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Joanna Klimek ; Oskar Kruc ; Joanna Ceklarz , et al. Molecules,2024,29(11):2646. DOI: 10.3390/molecules29112646
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Abstract: The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the PD-1/PD-L1 axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting PD-1/PD-L1 are monoclonal antibody-based drugs, which have several limitations. Therefore, small molecule compounds are emerging as an attractive alternative that can potentially overcome the drawbacks of mAb-based therapy. In this article, we present a novel class of small molecule compounds based on the terphenyl scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an m-terphenyl core, an additional aromatic ring, and a solubilizing agent. Using molecular docking, we designed a series of final compounds, which were subsequently synthesized and tested in HTRF assay and NMR binding assay to evaluate their activity. In addition, we performed an in-depth analysis of the mutual arrangement of the phenyl rings of the terphenyl core within the binding pocket of PD-L1 and found several correlations between the plane angle values and the affinity of the compounds towards the protein.
Keywords: PD-L1 ; immune checkpoint ; small molecule inhibitor ; cancer ; C2-symmetrical ligands
Purchased from AmBeed: 1611-92-3 ; 100-51-6 ; 69321-60-4
CAS No. : | 69321-60-4 | MDL No. : | MFCD00013524 |
Formula : | C7H6Br2 | Boiling Point : | No data available |
Linear Structure Formula : | - | InChI Key : | OCSKCBIGEMSDIS-UHFFFAOYSA-N |
M.W : | 249.93 | Pubchem ID : | 34681 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
With palladium diacetate; caesium carbonate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In 1,4-dioxane; at 90.0℃;Inert atmosphere; | A mixture of <strong>[1147422-00-1]tert-butyl octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate</strong> (Combi-Blocks catalog ST-7254: 60 mg, 0.265 mmol), 1,3-dibromo-2-methylbenzene (Combi-Blocks cat OT-1437: 199 mg, 0.795 mmol), palladium(II) acetate (5.95 mg, 0.027 mmol), (R)-(+)-2,2?-bis(diphenylphosphino)-1,1?-binaphthyl (16.51 mg, 0.027 mmol), and cesium carbonate (173 mg, 0.530 mmol) in 1,4-Dioxane (5.0 ml) was flushed with N2. The resulting slurry was stirred at 90 C. overnight. After being cooled to room temperature, the reaction mixture was quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel, eluting with ethyl acetate in hexanes (0-50%) to afford the desired product. LC-MS calculated for C19H28BrN2O2 (M+H)+: m/z=395.1; found 395.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 4h; | <strong>[489446-42-6](4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid</strong> (1 g, 4 mmol), 1,3-dibromo-2- methylbenzene (2 g, 8 mmol), Pd(dppf)C12CH2C12 (0.32 g, 0.4 mmol) and potassium carbonate (1.6 g, 12mmol) were suspended in 10 mL dioxane and 1 mL water. The mixture was sparged for 5 mm withargon and heated to 90 C in a heating block for 4 h. After cooling to room temperature, the reaction was diluted with EtOAc and brine. The organic layer was separated, dried with Na2SO4 and concentrated.Purified by silica gel chromatography (eluting with EtOAc-Hex) to provide tert-butyl ((3?-bromo-2?- methyl-[ 1,1 ?-biphenyll -4-yl)methyl)carbamate. |
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