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Systematic Study of Heteroarene Stacking Using a Congeneric Set of Molecular Glues for Procaspase-6
Togo, Takaya ; Tram, Linh ; Denton, Laura G. , et al. J. Med. Chem.,2023,66(14):9784-9796. DOI: 10.1021/acs.jmedchem.3c00590 PubMed ID: 37406165
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Abstract: Heteroaromatic stacking interactions are important in drug binding, supramolecular chemistry, and materials science, making protein-ligand model systems of these interactions of considerable interest. Here we studied 30 congeneric ligands that each present a distinct heteroarene for stacking between tyrosine residues at the dimer interface of procaspase-6. Complex X-ray crystal structures of 10 analogs showed that stacking geometries were well conserved, while high-accuracy computations showed that heteroarene stacking energy was well correlated with predicted overall ligand binding energies. Empirically determined KD values in this system thus provide a useful measure of heteroarene stacking with tyrosine. Stacking energies are discussed in the context of torsional strain, the number and positioning of heteroatoms, tautomeric state, and coaxial orientation of heteroarene in the stack. Overall, this study provides an extensive data set of empirical and high-level computed binding energies in a versatile new protein-ligand system amenable to studies of other intermolecular interactions.
Purchased from AmBeed: 56423-63-3 ; 88491-61-6 ; 72287-26-4 ; 109-04-6
CAS No. : | 56423-63-3 | MDL No. : | MFCD08275680 |
Formula : | C4H3BrN2 | Boiling Point : | No data available |
Linear Structure Formula : | - | InChI Key : | WGFCNCNTGOFBBF-UHFFFAOYSA-N |
M.W : | 158.98 | Pubchem ID : | 642800 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P210-P305+P351+P338 | UN#: | |
Hazard Statements: | H227-H315-H319 | Packing Group: | |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 75 - 90℃; for 1.75h;Microwave irradiation; | Preparation 133: 2-Chloro-4-(pyrazin-2-yl)aniline; [00303] To a mixture of 4-amino-3-chlorophenylboronic acid pinacol ester (0.1 10g, 0.434 mmol), 2-bromopyrazine (0.090 g, 0.56 mmol), 1 ,1 '- bis(diphenylphosphino)ferrocene)-dichloropalladium(ll) DCM complex (24 mg, 0.029 mmol) was added anhydrous DME (3.0 mL) followed by 2M aqueous sodium carbonate (0.53 mL, 1 .06 mmol). The microwave vial was heated at 75C for 40 minutes under microwave irradiation. Further catalyst (0.012 g) was added and the vial was heated at 90C for 25 minutes under microwave irradiation. Further 2-bromopyrazine (0.060g), catalyst (12 mg) and 2M aqueous sodium carbonate (0.25 mL) were added and the reaction mixture was heated at 90C for an additional 30 minutes under microwave irradiation. The reaction was partitioned between ethyl acetate (60 mL) and a saturated aqueous NaHC03 solution (15 mL). The organic layer was washed with a saturated aqueous NaHC03 solution (2 x 15 mL), dried (Na2S04) and concentrated in vacuo. The residue was purified using preparative TLC eluting with 7% ethyl acetate in CH2CI2. The product band was recovered and stirred with 2% MeOH in ethyl acetate / CH2CI2 (v/v; 1 :10) (20 mL). The silica was removed by filtration, washed with ethyl acetate / CH2CI2 (v/v; 1 :5) (2x5 mL) and acetone (3 x 4 mL) to give the title compound as an off- white solid (0.039 g, 44%). 1 H-NMR (500 MHz, DMSO-d6) 5.86 (s, 2H), 6.89 (d, J = 8.5, 1 H), 7.85 (dd, J = 2.1 , 8.5 Hz, 1 H), 8.02 (d, J = 2.1 Hz, 1 H), 8.44 (d, J = 2.5 Hz, 1 H), 8.57 (dd, J = 1 .6, 2.5 Hz, 1 H), 9.12 (d, J = 1 .5 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 75 - 90℃; for 1.58333h;Microwave irradiation; | Preparation 133 2-Chloro-4-(pyrazin-2-yl)aniline To a mixture of <strong>[721960-43-6]4-amino-3-chlorophenylboronic acid pinacol ester</strong> (0.110 g, 0.434 mmol), 2-bromopyrazine (0.090 g, 0.56 mmol), 1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) DCM complex (24 mg, 0.029 mmol) was added anhydrous DME (3.0 mL) followed by 2M aqueous sodium carbonate (0.53 mL, 1.06 mmol). The microwave vial was heated at 75 C. for 40 minutes under microwave irradiation. Further catalyst (0.012 g) was added and the vial was heated at 90 C. for 25 minutes under microwave irradiation. Further 2-bromopyrazine (0.060 g), catalyst (12 mg) and 2M aqueous sodium carbonate (0.25 mL) were added and the reaction mixture was heated at 90 C. for an additional 30 minutes under microwave irradiation. The reaction was partitioned between ethyl acetate (60 mL) and a saturated aqueous NaHCO3 solution (15 mL). The organic layer was washed with a saturated aqueous NaHCO3 solution (2*15 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified using preparative TLC eluting with 7% ethyl acetate in CH2Cl2. The product band was recovered and stirred with 2% MeOH in ethyl acetate/CH2Cl2 (v/v; 1:10) (20 mL). The silica was removed by filtration, washed with ethyl acetate/CH2Cl2 (v/v; 1:5) (2*5 mL) and acetone (3*4 mL) to give the title compound as an off-white solid (0.039 g, 44%). 1H-NMR (500 MHz, DMSO-d6) 5.86 (s, 2H), 6.89 (d, J=8.5, 1H), 7.85 (dd, J=2.1, 8.5 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 8.44 (d, J=2.5 Hz, 1H), 8.57 (dd, J=1.6, 2.5 Hz, 1H), 9.12 (d, J=1.5 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine; In tetrahydrofuran; at 40℃; for 48h;Inert atmosphere; | General procedure: Tris(4-ethynylphenyl)amine 7 (0.25 mmol) and correspondinghalogenated diazine 4ab or 5ac or 6 (1 mmol) were dissolved in dryTHF (10 ml) and Et3N (2.5 ml). Argon was bubbled through the solutionfor 10 min, whereupon [PdCl2(PPh3)2] (16 mg, 0.09 eq.) and CuI (4 mg,0.09 eq.) were added. The reaction mixture was stirred under argonatmosphere at 40 .C for 48 h. The solvents were evaporated in vacuo andthe residue was taken up in aq. NH4Cl (50 ml) and was extracted withCH2Cl2 (2 × 50 ml). The combined organic extracts were dried (Na2SO4)×and the solvents were evaporated in vacuo. The crude product was purifiedby column chromatography. |