Research ArticleChemistry

A polyaromatic receptor with high androgen affinity

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Science Advances  19 Apr 2019:
Vol. 5, no. 4, eaav3179
DOI: 10.1126/sciadv.aav3179
  • Fig. 1 Structures of steroid sex hormones, a natural androgen receptor, and a synthetic receptor.

    (A) Tetracyclic framework of steroid sex hormones. (B) Crystal structures of a human androgen receptor (6, left) and synthetic receptor 1 (right) shown at the same scale. The binding pocket and cavity are highlighted in yellow. (C) Polyaromatic receptor 1 used here and space-filling representation of the core framework (based on the crystal structure). (D) Representative male hormone, testosterone (2a), and female hormones, progesterone (3a) and β-estradiol (4a).

  • Fig. 2 Selective binding of testosterone by receptor 1 from mixtures.

    (A) Schematic representation of the selective binding of testosterone (2a) by receptor 1 from a mixture of 2a, progesterone (3a), and β-estradiol (4a) (1:1:1 or 1:100:100 ratio) in water. 1H NMR spectra (500 MHz, D2O) of (B) receptor 1 and (C) products obtained from an equimolar mixture of 2a, 3a, and 4a in the presence of 1 at 60°C for 10 min (gray square, 1•3a) and (D) 1•2a. (E) Changes of the 1H NMR chemical shifts (Δδ in ppm) of 2a upon encapsulation by 1. (F) ESI-TOF MS spectrum (H2O, room temperature) of 1•2a.

  • Fig. 3 X-ray crystal structure of 1’•2a.

    (A) Space-filling (for 2a) and cylindrical (for 1’) representation and (B) space-filling representation (the peripheral substituents of 1’ are replaced by hydrogen atoms for clarity). (C) Highlighted positions of 2a inside the polyaromatic shell of 1’ (three different views). (D) Highlighted host-guest interactions of 1’•2a in the cavity (blue, orange, and red dashed lines are CH-π, OH-π, and hydrogen-bonding interactions, respectively).

  • Fig. 4 Binding affinity of receptor 1 toward male hormones.

    (A) Schematic representation of the binding preference of receptor 1 toward male hormones 2a to 2e in water. (B) 1H NMR spectra (500 MHz, D2O, room temperature) of 1•2a (top), 1•2c (middle), and the product (bottom) obtained from an equimolar mixture of 2a and 2c with 1 (blue circle, 1•2a; pale blue square, 1•2c). (C) 1H NMR spectra (500 MHz, D2O, room temperature) of 1•2a (top), 1•2d (middle), and the product (bottom) obtained from an equimolar mixture of 2a and 2d with 1 (blue circle, 1•2a; pale blue triangle, 1•2d). Binding preference of 1 toward (D) 2a and methyltestosterone (5a) and (E) 2d and adrenosterone (5b) in water.

  • Fig. 5 Binding affinity of receptor 1 toward female hormones.

    (A) Schematic representation of the binding preference of receptor 1 toward female hormones 3a to 3c and 4a to 4c in water. 1H NMR spectra (500 MHz, D2O, room temperature) of products obtained from equimolar mixtures of (B) 2e and 3a, (C) 3a and 4a, and (D) 4a and 4c with 1. (E) Binding preference of 1 toward 3b and 5α-androstane (5c) in water.

  • Fig. 6 Fluorescent detection of testosterone by receptor-dye complex 1•6.

    (A) Schematic representation of nanogram-scale fluorescent detection of male hormone 2a using one drop of an aqueous 16 solution (8 μM) and their photographs (λex = 356 nm) on a petri dish. (B) Fluorescence spectra (room temperature, λex = 423 nm) of a H2O solution of 16 (78 μM, 0.5 ml) before and after addition of 2a (45 nmol) and their photographs (λex = 356 nm).

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/4/eaav3179/DC1

    Fig. S1. Chemical structures of steroid hormones.

    Fig. S2. Competitive binding experiment of 2a, 3a, and 4a with 1.

    Fig. S3. Competitive binding experiment of 2a and 3a with 1.

    Fig. S4. Competitive binding experiment of 2a and 4a with 1.

    Fig. S5. NMR spectra of 12a.

    Fig. S6. Correlation spectroscopy spectra of 12a.

    Fig. S7. Heteronuclear single quantum coherence spectra of 12a.

    Fig. S8. Homonuclear Hartmann-Hahn spectrum of 12a.

    Fig. S9. Nuclear Overhauser effect spectroscopy spectrum of 12a.

    Fig. S10. Diffusion-ordered spectroscopy spectrum of 12a.

    Fig. S11. MS spectrum of 12a.

    Fig. S12. NMR spectrum of 13a.

    Fig. S13. MS spectrum of 13a.

    Fig. S14. NMR spectrum of 14a.

    Fig. S15. MS spectrum of 14a.

    Fig. S16. Concentration-dependent binding experiment.

    Fig. S17. Competitive binding experiment of 2a/3a and CE with 1.

    Fig. S18. Crystal structures of 1’2a and 1”5c.

    Fig. S19. Optimized structures of 13a and 14a.

    Fig. S20. Competitive binding experiment of 2a and 2c with 1.

    Fig. S21. Competitive binding experiment of 2a and 2d with 1.

    Fig. S22. Competitive binding experiment of 2a and 2b with 1.

    Fig. S23. Competitive binding experiment of 2b and 2c with 1.

    Fig. S24. Competitive binding experiment of 2d and 2e with 1.

    Fig. S25. Competitive binding experiment of 2a and 5a with 1.

    Fig. S26. Competitive binding experiment of 2d and 5b with 1.

