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Chemical Structure| 273-53-0 Chemical Structure| 273-53-0

Structure of 273-53-0

Chemical Structure| 273-53-0

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Anushree Mondal ; Pronay Roy ; Jaclyn Carrannatto ; Prathamesh M. Datar ; Daniel J. DiRocco ; Katherine Huntera and E. Neil G. Marsh

Abstract: The prenylated-flavin mononucleotide-dependent decarboxylases (also known as UbiD-like enzymes) are the most recently discovered family of decarboxylases. The modified flavin facilitates the decarboxylation of unsaturated carboxylic acids through a novel mechanism involving 1,3-dipolar cyclo-addition chemistry. UbiD-like enzymes have attracted considerable interest for biocatalysis applications due to their ability to catalyse (de)carboxylation reactions on a broad range of aromatic substrates at otherwise unreactive carbon centres. There are now ∼35[thin space (1/6-em)]000 protein sequences annotated as hypothetical UbiD-like enzymes. Sequence similarity network analyses of the UbiD protein family suggests that there are likely dozens of distinct decarboxylase enzymes represented within this family. Furthermore, many of the enzymes so far characterized can decarboxylate a broad range of substrates. Here we describe a strategy to identify potential substrates of UbiD-like enzymes based on detecting enzyme-catalysed solvent deuterium exchange into potential substrates. Using ferulic acid decarboxylase (FDC) as a model system, we tested a diverse range of aromatic and heterocyclic molecules for their ability to undergo enzyme-catalysed H/D exchange in deuterated buffer. We found that FDC catalyses H/D exchange, albeit at generally very low levels, into a wide range of small, aromatic molecules that have little resemblance to its physiological substrate. In contrast, the sub-set of aromatic carboxylic acids that are substrates for FDC-catalysed decarboxylation is much smaller. We discuss the implications of these findings for screening uncharacterized UbiD-like enzymes for novel (de)carboxylase activity.

Karaj, Endri ; Sindi, Shaimaa H ; Kuganesan, Nishanth ; Perera, Lalith ; Taylor, William ; Tillekeratne, LM Viranga

Abstract: Once considered potential liabilities, the modern era witnesses a renaissance of interest in covalent inhibitors in drug discovery. The available toolbox of electrophilic warheads is limited by constraints on tuning reactivity and selectivity. Following our work on a class of ferroptotic agents termed CETZOLEs, we discovered new tunable heterocyclic electrophiles which are capable of inducing ferroptosis. The biological evaluation demonstrated that thiazoles with an alkyne electrophile at the 2-position selectively induce ferroptosis with high potency. Density functional theory calculations and NMR kinetic studies demonstrated the ability of our heterocycles to undergo thiol addition, an apparent prerequisite for cytotoxicity. Chemoproteomic analysis indicated several potential targets, the most prominent among them being GPX4 protein. These results were further validated by western blot analysis and the cellular thermal shift assay. Incorporation of these heterocycles into appropriate pharmacophores generated highly cytotoxic agents such as the analogue BCP-T.A, with low nM IC50 values in ferroptosis-sensitive cell lines.

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Product Details of [ 273-53-0 ]

CAS No. :273-53-0
Formula : C7H5NO
M.W : 119.12
SMILES Code : C1=CC=CC2=C1N=CO2
MDL No. :MFCD00005765
InChI Key :BCMCBBGGLRIHSE-UHFFFAOYSA-N
Pubchem ID :9228

Safety of [ 273-53-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 273-53-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 9
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 34.01
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

26.03 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.72
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

1.59
Log Po/w (WLOGP)?

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

1.83
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.

0.98
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

2.02
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.63

Water Solubility

Log S (ESOL):?

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

-2.32
Solubility 0.57 mg/ml ; 0.00478 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-1.75
Solubility 2.13 mg/ml ; 0.0179 mol/l
Class?

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

Very 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

-2.86
Solubility 0.163 mg/ml ; 0.00137 mol/l
Class?

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

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
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

No
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.

-5.9 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<1.0
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)

2.04

Application In Synthesis of [ 273-53-0 ]

* 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 [ 273-53-0 ]

