Structure of 1,3-Dibromo-5-methylbenzene
CAS No.: 1611-92-3
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Joanna Klimek ; Oskar Kruc ; Joanna Ceklarz ; Beata Kami ´nska ; Bogdan Musielak ; Robin van der Straat , et al.
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.
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Keywords: PD-L1 ; immune checkpoint ; small molecule inhibitor ; cancer ; C2-symmetrical ligands
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CAS No. : | 1611-92-3 |
Formula : | C7H6Br2 |
M.W : | 249.93 |
SMILES Code : | CC1=CC(Br)=CC(Br)=C1 |
MDL No. : | MFCD00013528 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 46.81 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.62 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.67 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.52 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
4.1 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.66 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.51 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.2 |
Solubility | 0.016 mg/ml ; 0.0000638 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.36 |
Solubility | 0.109 mg/ml ; 0.000437 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.49 |
Solubility | 0.00801 mg/ml ; 0.0000321 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.22 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.39 |
* 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 |
---|---|---|
21% | In 1-methyl-pyrrolidin-2-one; hexane; | Reference Example 38 3-Bromo-5-cyanotoluene To a solution of 3,5-dibromotoluene (10.00 g) in 1-methyl-2-pyrrolidone (70 ml) was added copper (I) cyanide (5.20) and the mixture was stirred at 200 C. for 1.5 hours. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The extract was washed with 1M hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=9/1 as an eluant to give the desired compound (1.70 g, yield 21%). 1H NMR (270 MHz, CDCl3) delta ppm: 2.39 (3H, s), 7.40 (1H, s), 7.57 (1H, s), 7.60 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In N,N-dimethyl-formamide; at 153℃; for 6h; | 3-Bromo-5-methylbenzonitrile A mixture of 1,3-dibromo-5-methylbenzene (4.97 g, 19.9 mmol), copper (I) cyanide (2.70 g, 30.1 mmol), pyridine (4.85 mL, 60.0 mmol), and N,N-dimethylformamide (35 mL). were heated at 153 C. for 6 h. The reaction was allowed to cool to ambient temperature, poured into a solution of H2O (200 mL) and NH4OH (100 mL), and extracted with methyl tert-butyl ether (100 mL*2). The combined organic extracts were washed with saturated aqueous NH4Cl (200 mL), and the resulting aqueous layer was extracted with methyl tert-butyl ether (50 mL). The combined organic extracts were then washed with saturated aqueous NaHCO3 (200 mL), and the resulting aqueous layer was extracted with methyl tert-butyl ether (50 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel with hexanes:EtOAc (99:1?1:99) to afford 3-bromo-5-methylbenzonitrile as an off-white solid. 1H NMR (CDCl3, 500 MHz) delta 7.60 (s, 1H), 7.57 (s, 1H), 7.40 (s, 1H), 2.39 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With pyridine; In N,N-dimethyl-formamide; at 190℃; for 10h;Microwave irradiation; | Intermediate 503-Bromo-5-methylbenzonitrile; A mixture of 1,3-dibromo-5-methylbenzene (1.0 g, 4.0 mmol), copper cyanide (0.179 g, 2.00 mmol), pyridine (0.323 mL, 4.00 mmol), and DMF (15 mL) were heated at 190 C. for 10 h in microwave reactor. The reaction mixture was allowed to cool to r.t., and then poured into a solution of H2O (20 mL) and aq. NH3 solution (25-35% NH3, 10 mL) and the water phase was extracted with EtOAc. The combined organic extracts were dried (Mg2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatograpy (hexane/EtOAc gradient elution) to afford the title compound (0.58 g, 74% yield): 1H NMR (500 MHz, CDCl3) delta ppm 2.39 (s, 3H) 7.41 (s, 1H) 7.58 (s, 1H) 7.60 (s, 1H); MS (EI) m/z 195 M |
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