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[ CAS No. 158407-04-6 ] {[proInfo.proName]}

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Chemical Structure| 158407-04-6
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Product Citations

Mokhtarpour, Nazanin ; Sterling, Alyssa ; Garcia, Joshua J. , et al. DOI: PubMed ID:

Abstract: Reactive oxygen species (ROS) are a heterogeneous group of highly reactive ions and mols. derived from mol. oxygen (O2) which can cause DNA damage and lead to skin cancer. NADPH oxidase 1 (Nox1) is a major producer of ROS in the skin upon exposure to UV light. Functionally, Nox1 forms a holoenzyme complex that generates two superoxide mols. and reduces NADPH. The signaling activation occurs when the organizer subunit Noxo1 translocates to the plasma membrane bringing a cytochrome P 450, through interaction with Cyba. We propose to design inhibitors that prevent Cyba-Noxo1 binding as a topical application to reduce UV-generated ROS in human skin cells. Design started from an apocynin backbone structure to generate a small mol. to serve as an anchor point. The initial compound was then modified by addition of a polyethylene glycol linked biotin. Both inhibitors were found to be non-toxic in human keratinocyte cells. Further in vitro experiments using isothermal calorimetric binding quantification showed the modified biotinylated compound bound Noxo1 peptide with a KD of 2 nM. Both using isothermal calorimetric binding and MALDI (TOF) MS showed that binding of a Cyba peptide to Noxo1 was blocked. In vivo experiments were performed using donated skin explants with topical application of the two inhibitors. Experiments show that UV light exposure of with the lead compound was able to reduce the amount of cyclobutene pyrimidine dimers in DNA, a mol. known to lead to carcinogenesis. Further synthesis showed that the polyethylene glycol but not the biotin was essential for inhibition.

Keywords: Reactive oxygen species ; Apocynin ; UV ; Noxo1 ; Cyba ; Cyclobutane pyrimidine dimer ; CPD ; UV protection

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Product Details of [ 158407-04-6 ]

CAS No. :158407-04-6 MDL No. :MFCD04115538
Formula : C11H20BrNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :YGJXBTRLYHCWGD-UHFFFAOYSA-N
M.W : 278.19 Pubchem ID :15512811
Synonyms :

Calculated chemistry of [ 158407-04-6 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.91
Num. rotatable bonds : 4
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 69.27
TPSA : 29.54 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.14 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.19
Log Po/w (XLOGP3) : 2.62
Log Po/w (WLOGP) : 2.65
Log Po/w (MLOGP) : 2.42
Log Po/w (SILICOS-IT) : 2.09
Consensus Log Po/w : 2.59

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.95
Solubility : 0.311 mg/ml ; 0.00112 mol/l
Class : Soluble
Log S (Ali) : -2.89
Solubility : 0.358 mg/ml ; 0.00129 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.53
Solubility : 0.825 mg/ml ; 0.00296 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.45

Safety of [ 158407-04-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 158407-04-6 ]

* 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.

  • Upstream synthesis route of [ 158407-04-6 ]
  • Downstream synthetic route of [ 158407-04-6 ]

