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Chemical Structure| 6404-29-1 Chemical Structure| 6404-29-1

Structure of Boc-ε-Acp-OH
CAS No.: 6404-29-1

Chemical Structure| 6404-29-1

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Synonyms: Boc-6-aminohexanoic acid

4.5 *For Research Use Only !

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Product Citations

Product Citations

Rathje, Oliver H. ; Perryman, Lara ; Payne, Richard J. ; Hamprecht, Dieter W. ;

Abstract: Mixed Lineage Kinase domain-Like pseudokinase (MLKL) is implicated in a broad range of diseases due to its role as the ultimate effector of necroptosis and has therefore emerged as an attractive drug target. Here, we describe the development of PROteolysis TArgeting Chimeras (PROTACs) as a novel approach to knock down MLKL through chem. means. A series of candidate degraders were synthesized from a high-affinity pyrazole carboxamide-based MLKL ligand leading to the identification of a PROTAC mol. that effectively degraded MLKL and completely abrogated cell death in a TSZ model of necroptosis. By leveraging the innate ability of these PROTACs to degrade MLKL in a dose-dependent manner, the quant. relationship between MLKL levels and necroptosis was interrogated. This work demonstrates the feasibility of targeting MLKL using a PROTAC approach and provides a powerful tool to further our understanding of the role of MLKL within the necroptotic pathway.

Alternative Products

Product Details of [ 6404-29-1 ]

CAS No. :6404-29-1
Formula : C11H21NO4
M.W : 231.29
SMILES Code : C(=O)(OC(C)(C)C)NCCCCCC(=O)O
Synonyms :
Boc-6-aminohexanoic acid
MDL No. :MFCD00037798
InChI Key :RUFDYIJGNPVTAY-UHFFFAOYSA-N
Pubchem ID :637602

Safety of [ 6404-29-1 ]

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

Computational Chemistry of [ 6404-29-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 0
Fraction Csp3 0.82
Num. rotatable bonds 9
Num. H-bond acceptors 4.0
Num. H-bond donors 2.0
Molar Refractivity 61.28
TPSA ?

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

75.63 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.47
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

1.5
Log Po/w (WLOGP)?

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

2.16
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.

1.42
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

1.24
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.76

Water Solubility

Log S (ESOL):?

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

-1.62
Solubility 5.48 mg/ml ; 0.0237 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-2.7
Solubility 0.466 mg/ml ; 0.00201 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

-2.24
Solubility 1.34 mg/ml ; 0.00579 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

No
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.

-6.65 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

0.0
Bioavailability Score?

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

0.56

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)

2.16

Application In Synthesis of [ 6404-29-1 ]

* 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 [ 6404-29-1 ]

