Structure of Boc-ε-Acp-OH
CAS No.: 6404-29-1
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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.
Synonyms: Boc-6-aminohexanoic acid
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PROTACs Targeting MLKL Protect Cells from Necroptosis
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.
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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 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
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 |
75.63 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.47 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.5 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.16 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.42 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.24 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.76 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.62 |
Solubility | 5.48 mg/ml ; 0.0237 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.7 |
Solubility | 0.466 mg/ml ; 0.00201 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.24 |
Solubility | 1.34 mg/ml ; 0.00579 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 |
-6.65 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 |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.16 |
* 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 |
---|---|---|
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)+. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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). |