[ 158407-04-6 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 158407-04-6 ]
  • [ 145508-94-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 17, p. 5176 - 5197
  • 2
  • [ 123855-51-6 ]
  • [ 158407-04-6 ]
YieldReaction ConditionsOperation in experiment
94% With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 22 h; Compound 14; EPO <DP n="122"/> N-BOC piperidine-4-methanol (1 g; 46.5 mmol) and carbon tetrabromide (1.7 g; 51.3 mmol) were dissolved in dichloromethane (20 ml) and cooled to 0 0C. Triphenyl phosphine (0.98 g; 37.3 mmol) was added and the reaction stirred at room temperature for 16 hours. Further triphenyl phosphine (0.4 g; 15.7 mmol) and carbon tetrabromide (0.24 g; 7.2 mmol) were added and stirring continued for 6 hours. The solvent was evaporated and the residue chromatograplied on silica. N-BOC piperidine-4 methyl bromide was eluted with 20percent ethyl acetate in heptane (1.22 g, 94percent).
61.9% With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.0 g,9.29 mmol) in DCM (30 mL) was added CBr4 (5.1 g, 15.51 mmol) in one portion. The resultingcolorless solution was cooled to 0°C and PPh3 (4.1 g, 15.51 mmol) was added in one portion. The resulting dark orange solution was first stirred at 0°C for 1 h and then warmed to rt and stirred overnight. The mixture was washed by H20 (20 mL x 2) and the organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel columnchromatography (petroleum ether: EtOAc = 20: 1) to give tert-butyl 4- (bromomethyl)piperidine-1-carboxylate (1.6 g, 61.9percent yield) as a yellow oil. LC-MS m/z: 263 [M+H- 15j.
55 mg With carbon tetrabromide; triphenylphosphine In diethyl ether at 20℃; for 18 h; 4-N-Boc-piperidine-methanol (200 mg, 0.93 mmol) was dissolved in diethyl ether (9 mL) and carbon tetrabromide (370 mg, 1.1 mmol) and PPh3(292 mg, 1.1 mmol) were added at rt. The reaction was allowed to stir for 18 h at rt and filtered over a pad of celite. The filtrate was concentrated and purified by flash chromatography (hexane/EtOAc, 1 :0→ 4:1 ) to give 55 mg of the title compound. H-NMR (400 MHz, DMSO-c/6) δ ppm 4.02-3.98 (m, 2 H), 3.47 (d, 2 H), 2.78-2.65 (m, 2 H), 1.89-1.74 (m, 3 H), 1.45 (s, 9 H), 1.12-0.98 (m, 2 H).
960 mg With carbon tetrabromide; triphenylphosphine In tetrahydrofuran at 0 - 20℃; A solution of 1 g (4.41 mmol) of tert-butyl 4-hydroxymethylpiperidine-1-carboxylate in 25 mL of THF is cooled to 0°C. 1.34 g (5.07 mmol) of triphenylphosphine and 2.02 g (5.96 mmol) of carbon tetrabromide are then added. The reaction mixture is stirred at room temperature over the weekend. The solution is taken up in ethyl ether, the insoluble matter is filtered off and the organic phase is evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 80/20 EtOAc/heptane) to give 960 mg of tert-butyl 4- bromomethylpiperidine-1-carboxylate, the characteristics of which are as follows: LC/MS (method G): ESI+ [M+H]+: m/z 279. tr (min) = 2.13. 1H NMR (300 MHz, δ in ppm, CDCl3): 1 .09-1.29 (m, 2H), 1.47 (s, 9H), 1 .71-1.88 (m, 3H), 2.62-2.78 (m, 2H), 3.31 (d, 2H), 4.07-4.25 (m, 2H).
960 mg With carbon tetrabromide; triphenylphosphine In tetrahydrofuran at 20℃; A solution of 1 g (4.41 mmol) of tert-butyl 4-hydroxymethylpiperidine-1-carboxylate in 25 mL of THF is cooled to 0° C. 1.34 g (5.07 mmol) of triphenylphosphine and 2.02 g (5.96 mmol) of carbon tetrabromide are then added.
The reaction mixture is stirred at room temperature over the weekend.
The solution is taken up in ethyl ether, the insoluble matter is filtered off and the organic phase is evaporated to dryness.
The residue is purified by chromatography on silica gel (eluent: 80/20 EtOAc/heptane) to give 960 mg of tert-butyl 4-bromomethylpiperidine-1-carboxylate, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 279 tr (min)=2.13
1H NMR (300 MHz, δ in ppm, CDCl3): 1.09-1.29 (m, 2H), 1.47 (s, 9H), 1.71-1.88 (m, 3H), 2.62-2.78 (m, 2H), 3.31 (d, 2H), 4.07-4.25 (m, 2H).

Reference: [1] Patent: WO2016/75661, 2016, A1, . Location in patent: Page/Page column 30
[2] Patent: WO2006/50506, 2006, A1, . Location in patent: Page/Page column 120-121
[3] RSC Advances, 2016, vol. 6, # 52, p. 46170 - 46185
[4] Patent: WO2017/27684, 2017, A1, . Location in patent: Paragraph 00266
[5] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 17, p. 2615 - 2620
[6] Patent: WO2006/46031, 2006, A1, . Location in patent: Page/Page column 82
[7] Patent: US2008/76758, 2008, A1, . Location in patent: Page/Page column 95-96
[8] Patent: US2004/77646, 2004, A1, . Location in patent: Page 130
[9] Patent: WO2013/80141, 2013, A1, . Location in patent: Page/Page column 139
[10] Patent: WO2013/190123, 2013, A1, . Location in patent: Page/Page column 129; 130
[11] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 6, p. 1318 - 1323
[12] Patent: US2015/183804, 2015, A1, . Location in patent: Paragraph 1080; 1081; 1082; 1083; 1084
[13] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 96 - 112
  • 3
  • [ 161975-39-9 ]
  • [ 158407-04-6 ]
YieldReaction ConditionsOperation in experiment
85.4% With lithium bromide In acetoneReflux Amixture of 2 (1eq, 11.72 g, 40 mmol) and lithium bromide (5eq,17.20 g, 200 mmol) in acetone (80 mL) was heated to reflux overnight.The mixture was evaporated, then the residue was partitionedbetween EtOAc and water. The organic layer was washedwith s brine, dried over Na2SO4, filtered, and evaporated to offer the title product 3 as pale yellow oil (9.46 g, 85.40percent yield).
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 96 - 112
  • 4
  • [ 84358-13-4 ]
  • [ 158407-04-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 17, p. 2615 - 2620
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