[ 273-53-0 ] Synthesis Path-Downstream   1~18

  • 1
  • [ 273-53-0 ]
  • [ 3621-82-7 ]
  • [ 615-18-9 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 2 Using the method of Example 1, 11.9 g (0.1 mol) of 1,3-benzoxazole were reacted under the same conditions to give 2-chlorobenzoxazole.
  • 3
  • [ 273-53-0 ]
  • [ 7635-54-3 ]
  • [ 1158181-10-2 ]
  • 4
  • [ 273-53-0 ]
  • [ 769-26-6 ]
  • [ 1226889-57-1 ]
  • 5
  • [ 273-53-0 ]
  • [ 2905-56-8 ]
  • [ 2851-09-4 ]
  • 6
  • [ 273-53-0 ]
  • [ 14752-66-0 ]
  • [ 1141-35-1 ]
YieldReaction ConditionsOperation in experiment
83% General procedure: Under nitrogen atmosphere, a sealable reaction tube equipped with a magnetic stirrer bar was charged with azole (0.50 mmol), sodium arylsulfinate (1.0 mmol), Pd(OAc)2 (0.025 mmol), Cu(OAc)2 (1.0 mmol), CF3COOH (0.50 mmol), and dimethylglycol (2.0 mL). The rubber septum was then replaced by a Teflon-coated screw cap, and the reaction vessel placed in an oil bath at 120 C for 24 h. After the reaction was completed, it was cooled to room temperature and the mixture was treated with K2CO3 solution (1.0 mol/L, 3.0 mL), then extracted with ethyl acetate. The resulting solution was dried by Na2SO4 then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluant: petroleum ether/ethyl acetate=12:1, v/v) to give the desired product.
  • 7
  • [ 273-53-0 ]
  • [ 221044-05-9 ]
  • [ 1402228-00-5 ]
YieldReaction ConditionsOperation in experiment
94% With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; oxygen; silver carbonate; Trimethylacetic acid; In 1,2-dichloro-benzene; at 140℃; for 24h;Schlenk technique; Sealed tube; General procedure: 25 mL flame-dried Schlenk tube with a magnetic stir barwas charged with 1-(pyrimid-2-yl)-1H-indoles (1), benzoxazole(2a), catalyst, additive, and solvent. The tube was sealed under an O2 atmosphere. The reaction mixture was stirredvigorously and heated at 140 C for 24 h, and then cooled toambient temperature. The final reaction mixture was dilutedwith 10-20 mL of CH2Cl2, filtered through a Celite pad toremove insoluble salts, and then washed with 10-20 mL ofCH2Cl2. The combined CH2Cl2 extracts were concentratedin a vacuum evaporator and the crude product was purifiedby flash column chromatography on silica gel (petroleumether/ethyl acetate=3/1, v/v) to provide the cross-coupledproduct 3.
  • 8
  • [ 273-53-0 ]
  • [ 667463-64-1 ]
  • 3-(benzo[d]oxazol-2-yl)-6-bromo-3-hydroxy-1-methylindolin-2-one [ No CAS ]
  • 9
  • [ 273-53-0 ]
  • [ 38383-51-6 ]
  • [ 1582789-82-9 ]
  • 12
  • [ 273-53-0 ]
  • [ 941-91-3 ]
  • 3-(benzo[d]oxazol-2-yl)-1-methylquinolin-2(1H)-one [ No CAS ]
  • 13
  • [ 273-53-0 ]
  • [ 6563-13-9 ]
  • 6-methoxy-2-(2-benzoxazolyl)quinoline [ No CAS ]
  • 14
  • [ 273-53-0 ]
  • [ 13506-76-8 ]
  • 2-(2-methyl-6-nitrophenyl)benzo[d]oxazole [ No CAS ]
  • 15
  • [ 273-53-0 ]
  • [ 3132-99-8 ]
  • [ 99586-31-9 ]
  • 16
  • [ 273-53-0 ]
  • [ 461-97-2 ]
  • [ 154715-81-8 ]
  • 17
  • [ 273-53-0 ]
  • [ 10485-09-3 ]
  • [ 104655-32-5 ]
YieldReaction ConditionsOperation in experiment
67% With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; nixantphos; In N,N-dimethyl-formamide; at 70℃; for 24h;Glovebox; Inert atmosphere; General procedure: An oven-dried 10 mL reaction vial equipped with a stir bar was charged with azole heterocycles (1, 0.2 mmol, 1.0 equiv) and alkenyl bromides (2, 0.30 mmol, 1.5 equiv) in a glove box under a nitrogen atmosphere. A solution of catalytic Pd2(dba)3 (9.15 mg, 0.01 mmol, 5 mol%) and NiXantphos (11.03 mg, 0.02 mmol, 10 mol%) was stirred in 1 mL of dry tetrahydrofuran (THF) for 2 h at room temperature. Then, t-BuONa (57.7 mg, 0.6 mmol, 3.0 equiv) and reagent mixed with catalyst were added to the reaction mixture. And thenthe vial was capped. According to the temperature requirements for different products, some vials were stirred in the glove box for 24 h, but others were removed from the glove box, and stirred for 24 h at 70 or 150 . The reaction mixture was quenched with three drops of H2O, diluted with 3 mL of ethyl acetate, and filtered over a pad of silica. The pad was rinsed with ethyl acetate (15-25 mL), and the combined solutions were concentrated in vacuo. The crude material was loaded onto a deactivated silica gel column and purified by flash chromatography to afford the desired product.
  • 18
  • [ 110-85-0 ]
  • [ 273-53-0 ]
  • [ 111628-39-8 ]
YieldReaction ConditionsOperation in experiment
With tetra-(n-butyl)ammonium iodide; acetic acid; In acetonitrile; at 20℃;Electrochemical reaction; Green chemistry; General procedure: A 30 mL screw capped vial with a septum was inserted carbon anode and aluminum cathode (CAUTION: Electrodes should not come in contact with each other). The electrodes were connected to a cell phone charger (5V) by use of alligator clips. To the reaction vial were added benzoxazole 1 (119 mg, 1 mmol), N-Boc piperazine 2a (372 mg, 2 mmol), acetic acid (300 mg, 5 mmol, 5 equiv.) and TBAI (37 mg, 10 mol%) and the mixture was dissolved in 20mL of acetonitrile and stirred gently at room temperature. Electric current was passed through the reaction vial at room temperature for 3 h. The progress of the reaction was monitored by TLC and LC-MS. After the completion of the reaction, the solvent was removed in vacuo and the crude material was re-dissolved in ethyl acetate (25 mL) and then washed with saturated aqueous sodium carbonate solution (3×10mL). The organic layer was separated, washed with water and then dried over sodium sulfate. The product was purified by column chromatography using hexane and ethyl acetate as eluent to afford 282 mg of compound 3a (93 % yield).
 

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