    Fig. S27. Competitive binding experiment of 2e and 3a with 1.

    Fig. S28. Competitive binding experiment of 3a and 4a with 1.

    Fig. S29. Competitive binding experiment of 3a and 3b with 1.

    Fig. S30. Competitive binding experiment of 3b and 4a with 1.

    Fig. S31. Competitive binding experiment of 4a and 4b with 1.

    Fig. S32. Competitive binding experiment of 3c and 4a with 1.

    Fig. S33. Competitive binding experiment of 3c and 4c with 1.

    Fig. S34. Competitive binding experiment of 4a and 4c with 1.

    Fig. S35. Competitive binding experiment of 3b and 5c with 1.

    Fig. S36. Competitive binding experiment of 4a and 5c with 1.

    Fig. S37. NMR and MS spectra of 12b.

    Fig. S38. NMR and MS spectra of 12c.

    Fig. S39. NMR and MS spectra of 12d.

    Fig. S40. NMR and MS spectra of 12e.

    Fig. S41. NMR and MS spectra of 13b.

    Fig. S42. NMR and MS spectra of 13c.

    Fig. S43. NMR and MS spectra of 14b.

    Fig. S44. NMR and MS spectra of 14c.

    Fig. S45. NMR and MS spectra of 15a.

    Fig. S46. NMR and MS spectra of 15b.

    Fig. S47. NMR spectrum of 15c.

    Fig. S48. Competitive binding experiment of 2a and 6 with 1.

    Table S1. Binding constants of 1 toward 2a and 3a in water.

    Table S2. Packing coefficients of host-guest complexes.

    Table S3. Water solubilities of steroid hormones.

    Table S4. Crystal data and structure refinement for 1’2a.

    Table S5. Crystal data and structure refinement for 1”5c.

    Crystal data of 1’•2a

    Crystal data of 1”•5c

  • Supplementary Materials

    The PDF file includes:

    • Fig. S1. Chemical structures of steroid hormones.
    • Fig. S2. Competitive binding experiment of 2a, 3a, and 4a with 1.
    • Fig. S3. Competitive binding experiment of 2a and 3a with 1.
    • Fig. S4. Competitive binding experiment of 2a and 4a with 1.
    • Fig. S5. NMR spectra of 12a.
    • Fig. S6. Correlation spectroscopy spectra of 12a.
    • Fig. S7. Heteronuclear single quantum coherence spectra of 12a.
    • Fig. S8. Homonuclear Hartmann-Hahn spectrum of 12a.
    • Fig. S9. Nuclear Overhauser effect spectroscopy spectrum of 12a.
    • Fig. S10. Diffusion-ordered spectroscopy spectrum of 12a.
    • Fig. S11. MS spectrum of 12a.
    • Fig. S12. NMR spectrum of 13a.
    • Fig. S13. MS spectrum of 13a.
    • Fig. S14. NMR spectrum of 14a.
    • Fig. S15. MS spectrum of 14a.
    • Fig. S16. Concentration-dependent binding experiment.
    • Fig. S17. Competitive binding experiment of 2a/3a and CE with 1.
    • Fig. S18. Crystal structures of 1’2a and 1”5c.
    • Fig. S19. Optimized structures of 13a and 14a.
    • Fig. S20. Competitive binding experiment of 2a and 2c with 1.
    • Fig. S21. Competitive binding experiment of 2a and 2d with 1.
    • Fig. S22. Competitive binding experiment of 2a and 2b with 1.
    • Fig. S23. Competitive binding experiment of 2b and 2c with 1.
    • Fig. S24. Competitive binding experiment of 2d and 2e with 1.
    • Fig. S25. Competitive binding experiment of 2a and 5a with 1.
    • Fig. S26. Competitive binding experiment of 2d and 5b with 1.
    • Fig. S27. Competitive binding experiment of 2e and 3a with 1.
    • Fig. S28. Competitive binding experiment of 3a and 4a with 1.
    • Fig. S29. Competitive binding experiment of 3a and 3b with 1.
    • Fig. S30. Competitive binding experiment of 3b and 4a with 1.
    • Fig. S31. Competitive binding experiment of 4a and 4b with 1.
    • Fig. S32. Competitive binding experiment of 3c and 4a with 1.
    • Fig. S33. Competitive binding experiment of 3c and 4c with 1.
    • Fig. S34. Competitive binding experiment of 4a and 4c with 1.
    • Fig. S35. Competitive binding experiment of 3b and 5c with 1.
    • Fig. S36. Competitive binding experiment of 4a and 5c with 1.
    • Fig. S37. NMR and MS spectra of 12b.
    • Fig. S38. NMR and MS spectra of 12c.
    • Fig. S39. NMR and MS spectra of 12d.
    • Fig. S40. NMR and MS spectra of 12e.
    • Fig. S41. NMR and MS spectra of 13b.
    • Fig. S42. NMR and MS spectra of 13c.
    • Fig. S43. NMR and MS spectra of 14b.
    • Fig. S44. NMR and MS spectra of 14c.
    • Fig. S45. NMR and MS spectra of 15a.
    • Fig. S46. NMR and MS spectra of 15b.
    • Fig. S47. NMR spectrum of 15c.
    • Fig. S48. Competitive binding experiment of 2a and 6 with 1.
    • Table S1. Binding constants of 1 toward 2a and 3a in water.
    • Table S2. Packing coefficients of host-guest complexes.
    • Table S3. Water solubilities of steroid hormones.
    • Table S4. Crystal data and structure refinement for 1’2a.
    • Table S5. Crystal data and structure refinement for 1”5c.

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