Synthesis of Functionalized Triazoles on DNA via Azide-Acetonitrile "Click" Reaction.

Triazoles are privileged structural motifs that are embedded in a number of molecules with interesting biological activities. In this work, we developed a practical and general synthetic strategy to construct a medicinally important 5-amino-1,2,3-triazole moiety on DNA by coupling DNA-conjugated azides and monosubstituted acetonitriles via azide-acetonitrile "click" reaction. Under mild reaction conditions, this reaction displayed a broad substrate scope. Most substrates gave moderate-to-excellent conversions. Thus, this DNA-compatible reaction could be employed in practical DNA-encoded library (DEL) construction and potentially expand the chemical space of DNA-encoded libraries.

DNA-Compatible Synthesis of Thiazolidione Derivatives via Three-Component Annulation and Knoevenagel Condensation.

Thiazolidione, conferring drug-like properties, is an important heterocycle that widely exists in medicinally relevant molecules. In this work, by efficiently assembling various DNA-tagged primary amines, abundant aryl isothiocyanates, and ethyl bromoacetate, we present a DNA-compatible three-component annulation to generate a 2-iminothiazolidin-4-one scaffold, which was further decorated via Knoevenagel condensation by employing (hetero)aryl and alkyl aldehydes. These thiazolidione derivatives should find broad use in focused DNA-encoded library construction.

Incorporation of viridicatin alkaloid-like scaffolds into DNA-encoded chemical libraries.

Viridicatin alkaloids as natural products have attracted great interest due to their unique core scaffold. To fully exploit their potential application in DNA-encoded chemical libraries that would facilitate drug discovery, we here describe an efficient on-DNA synthesis of viridicatin alkaloid-like scaffolds from isatins and DNA-tagged aldehydes. Promoted by benzenesulfonyl hydrazide, this reaction provided the corresponding DNA-conjugated viridicatin alkaloid-like products in moderate-to-excellent conversion yields, and DNA compatibility validated by enzymatic ligation and qPCR evaluation exhibited the feasible utility of this methodology in DEL synthesis. Cross substrate scope study, together with subsequent on-DNA chemical diversification, further showed the competence of this approach in focused natural product-like encoded library construction.

Vinyl azide as a synthon for DNA-compatible divergent transformations into N-heterocycles.

Inspired by diversity-oriented synthesis, we have developed a series of DNA-compatible transformations utilizing on-DNA vinyl azide as a synthon to forge divergent N-heterocyclic scaffolds. Polysubstituted imidazoles and isoquinolines were efficiently obtained with moderate-to-excellent conversions. Besides, the "one-pot" strategy to prepare in-house on-DNA vinyl azides afforded synthons readily. Results from substrate scope exploration and enzymatic ligation further demonstrate the feasibility of these N-heterocycle syntheses in DNA-encoded chemical library construction.

Visible Light-Promoted Divergent Benzoheterocyclization from Aldehydes for DNA-Encoded Chemical Libraries.

Benzoheterocyclics have been widely adopted as drug-like core scaffolds that can be incorporated into DNA-encoded chemical library technology for high-throughput hit discovery. Here, we present a visible light-promoted divergent synthesis of on-DNA benzoheterocycles from aldehydes. Four types of DNA-conjugated benzoheterocyclics were obtained under mild conditions with a broad substrate scope. A cross substrate scope study, together with enzymatic ligation and subsequent chemical diversifications, were conducted, demonstrating the feasibility of this approach in DNA-encoded chemical library construction.

DNA-Compatible Diversification of Indole π-Activated Alcohols via a Direct Dehydrative Coupling Strategy.

Indole-based diversification is highly desired in the DNA-encoded chemical library construction. Herein, we present a general strategy for on-DNA synthesis of diverse C3-functionalized indole derivatives via indole π-activated alcohol formation followed by direct dehydrative coupling. Highly efficient bond linkages of C-C, C-N, and C-S were achieved to fuse building blocks that are widely commercially available. DNA-encoding compatibility of the method has been further demonstrated to pave an avenue for application in constructing indole-focused three-dimensional libraries.

DNA-Compatible ortho-Phthalaldehyde (OPA)-Mediated 2-Substituted Isoindole Core Formation and Applications.

The incorporation of the isoindole core into the DNA-encoded chemical library is highly desirable for the great potential pharmacological characters exampled by molecules like lenalidomide. Herein, we reported a DNA-compatible protocol for the OPA-mediated transformation of amines into drug-like moieties represented by isoindolinone and thio-2-isoindole, respectively. The high conversion and wide substrate-scope property of our protocol render its feasibility in the manipulation of terminal amines on oligonucleotide conjugates, including "cap-and-catch" purification, sequential synthesis during DEL construction, and on-DNA macrocyclization.

Novel organophosphorus aminopyrimidines as unique structural DNA-targeting membrane active inhibitors towards drug-resistant methicillin-resistant Staphylococcus aureus.

A series of novel unique structural organophosphorus aminopyrimidines were developed as potential DNA-targeting membrane active inhibitors through an efficient one-pot procedure from aldehydes, phosphonate and aminopyrimidine. The biological assay revealed that some of the prepared compounds displayed antibacterial activities. In particular, imidazole derivative 2c exhibited more potent inhibitory activity against MRSA with an MIC value of 4 µg mL-1 in comparison with the clinical drugs chloromycin and norfloxacin. Experiments revealed that the active molecule 2c had the ability to rapidly kill the tested strains without obviously triggering the development of bacterial resistance, showed low toxicity to L929 cells and could disturb the cell membrane. The molecular docking study discovered that compound 2c could bind with DNA gyrase via hydrogen bonds and other weak interactions. Further exploration disclosed that the active molecule 2c could also effectively intercalate into MRSA DNA and form a steady 2c-DNA supramolecular complex, which might further block DNA replication to exert powerful antibacterial effects.

Novel potentially antifungal hybrids of 5-flucytosine and fluconazole: Design, synthesis and bioactive evaluation.

A series of novel potentially antifungal hybrids of 5-flucytosine and fluconazole were designed, synthesized and characterized by 1H NMR, 13C NMR, IR and HRMS spectra. Bioactive assay manifested that some prepared compounds showed moderate to good antifungal activities in comparison with fluconazole and 5-flucytosine. Remarkably, the 3,4-dichlorobenzyl hybrid 7h could inhibit the growth of C. albicans ATCC 90023 and clinical resistant strain C. albicans with MIC values of 0.008 and 0.02 mM, respectively. The active molecule 7h could not only rapidly kill C. albicans but also efficiently permeate membrane of C. albicans. Molecular docking study revealed that compound 7h could interact with the active site of CACYP51 through hydrogen bond. Quantum chemical studies were also performed to explain the high antifungal activity. Further preliminary mechanism research suggested that molecule 7h could intercalate into calf thymus DNA to form a steady supramolecular complex, which might block DNA replication to exert the powerful bioactivities.