma-polymerized films is elucidated by Fourier-transform infrared spectroscopy, solid-state carbon-13 nuclear magnetic resonance spectroscopy, and X-ray photoelectron spectroscopy. Based on spectroscopic measurements, the intermediary reactions during film growth may be presumed.     

Structures of N—（2,3,4,6—Tetra—O—acetyl—β—D—glycosyl） thiocarbamic Benzoyl Hydrazine

The crystal structure of N-(2,3,4,6-tetra-O-acetyl-β-D-gly-cosyl)-thiocarbamic benzoyl hydrazine(C22H27N3O9S) was determined by X-ray diffracton method.The hexopyranosyl ring adopts a chair conformation.All the ring substituents are in the equatorial positions.The acetoxyl-methyl group is in synclinal conformation.The S atom is in synperiplanar conformation while the benzoyl hydrazine moiety is anti-periplanar.The thiocarbamic moiety is almost companar with the benzoyl hydrazine group.There are two intramolecular hydrogen bonds and one intermolecular hydrogen bond for each molecule in the crystal structure.The molecules form a network structure through intermolecular hydrogen bonds.     

Control of Chemical Reactions by Using Molecules that Buffer Non-aqueous Solutions

Control of chemical reactions is necessary to obtain designer chemical transformation products and for preventing decomposition and isomerization reactions of compounds of interest. For the control of chemical events in aqueous solutions, the use of aqueous buffers is a common practice. However, no molecules that buffer non-aqueous solutions were commonly used. Herein, we demonstrate that 1,3-cyclohexanedione derivatives have buffering functions in non-aqueous solutions. It was also shown that these molecules can be utilized to alter and control chemical reactions. 1,3-Cyclohexanedione derivatives inhibited both acid- and base-catalyzed isomerizations and decompositions in organic solvents. The reaction products obtained in the presence of the buffering molecule 2-methyl-1,3-cyclohexanedione differed from those obtained in the absence of the buffering molecule. The use of buffering molecules that work in organic solvents provides a strategy to control chemical reactions and expands the range of compounds that can be synthesized.     

A Novel Chemical Sensor Based on Sb2S3 Film for Highly Sensitive Detection of Hydrazine

The Sb₂S₃ film on indium‐tin oxide (ITO) substrate has been used as an efficient electron transfer mediator for the fabrication of novel chemical sensor towards hydrazine, which is a diamine known as neurotoxin and carcinogen. Sb₂S₃ film is deposited on ITO substrate by drop‐casting process using Sb₂S₃ solution as precursor and possesses reticular structure with the morphology of uniform hollow hemispheres. The fabricated chemical sensor for selective detection of hydrazine displays a high sensitivity of 106.25 μA/(mM cm²) with a low detection limit of 0.5 μM and it also exhibits excellent reproducibility and stability in hydrazine detection.     

Template-free sol–gel synthesis of high surface area mesoporous silica based catalysts for esterification of di-carboxylic acids

High surface area mesoporous silica based catalysts have been prepared by a simple hydrolysis/sol–gel process without using any organic template and hydrothermal treatment. A controlled hydrolysis of ethyl silicate-40, an industrial bulk chemical, as a silica precursor, resulted in the formation of very high surface area (719 m²/g) mesoporous (pore size 67 Å and pore volume 1.19 cc/g) silica. The formation of mesoporous silica has been correlated with the polymeric nature of the ethyl silicate-40 silica precursor which on hydrolysis and further condensation forms long chain silica species which hinders the formation of a close condensed structure thus creating larger pores resulting in the formation of high surface mesoporous silica. Ethyl silicate-40 was used further for preparing a solid acid catalyst by supporting molybdenum oxide nanoparticles on mesoporous silica by a simple hydrolysis sol–gel synthesis procedure. The catalysts showed very high acidity as determined by NH₃-TPD with the presence of Lewis as well as Brønsted acidity. These catalysts showed very high catalytic activity for esterification; a typical acid catalyzed organic transformation of various mono- and di-carboxylic acids with a range of alcohols. The in situ formed silicomolybdic acid heteropoly-anion species during the catalytic reactions were found to be catalytically active species for these reactions. Ethyl silicate-40, an industrial bulk silica precursor, has shown a good potential for its use as a silica precursor for the preparation of mesoporous silica based heterogeneous catalysts on a larger scale at a lower cost.     

Nickel(II) chelates of Schiff bases derived from isatin and chromone with amino acids and substituted hydrazines

Summary Nickel(II) complexes of the Schiff base derivatives of isatin with glycine, -alanine, anthranilic acid, S-methyl hydrazine carbodithioate, the ammonium salt of hydrazine carbodithioate, thiosemicarbazide, and benzoyl hydrazine, and nickel(II) complexes of 6-formyl-7-hydroxy-5-methoxy-2-methyl chromonelideneS-methyl hydrazine carbodithioate and benzoyl hydrazone, were prepared and characterized by elemental analysis, i.r., u.v.-vis spectra and magnetic measurements. All the complexes are octahedral.