Research ArticleChemistry

Rapid approach to complex boronic acids

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Science Advances  05 Jul 2019:
Vol. 5, no. 7, eaaw4607
DOI: 10.1126/sciadv.aaw4607
  • Fig. 1 Importance of boronic acids, commonly used synthetic methods for the ─B(OH)2 introduction, and our proposed building block–centered approach.

    (A) Marketed drugs containing free ─B(OH)2 moieties. (B) Common methods for late-stage introduction of the ─B(OH)2 moiety. THF-DMF, tetrahydrofuran-dimethylformamide. (C) Building block approach to prepare complex ─B(OH)2 moiety containing molecules in large numbers.

  • Fig. 2 Boronic acid building blocks used in this study, first synthesis of boronic acid isocyanide, and evaluated reactions.

    [B], phenyl boronic acid moiety.

  • Fig. 3 HT synthesis of boronic acids using the building block approach.

    (A) Exemplary analytical 384-well plate of the U-4CR scaffold 12 (green, major product formation; yellow, product present; blue, product not present). (B) Statistical analysis of the quality of reactions of the different scaffolds. (C) Structures of some unusual reaction products from different IMCRs.

  • Fig. 4 Resynthesized complex boronic acid derivatives based on different scaffolds on a millimole scale and corresponding yields.

  • Fig. 5 HT Suzuki reaction of boronic acids using the building block approach.

    (A) Statistical analysis of the aryl halides that were used in the HT screening (green, major peak in MS; yellow, product present; blue, product not present). (B) A one-pot resynthesized compound 28 on a millimole scale and isolated yield. DME, dimethoxyethane.

  • Fig. 6 Covalent inhibition of tuberculosis target MptpB.

    (A) Screening of the boronic acid library by a colorimetric enzyme assay. (B) Median inhibitory concentration (IC50) of compound 18a. (C and D) Modeling of compound 18a into MptpB [Protein Data Bank (PDB) ID: 2OZ5], where it forms a covalent adduct with active-site cysteine. Van der Waals interactions, hydrogen bonding, and cation-π interactions are indicated by yellow, red, and blue dotted lines, respectively.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/7/eaaw4607/DC1

    Supplementary Materials and Methods

    Fig. S1. Isocyanide syntheses.

    Fig. S2. Reactions in destination plate I.

    Fig. S3. Reactions in destination plate II.

    Fig. S4. Reactions in destination plate III.

    Fig. S5. Reactions in destination plate IV.

    Fig. S6. Labcyte Echo plate reformat software.

    Fig. S7. Heat plots with product structures, green for major product formation, yellow for medium product formation, and blue for no product formation.

    Fig. S8. Stabilization effect of 18a as proof of interaction with MptpB as assessed by DSF.

    Fig. S9. Binding curve of 18a to the fluorescently labeled MptpB sample as assessed by MST.

    Fig. S10. Three-dimensional structure of the target phosphatase.

    Fig. S11. Proposed docking model for 18a covalently bound to Cys160 (PDB ID: 2OZ5).

    Fig. S12. Proposed docking model for 18a covalently bound to Ser57 (PDB ID: 2OZ5).

    Fig. S13. Proposed docking model for 18a covalently bound to Thr223 (PDB ID: 2OZ5).

    Fig. S14. ADE technology.

    Table S1. Summary table of the docking scores for Covdock and Scorpion.

    Scheme S1. Quality control results for destination plate I.

    Scheme S2. Performance of formylphenyl boronic acids in destination plate I.

    Scheme S3. Performance of isocyanides in GBB-3CR reaction in destination plate I.

    Scheme S4. Performance of isocyanides in Ugi-based macrocycles in destination plate I.

    Scheme S5. Performance of isocyanides in U-4CR in destination plate I.

    Scheme S6. Performance of isocyanides in UT-4CR in destination plate I.

    Scheme S7. Performance of carboxylic acids in U-4CR in destination plate I.

    Scheme S8. Performance of amines in U-4CR in destination plate I.

    Scheme S9. Performance of amines in UT-4CR in destination plate I.

    Scheme S10. Performance of amidines in GBB-3CR reaction in destination plate I.

    Scheme S11. Performance of α,ω-amino carboxylic acids in Ugi-based macrocycles in destination plate I.

    Scheme S12. Quality control results for destination plate II.

    Scheme S13. Performance of aminophenyl boronic acids in destination plate II.

    Scheme S14. Performance of isocyanides in U-4CR in destination plate II.

    Scheme S15. Performance of isocyanides in UT-4CR in destination plate II.