[ 6404-29-1 ] Synthesis Path-Downstream   1~7

  • 1
  • [ 580-15-4 ]
  • [ 6404-29-1 ]
  • [ 960129-44-6 ]
YieldReaction ConditionsOperation in experiment
56% With C15H23N3Pol(1+)*Cl(1-); benzotriazol-1-ol; In dichloromethane; at 35℃; Example 2a; N-(Quinolin-6-yl)-6-(sulfamoylamino)hexanamide (5a) Step 1: tert-Butyl 6-oxo-6-(quinolin-6-ylamino)hexylcarbamate (1a) To a solution of N-Boc caproic acid (0.23 g, 1.0 mmol) in DCM (5 ml) was added PS-carbodiiminde (0.8 g, 1.1 mmol). After 10 minutes <strong>[580-15-4]6-aminoquinoline</strong> (0.1 g, 0.7 mmol) and HOBt (0.13 g, 1.0 mmol) were added and stirred over night at 35 C. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (20-100%) in Hexane to afford 1a (0.2 g, 56%) as a beige solid. LRMS (ESI): (calc.) 357.2; (found) 358.3 (MH)+.
  • 2
  • [ 7724-12-1 ]
  • tert-butyl 6-(2-cyanobenzo[d]thiazol-6-ylamino)-6-oxohexylcarbamate [ No CAS ]
  • [ 6404-29-1 ]
  • [ 543-27-1 ]
  • 4-(6-(2-cyanobenzo[d]thiazol-6-ylamino)-6-oxohexylcarbamoyl)-2-(3-(dimethylamino)-6-(dimethyliminio)-6H-xanthen-9-yl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; trifluoroacetic acid; In tetrahydrofuran; diethyl ether; dichloromethane; ethyl acetate; methoxybenzene; acetonitrile; Part E. Synthesis of 4-(6-(2-cyanobenzo[d]thiazol-6-ylamino)-6-oxohexylcarbamoyl)-2-(3-(dimethylamino)-6-(dimethyliminio)-6H-xanthen-9-yl)benzoate (compound 3082) 6-(tert-Butoxycarbonylamino)hexanoic acid (316 mg) was mixed with anhydrous THF (10 mL), <strong>[7724-12-1]6-aminobenzo[d]thiazole-2-carbonitrile</strong> (200 mg), iso-butylchloroformate (193 muL), and N-methylmorpholine (314 muL) at -4° C. The reaction was allowed to stir overnight at RT. The reaction was partitioned between ethyl acetate and bicarbonate. The ethyl acetate layer was evaporated, and the residue was eluted through silica with heptane: ethyl acetate (1:2). Yield 354 mg. tert-Butyl 6-(2-cyanobenzo[d]thiazol-6-ylamino)-6-oxohexylcarbamate (350 mg) was added to cold (0° C.) solution of dichloromethane (4 mL), trifluoroacetic acid (4 mL), and anisole (400 muL). After 135 minutes, the majority of solvent was evaporated, and 10 mL acetonitrile and 30 mL of diethyl ether was added. The mixture was allowed to sit overnight. The precipitate was isolated and used without further purification.
  • 3
  • [ 6404-29-1 ]
  • [ 35661-51-9 ]
  • [ 151890-12-9 ]
YieldReaction ConditionsOperation in experiment
79% A solution of Boc-Ahx-OH (1.29 g, 5.58 mmol), HOBt (1.02 g, 6.66 mmol), HBTU (2.54 g, 6.66 mmol) and DIEA (2.44 niL, 14.0 mmol) in anhydrous DMF (10 mL) was stirred at ambient temperatures under nitrogen for 20 minutes, and treated with 9-fluorenylmethyl carbazate (1.42 g, 5.58 mmol) and DIEA (0.5 mL, 2.87 mmol). The solution was stirred for 3.5 hours, diluted with dichloromethane (30 mL), washed consecutively with 10percent citric acid (50 mL), saturated NaHCO3 (3 X 50 mL), and saturated NaCl (3 X 50 mL), dried over MgSO4, filtered, and concentrated to give a yellow oil. The oil was purified by flash chromatography over silica gel, eluting with 2:1 ethyl acetate:hexanes to give the title compound as a colorless solid (2.061 g, 79percent, HPLC purity 100percent). 1H NMR (CDCl3): delta 7,75 (d, J= 7.5 Hz, 2H), 7.58 (d, J= 7.4 Hz, 2H), 7.50 (br, IH), 7.39 (t, J= 7.4 Hz, 2H), 7.30 (dt, J- 7.0 Hz, 2H), 6.87 (br, IH), 4.63 (s, IH), 4.44 (d, J= 6.9 Hz, 2H), 4.24 (t, J= 7.1 Hz, IH), 3.08 (s, 2H), 2.23 (s, 2H), 1.68 (m, 2H), 1.42 (s, 9H), 1.47-1.35 (m, 4H); 13C NMR (CDCI3): delta 172.6, 171.2, 156.2, 143.5, 141.3, 127.9, 127.8, 127.1, 125.1, 124.9, 120.0, 79.2, 68.0, 60.4, 46.9, 40.2, 33.8, 29.6, 28.4, 26.0, 24.7, 21.1, 14.2. MS (ESI): 368.4(100, M-Boc+H).
  • 4
  • [ 7724-12-1 ]
  • [ 6404-29-1 ]
  • tert-butyl 6-(2-cyanobenzo[d]thiazol-6-ylamino)-6-oxohexylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
354 mg With 4-methyl-morpholine; isobutyl chloroformate; In tetrahydrofuran; at -4 - 20℃; 6-(tert-Butoxycarbonylamino)hexanoic acid (316 mg) was mixed with anhydrous THF (10 mL), <strong>[7724-12-1]6-aminobenzo[d]thiazole-2-carbonitrile</strong> (200 mg), iso-butylchloroformate (193 muL), and N-methylmorpholine (314 muL) at ?4° C. The reaction was allowed to stir overnight at RT. The reaction was partitioned between ethyl acetate and bicarbonate. The ethyl acetate layer was evaporated, and the residue was eluted through silica with heptane: ethyl acetate (1:2). Yield 354 mg.
354 mg With 4-methyl-morpholine; isobutyl chloroformate; In tetrahydrofuran; dichloromethane; at -4 - 20℃; 6-(tert-Butoxycarbonylamino)hexanoic acid (316 mg) was mixed with anhydrous THF (10 mL), <strong>[7724-12-1]6-aminobenzo[d]thiazole-2-carbonitrile</strong> (200 mg), iso-butylchloroformate (193 muL), and N-methylmorpholine (314 muL) at ?4° C. The reaction was allowed to stir overnight at RT. The reaction was partitioned between ethyl acetate and bicarbonate. The ethyl acetate layer was evaporated, and the residue was eluted through silica with heptane: ethyl acetate (1:2). Yield 354 mg.
  • 5
  • [ 7724-12-1 ]
  • [ 6404-29-1 ]
  • 6-amino-N-(2-cyanobenzo[d]thiazol-6-yl)hexanamide [ No CAS ]
  • 6
  • [ 745017-94-1 ]
  • [ 6404-29-1 ]
  • C50H84N6O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% 6-((tert-butoxycarbonyl)amino)hexanoic acid (46.5 mg,0.201 mmol) was dissolved in DMSO (1 mE) and Huenig?s Base (0.08 mE, 0.458 mmol) and HATU (76 mg, 0.201 mmol) were added. The reaction stirred at RT for 30 minutes before adding the reaction mixture to MMAF (50 mg, 0.067 mmol). The reaction then stirred at RT for 4 hours. The reaction mixture was loaded directly onto 35 g c-i 8 colunm for purification by column chromatography (5-75percent MeCN/Water 0.1percent formic acid). The solvent was removed on rotovap and placed on high vac overnight.The resulting product was treated with TFA (2 mE) at 00 C. and brought to room temp to stir for 5 mm. The reaction was loaded directly onto a 35 g C-18 colunm for column purification. The solvent was removed under reduced pressure toyield 30 mg (52percent yield).
  • 7
  • [ 6404-29-1 ]
  • [ 123639-61-2 ]
  • Fmoc-L-Hyp(Bzl)-OH [ No CAS ]
  • [ 159766-56-0 ]
  • C43H61N5O11 [ No CAS ]
 

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