Research ArticleBIOCHEMISTRY

Multicomponent reaction–derived covalent inhibitor space

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Science Advances  03 Feb 2021:
Vol. 7, no. 6, eabd9307
DOI: 10.1126/sciadv.abd9307
  • Fig. 1 Covalent inhibitors in medicinal chemistry and natural products.

    (A and B) Three compounds covalently binding to their protein targets. AMG510, a G12C RAS inhibitor [Protein Data Bank (PDB) ID: 6OIM], cyclostreptin binding to His229 of tubulin (PDB ID: 6QTN), and Bruton’s tyrosine kinase inhibitor zanubrutinib (PDB ID: 6J6M). (C) Common electrophilic warheads and nucleophilic amino acid targets. (D) Synthetic strategies to covalent inhibitors.

  • Fig. 2 Design of electrophile libraries.

    (A) The use of multiple MCRs allows for great scaffold diversity. (B) The electrophile building blocks consist of three parts: the electrophile functional group, the linker, and the MCR-compatible functional group. The colored forms graphically represent different types of building blocks.

  • Fig. 3 Synthesis of specific bifunctional electrophile building blocks.

    The electrophile and the MCR functional groups are marked in yellow and blue, respectively. rt, room temperature.

  • Fig. 4 Millimole-scale synthesis of electrophiles based on acrylamide amine building blocks 6 and 7.

    (*yield over two steps). The color of the boxes refers to the scaffolds shown in Table 1.

  • Fig. 5 Millimole-scale synthesis of electrophiles based on acrylamide isocyanide building block 25.

    The color of the boxes refers to the scaffolds shown in Table 1.

  • Fig. 6 Millimole-scale synthesis of electrophiles based on acrylamide ketone building block 24.

    The color of the boxes refers to the scaffolds shown in Table 1.

  • Fig. 7 Millimole-scale synthesis of electrophiles based on acrylic acid building blocks 29 to 32.

    The color of the boxes refers to the scaffolds shown in Table 1.

  • Fig. 8 Millimole-scale synthesis of electrophiles based on singleton building blocks 10, 14, 18, 27, 28, and 33 to 37 (*yield over two steps).

    Boxed color code is according to scaffold type of Table 1.

  • Fig. 9 Automated nanoscale synthesis of acrylamides using ADE.

    (A) ADE-enabled nanoscale automated electrophile synthesis based on the U-4CR of isocyanide building block 22. (B) Heat plot of 192 compounds based on mass spectrometry analysis: green for major product formation, yellow for medium product formation, blue for no product formation, and white for Echo reagent transfer failure. (C) Exemplary amine and carboxylic acid building blocks used. (D) Exemplary product structures of the first two columns A and B. (E) Structures of resynthesized compounds on a millimole scale (red-boxed in heat plot).

  • Table 1 The MCRs used to create libraries with electrophilic moieties.

    The different scaffolds are boxed in different colors that will be used throughout the manuscript.


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Supplementary Materials

  • Supplementary Materials

    Multicomponent reaction–derived covalent inhibitor space

    Fandi Sutanto, Shabnam Shaabani, Constantinos G. Neochoritis, Tryfon Zarganes-Tzitzikas, Pravin Patil, Ehsan Ghonchepour, Alexander Dömling

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