Structure of 454-81-9
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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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Qi Su ;
Abstract: Iodotyrosine deiodinases (IYDs) are versatile flavoenzymes. IYD was first discovered in humans as a deiodinase involved in iodide salvage for thyroid hormone biosynthesis. Mechanistic study suggested that IYD catalyzed deiodination of mono- and di-iodotyrosine using a series of single electron transfer. In the first part of this thesis, IYDs from a range of organisms were evaluated for their ability to catalyze nitroreduction by cofactor engineering. The cofactor FMN was replaced by 5-deaza FMN to suppress the sequential one-electron transfer for deiodination by 10000-fold and to promote a non-natural nitroreduction activity with a turnover frequency of 1.4 min-1. The engineered IYD∙5dFMN reduced nitroaromatics to aromatic amines catalytically using NaBH4 as a reducing source. The full 6-electron reduction of nitroaromatics to amines is rarely possible by other nitroreductases (NRs). In the second part of this thesis, the biological function of IYD was investigated in a model invertebrate, Drosophila melanogaster, which does not have a thyroid nor known to require iodide. A knockout or inactivated mutation of the cdt gene (encoding IYD) in male Drosophila using CRISPRCas9 gene editing suppressed fecundity by more than 90% over 6 days. The role of IYD in Drosophila spermatogenesis was studied using a combination of LC-MS based metabolite profiling, immunofluorescent imaging and genetic rescue. Drosophila IYD was previously known to promote debromination and dechlorination as well as deiodination. Accumulation of mono- and di-bromotyrosine at nanomolar concentrations was detected from either IYD suppression or the presence of excess bromotyrosine in diet. This accumulation disrupted over 80% of the assembly of actin cones in Drosophila testes and led to defects in spermatids individualization. Overexpression of transgenic IYD lowered the concentration of bromotyrosine in testes, restored normal spermatids individualization and rescued Drosophila fertility. Taken together, IYD is proposed to affect Drosophila fertility by regulating bromotyrosine concentration and normal spermatids individualization. The many faces of IYD functions beyond deiodination and iodide recycling should facilitate the application of IYD in bioremediation and studies of coevolution of halogenated compounds and dehalogenase in biology.
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CAS No. : | 454-81-9 |
Formula : | C7H6F3NO |
M.W : | 177.12 |
SMILES Code : | NC1=C(O)C=CC(=C1)C(F)(F)F |
MDL No. : | MFCD01731750 |
InChI Key : | BHTKIYIEMXRHGL-UHFFFAOYSA-N |
Pubchem ID : | 120246 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 37.87 |
TPSA ? Topological Polar Surface Area: Calculated from |
46.25 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.23 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.68 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.15 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.91 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.65 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.92 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.3 |
Solubility | 0.887 mg/ml ; 0.00501 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.27 |
Solubility | 0.96 mg/ml ; 0.00542 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.35 |
Solubility | 0.797 mg/ml ; 0.0045 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
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) |
No |
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 |
-6.19 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 |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.09 |
* 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 |
---|---|---|
Reference Production Example 11A mixture of 1 g of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> and 5 ml of thionyl chloride was heated to reflux for seven hours. Then, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of DMF, which was added dropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMF and 1.05 g of triethylamine at 0C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.75 g of 3,5-dichloro-N-(2-hydroxy-5- trifluoromethylphenyl)isonicotinamide.1H-NMR (CDCl3+DMSO-d6) delta: 9.03 (br s, 1H), 8.59 (s, 2H), 8.45 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.5, 2.2 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H) | ||
A mixture of 1 g of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> and 5 ml of thionyl chloride was heated to reflux for seven hours. Then, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of DMF, which was added dropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMF and 1.05 g of triethylamine at 0C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.75 g of 3,5-dichloro-N-(2-hydroxy-5- trifluoromethylphenyl)isonicotinamide.1H-NMR (CDCl3+DMSO-d6) delta: 9.03 (br s, IH), 8.59 (s, 2H), 8.45 (d, J=2.0 Hz, IH), 7.30 (dd, J=8.5, 2.2 Hz, IH), 7.04 (d, J=8.5 Hz, IH) | ||
A mixture of 1 g of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> and 5 ml of thionyl chloride was heated to reflux for seven hours. Then, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of DMF, which was added dropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMF and 1.05 g of triethylamine at 0C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.75 g of 3,5-dichloro-N-(2-hydroxy-5- trifluoromethylphenyl)isonicotinamide.1 H-NMR (CDCl3+DMSO-d6) delta: 9.03 (br s, IH), 8.59 (s, 2H), 8.45 (d, J=2.0 Hz, IH), 7.30 (dd, J=8.5, 2.2 Hz, IH), 7.04 (d, J=8.5 Hz, IH) |
Reference Production Example 11A mixture of 1 g of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> and 5 ml of thionyl chloride was heated to reflux for seven hours. Then, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of DMF, which was added dropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMF and 1.05 g of triethylamine at 0C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.75 g of 3,5-dichloro-N-(2-hydroxy-5- trifluoromethylphenyl)isonicotinamide.1H-NMR (CDCl3+DMSO-d6) delta: 9.03 (br s, 1H), 8.59 (s, 2H), 8.45 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.5, 2.2 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H) | ||
Reference Production Example 11A mixture of 1 g of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> and 5 ml of thionyl chloride was heated to reflux for seven hours. Then, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of DMF, which was added dropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMF and 1.05 g of triethylamine at 0C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.75 g of 3,5-dichloro-N-(2-hydroxy-5- trifluoromethylphenyl)isonicotinamide.-NMR (CDCl3+DMSO-d6) delta: 9.03 (br s, 1H), 8.59 (s, 2H), 8.45 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.5, 2.2 Hz, IH), 7.04 (d, J=8.5 Hz, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | at 130℃; | A solution of 2-amino-4-(trifluoromethyl)phenol (5g, 28.2mmol) in triethoxymethane (30g, 283mmo1) was heated at 130 C for 5h. The TLC showed reaction to be complete. The solvent was removed under reduced pressure. The residue was purified by column chromatography using silica gel (1 00-200 mesh), eluting with 4% EtOAc in hexane to afford 5-(trifluoromethyl)benzo[d]oxazole as a yellow solid. Yield: 2.5g (48%); 1H NMR (400 MHz, DMSO-d6): 8.20 (5, 1H), 8.10 (5, 1H), 7.63- 7.74 (m, 2H). |
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