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Chemical Structure| 1611-92-3 Chemical Structure| 1611-92-3

Structure of 1,3-Dibromo-5-methylbenzene
CAS No.: 1611-92-3

Chemical Structure| 1611-92-3

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Product Citations

Product Citations

Joanna Klimek ; Oskar Kruc ; Joanna Ceklarz ; Beata Kami ´nska ; Bogdan Musielak ; Robin van der Straat , et al.

Abstract: The complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting 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 scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an 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 .

Keywords: PD-L1 ; immune checkpoint ; small molecule inhibitor ; cancer ; C2-symmetrical ligands

Purchased from AmBeed: ; ;

Alternative Products

Product Details of [ 1611-92-3 ]

CAS No. :1611-92-3
Formula : C7H6Br2
M.W : 249.93
SMILES Code : CC1=CC(Br)=CC(Br)=C1
MDL No. :MFCD00013528

Safety of [ 1611-92-3 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 1611-92-3 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

0.0 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.62
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

3.67
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.52
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

4.1
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

3.66
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.51

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-4.2
Solubility 0.016 mg/ml ; 0.0000638 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-3.36
Solubility 0.109 mg/ml ; 0.000437 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-4.49
Solubility 0.00801 mg/ml ; 0.0000321 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

Yes
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.22 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<2.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.39

Application In Synthesis of [ 1611-92-3 ]

* 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.

  • Downstream synthetic route of [ 1611-92-3 ]

[ 1611-92-3 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 1611-92-3 ]
  • [ 141-78-6 ]
  • [ 124289-21-0 ]
YieldReaction ConditionsOperation 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).
  • 2
  • [ 1611-92-3 ]
  • [ 544-92-3 ]
  • [ 124289-21-0 ]
YieldReaction ConditionsOperation 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).
  • 3
  • [ 188641-21-6 ]
  • [ 148-25-4 ]
  • [ 1611-92-3 ]
  • [ 98-11-3 ]
  • 4
  • [ 1611-92-3 ]
  • copper(l) cyanide [ No CAS ]
  • [ 124289-21-0 ]
YieldReaction ConditionsOperation 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
  • 5
  • [ 1611-92-3 ]
  • [ 74204-00-5 ]
 

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