DNA-Compatible Cyanomethylation of (Hetero)aryl Halides or Triflates under a Tandem Reaction for DNA-Encoded Library Synthesis

Zhang, Jie; Wang, Lu; Ji, Qian; Liu, Fei

doi:10.1021/acs.orglett.3c02850

Org. Lett.

2023

DOI: 10.1021/acs.orglett.3c02850

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DNA-Compatible Cyanomethylation of (Hetero)aryl Halides or Triflates under a Tandem Reaction for DNA-Encoded Library Synthesis

Jie Zhang,

Lu Wang,

Qian Ji

et al.

Abstract: A DNA-compatible reaction has been developed for the cyanomethylation of (hetero)aryl halides or triflates via a tandem process involving palladium-mediated Suzuki–Miyaura coupling and base-promoted isoxazole fragmentation. This one-pot protocol employs easily accessible starting materials, exhibits a wide substrate scope, and results in no significant DNA damage. Additionally, the resulting (hetero)arylacetonitriles can be converted into the corresponding carboxylic acids, which may be utilized for the syn… Show more

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Cited by 3 publications

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Synthesis of Functionalized Triazoles on DNA via Azide-Acetonitrile “Click” Reaction

Fang,

Zhang,

Fang

et al. 2023

Org. Lett.

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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.Letter pubs.acs.org/OrgLett

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Synthesis of Functionalized Triazoles on DNA via Azide-Acetonitrile “Click” Reaction

Fang,

Zhang,

Fang

et al. 2023

Org. Lett.

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Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology

Madasu,

Liao,

Parks

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface–associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that EPHA2 and EPHA4 expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value. We screened DNA-encoded chemical libraries (DECL) to rapidly identify EPHA2/4 kinase inhibitors. Hit compound, CDD-2693, exhibited picomolar/nanomolar kinase activity against EPHA2 (K i : 4.0 nM) and EPHA4 (K i : 0.81 nM). Kinome profiling revealed that CDD-2693 bound to most EPH family and SRC family kinases. Using NanoBRET target engagement assays, CDD-2693 had nanomolar activity versus EPHA2 (IC 50 : 461 nM) and EPHA4 (IC 50 : 40 nM) but was a micromolar inhibitor of SRC, YES, and FGR. Chemical optimization produced CDD-3167, having picomolar biochemical activity toward EPHA2 (K i : 0.13 nM) and EPHA4 (K i : 0.38 nM) with excellent cell-based potency EPHA2 (IC 50 : 8.0 nM) and EPHA4 (IC 50 : 2.3 nM). Moreover, CDD-3167 maintained superior off-target cellular selectivity. In 12Z endometriotic epithelial cells, CDD-2693 and CDD-3167 significantly decreased EFNA5 (ligand) induced phosphorylation of EPHA2/4, decreased 12Z cell viability, and decreased IL-1β-mediated expression of prostaglandin synthase 2 ( PTGS2 ). CDD-2693 and CDD-3167 decreased expansion of primary endometrial epithelial organoids from patients with endometriosis and decreased Ewing’s sarcoma viability. Thus, using DECL, we identified potent pan-EPH inhibitors that show specificity and activity in cellular models of endometriosis and cancer.

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Using DNA-encoded libraries of fragments for hit discovery of challenging therapeutic targets

Zhao,

Zhu,

et al. 2024

Expert Opinion on Drug Discovery

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DNA-Compatible Cyanomethylation of (Hetero)aryl Halides or Triflates under a Tandem Reaction for DNA-Encoded Library Synthesis

Cited by 3 publications

References 36 publications

Synthesis of Functionalized Triazoles on DNA via Azide-Acetonitrile “Click” Reaction

Synthesis of Functionalized Triazoles on DNA via Azide-Acetonitrile “Click” Reaction

Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology

Using DNA-encoded libraries of fragments for hit discovery of challenging therapeutic targets

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