    Scheme S16. Performance of oxo components in U-4CR in destination plate II.

    Scheme S17. Performance of oxo components in UT-4CR in destination plate II.

    Scheme S18. Performance of carboxylic acids in U-4CR in destination plate II.

    Scheme S19. Quality control results for destination plate III.

    Scheme S20. Performance of carboxyphenyl boronic acids in destination plate III.

    Scheme S21. Performance of isocyanides in U-4CR in destination plate III.

    Scheme S22. Performance of isocyanides in U-4CR with CH2O in destination plate III.

    Scheme S23. Performance of oxo component in U-4CR in destination plate III.

    Scheme S24. Performance of amines in U-4CR in destination plate III.

    Scheme S25. Performance of amines in U-4CR with CH2O in destination plate III.

    Scheme S26. Quality control results for destination plate IV.

    Scheme S27. Performance of MCR boronic acid building blocks in destination plate IV.

    Scheme S28. Performance of aryl halides in destination plate IV.

    References (4258)

  • Supplementary Materials

    This PDF file includes:

    • Supplementary Materials and Methods
    • Fig. S1. Isocyanide syntheses.
    • Fig. S2. Reactions in destination plate I.
    • Fig. S3. Reactions in destination plate II.
    • Fig. S4. Reactions in destination plate III.
    • Fig. S5. Reactions in destination plate IV.
    • Fig. S6. Labcyte Echo plate reformat software.
    • Fig. S7. Heat plots with product structures, green for major product formation, yellow for medium product formation, and blue for no product formation.
    • Fig. S8. Stabilization effect of 18a as proof of interaction with MptpB as assessed by DSF.
    • Fig. S9. Binding curve of 18a to the fluorescently labeled MptpB sample as assessed by MST.
    • Fig. S10. Three-dimensional structure of the target phosphatase.
    • Fig. S11. Proposed docking model for 18a covalently bound to Cys160 (PDB ID: 2OZ5).
    • Fig. S12. Proposed docking model for 18a covalently bound to Ser57 (PDB ID: 2OZ5).
    • Fig. S13. Proposed docking model for 18a covalently bound to Thr223 (PDB ID: 2OZ5).
    • Fig. S14. ADE technology.
    • Table S1. Summary table of the docking scores for Covdock and Scorpion.
    • Scheme S1. Quality control results for destination plate I.
    • Scheme S2. Performance of formylphenyl boronic acids in destination plate I.
    • Scheme S3. Performance of isocyanides in GBB-3CR reaction in destination plate I.
    • Scheme S4. Performance of isocyanides in Ugi-based macrocycles in destination plate I.
    • Scheme S5. Performance of isocyanides in U-4CR in destination plate I.
    • Scheme S6. Performance of isocyanides in UT-4CR in destination plate I.
    • Scheme S7. Performance of carboxylic acids in U-4CR in destination plate I.
    • Scheme S8. Performance of amines in U-4CR in destination plate I.
    • Scheme S9. Performance of amines in UT-4CR in destination plate I.
    • Scheme S10. Performance of amidines in GBB-3CR reaction in destination plate I.
    • Scheme S11. Performance of α,ω-amino carboxylic acids in Ugi-based macrocycles in destination plate I.
    • Scheme S12. Quality control results for destination plate II.
    • Scheme S13. Performance of aminophenyl boronic acids in destination plate II.
    • Scheme S14. Performance of isocyanides in U-4CR in destination plate II.
    • Scheme S15. Performance of isocyanides in UT-4CR in destination plate II.
    • Scheme S16. Performance of oxo components in U-4CR in destination plate II.
    • Scheme S17. Performance of oxo components in UT-4CR in destination plate II.
    • Scheme S18. Performance of carboxylic acids in U-4CR in destination plate II.
    • Scheme S19. Quality control results for destination plate III.
    • Scheme S20. Performance of carboxyphenyl boronic acids in destination plate III.
    • Scheme S21. Performance of isocyanides in U-4CR in destination plate III.
    • Scheme S22. Performance of isocyanides in U-4CR with CH2O in destination plate III.
    • Scheme S23. Performance of oxo component in U-4CR in destination plate III.
    • Scheme S24. Performance of amines in U-4CR in destination plate III.
    • Scheme S25. Performance of amines in U-4CR with CH2O in destination plate III.
    • Scheme S26. Quality control results for destination plate IV.
    • Scheme S27. Performance of MCR boronic acid building blocks in destination plate IV.
    • Scheme S28. Performance of aryl halides in destination plate IV.
    • References (4258)

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