Structure of Fmoc-ACC-OH
CAS No.: 378247-75-7
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CAS No. : | 378247-75-7 |
Formula : | C26H19NO6 |
M.W : | 441.43 |
SMILES Code : | O=C(O)CC(C1=C(O2)C=C(NC(OCC3C4=C(C5=C3C=CC=C5)C=CC=C4)=O)C=C1)=CC2=O |
MDL No. : | MFCD13195295 |
InChI Key : | RCUKLQDGAASIAX-UHFFFAOYSA-N |
Pubchem ID : | 10993900 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 33 |
Num. arom. heavy atoms | 22 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 7 |
Num. H-bond acceptors | 6.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 122.59 |
TPSA ? Topological Polar Surface Area: Calculated from |
105.84 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.41 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.62 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.59 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.33 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
4.43 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.67 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.89 |
Solubility | 0.0057 mg/ml ; 0.0000129 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-5.53 |
Solubility | 0.0013 mg/ml ; 0.00000295 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-8.49 |
Solubility | 0.00000142 mg/ml ; 0.0000000032 mol/l |
Class? Solubility class: Log S scale |
Poorly 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 |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
Yes |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
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 |
-6.42 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 |
1.0 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) |
4.26 |
* 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 |
---|---|---|
General procedure: Synthesis of NH2-ACC-Rink Amide resin. Preparation of ACC wascarried out as described previously according to Maly et al.18 To glass reactionvessel, 1 eq (6.24 mmol, 13 g) of Rink AM resin was added and stirred gentlyonce per 10 min in DCM for 1 h, and then filtered and washed 3 times with DMF.Fmoc-protecting group was removed using 20percent piperidine in DMF (5, 5, and25 min), filtered each time and washed with DMF (six times). Next, 2.50 eq of Fmoc-ACC-OH (15.6 mmol, 6.9 g) was preactivated with 2.50 eq HOBt monohydrate (15.6 mmol, 2.34 g) and 2.50 eq DICI (15.6 mmol, 2.0 ml) in DMFand mixture was added to the resin. Reaction was stirred gently for 24 h at room temperature. Resin was washed four times with DMF and reaction was repeatedusing 1.5 eq of above reagents to improve yield of ACC coupling to the resin. Afterreaction, resin was washed with DMF and Fmoc group was removed using 20percentpiperidine in DMF (5, 5, and 25 min), filtered and washed with DMF (six times). Synthesis of NH2-Asp(t-Bu)-ACC-Rink Amide resin. Next, 2.5 eqFmoc-Asp(t-Bu)-OH (15.6 mmol, 6.42 g) with 2.5 eq HATU (15.6 mmol, 5.93 g),2.5 eq collidine (15.6 mmol, 2.03 ml) in DMF were activated for 2 min and added tofilter cannula with 1 eq (6.24 mmol) NH2-ACC-resin and reaction was carried outfor 24 h. Next, resin was washed four times with DMF and reaction was repeatedusing 1.5 eq of above reagents. After washing with DMF, Fmoc-protecting groupwas removed using 20percent piperidine in DMF (5, 5, and 25 min). Resin wasadditional washed with DCM (3 times) and MeOH (3 times) and dried over P2O5. Synthesis of individual optimized substrates. The 2.5 eqFmoc-P2-OH was preactivated with 2.5 eq HOBt and 2.5 eq DICI in DMF andadded to cartridge with 1 eq NH2-Asp(t-Bu)-ACC-resin (all substrates containedAsp at P1 position) and followed by gentle agitation for 3 h. Then, it was filteredand washed with DMF (six times). Fmoc-protecting group was removed using 20percent piperidine in DMF (5, 5, and 25 min). Ninhydrin test was carried out each time aftercoupling and deprotection. A solution of 2.5 eq Fmoc-P3-OH, 2.5 eq HOBt, and2.5 eq DICI in DMF was added to the resin and the slurry was agitated for 3 h.After removal of the solution, the resin was washed with DMF (six times), andcoupling and deprotection of Fmoc-P4-OH was carried in identical conditions likeP2 position. N-terminus was protected with acetyl group using 5 eq AcOH, 5 eqHBTU, and 5 eq DIPEA in DMF as previous described. After solvent removal, theresin was washed with DMF (six times), DCM (three times), and MeOH (threetimes) dried over P2O5 and cleaved from the resin with a mixture of TFA/TIPS/H2O(percent, v/v/v 95 : 2.5 : 2.5). The crude product was purified by HPLC and lyophilized.Its purity was confirmed by analytical HPLC. Each optimized substrate wasanalyzed using HRMS. Optimized substrates were dissolved in peptide gradeDMSO to 20mM concentration and stored at -80 °Cuntil use. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Synthesis of NH2-ACC-Rink Amide resin. Preparation of ACC wascarried out as described previously according to Maly et al.18 To glass reactionvessel, 1 eq (6.24 mmol, 13 g) of Rink AM resin was added and stirred gentlyonce per 10 min in DCM for 1 h, and then filtered and washed 3 times with DMF.Fmoc-protecting group was removed using 20% piperidine in DMF (5, 5, and25 min), filtered each time and washed with DMF (six times). Next, 2.50 eq of Fmoc-ACC-OH (15.6 mmol, 6.9 g) was preactivated with 2.50 eq HOBt monohydrate (15.6 mmol, 2.34 g) and 2.50 eq DICI (15.6 mmol, 2.0 ml) in DMFand mixture was added to the resin. Reaction was stirred gently for 24 h at room temperature. Resin was washed four times with DMF and reaction was repeatedusing 1.5 eq of above reagents to improve yield of ACC coupling to the resin. Afterreaction, resin was washed with DMF and Fmoc group was removed using 20%piperidine in DMF (5, 5, and 25 min), filtered and washed with DMF (six times). Synthesis of NH2-Asp(t-Bu)-ACC-Rink Amide resin. Next, 2.5 eqFmoc-Asp(t-Bu)-OH (15.6 mmol, 6.42 g) with 2.5 eq HATU (15.6 mmol, 5.93 g),2.5 eq collidine (15.6 mmol, 2.03 ml) in DMF were activated for 2 min and added tofilter cannula with 1 eq (6.24 mmol) NH2-ACC-resin and reaction was carried outfor 24 h. Next, resin was washed four times with DMF and reaction was repeatedusing 1.5 eq of above reagents. After washing with DMF, Fmoc-protecting groupwas removed using 20% piperidine in DMF (5, 5, and 25 min). Resin wasadditional washed with DCM (3 times) and MeOH (3 times) and dried over P2O5. Synthesis of individual optimized substrates. The 2.5 eqFmoc-P2-OH was preactivated with 2.5 eq HOBt and 2.5 eq DICI in DMF andadded to cartridge with 1 eq NH2-Asp(t-Bu)-ACC-resin (all substrates containedAsp at P1 position) and followed by gentle agitation for 3 h. Then, it was filteredand washed with DMF (six times). Fmoc-protecting group was removed using 20% piperidine in DMF (5, 5, and 25 min). Ninhydrin test was carried out each time aftercoupling and deprotection. A solution of 2.5 eq Fmoc-P3-OH, 2.5 eq HOBt, and2.5 eq DICI in DMF was added to the resin and the slurry was agitated for 3 h.After removal of the solution, the resin was washed with DMF (six times), andcoupling and deprotection of Fmoc-P4-OH was carried in identical conditions likeP2 position. N-terminus was protected with acetyl group using 5 eq AcOH, 5 eqHBTU, and 5 eq DIPEA in DMF as previous described. After solvent removal, theresin was washed with DMF (six times), DCM (three times), and MeOH (threetimes) dried over P2O5 and cleaved from the resin with a mixture of TFA/TIPS/H2O(%, v/v/v 95 : 2.5 : 2.5). The crude product was purified by HPLC and lyophilized.Its purity was confirmed by analytical HPLC. Each optimized substrate wasanalyzed using HRMS. Optimized substrates were dissolved in peptide gradeDMSO to 20mM concentration and stored at -80 Cuntil use. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a 10 mL glass peptide synthesis vessel was added Rink Amide AM resin (0.60 g, 0.31 mmol)and DMF (4 mL). The mixture was gently agitated with a wrist-action Burrel shaker for 1h andthen filtered. A 20% solution of piperidine in DMF (4 mL) was added and the mixture wasagitated for 30 min. The resin was filtered and then washed with DMF (3 × 4 mL). 7-N-(Fluorenylmethoxycarbonyl)aminocoumarin-4-acetic acid1 (0.40 g, 0.91 mmol), HOBt.H2O (140mg, 0.95 mmol) and DMF (4 mL) was added to the resin followed by DIC (144 muL, 0.93 mmol).The mixture was agitated for 24h, filtered and then washed with DMF (3 × 4mL), THF (3 × 4mL)and MeOH (3 × 4mL) respectively.General Procedure for Coupling the First Fmoc-Amino Acid to the ACC-ResinTo a 10 mL glass peptide synthesis vessel was added ACC-resin (0.31 mmol) and DMF (4 mL).The mixture was gently agitated with a wrist-action Burrel shaker for 1h and then filtered. A 20%solution of piperidine in DMF (4 mL) was added and the mixture was agitated for 30 min. Theresin was filtered and then washed with DMF (3 × 4 mL). In a separate scintillation vial wereadded Fmoc-amino acid (1.32 mmol), HOBt (200 mg, 1.32 mmol), DMF (4 mL) and DIC (200 muL,1.29 mmol). After a preactivation time of 5 min, the mixture was added to the resin and agitatedovernight. The resin was filtered and washed with DMF (3 × 4 mL).Representative Synthesis of a Di-peptide -ACCAs a representative example, the synthesis of N-suc-L-Phe-Gly-ACC is described. To a 10 mLglass peptide synthesis vessel was added Fmoc-Gly-ACC-resin (0.1 mmol) and DMF (3 mL). The mixture was gently agitated for 1h and then filtered. A 20% solution of piperidine in DMF (3mL) was added and the mixture was agitated for 30 min. The resin was filtered and then washedwith DMF (3 × 3 mL). In a separate scintillation vial were added Fmoc-L-Phe-OH (190 mg, 0.5mmol), HOBt (76 mg, 0.5 mmol), DMF (3 mL) and DIC (76 muL, 0.5 mmol). After a preactivationtime of 5 min, the mixture was added to the resin and agitated for 5h. The resin was filtered andwashed with DMF (3 × 4 mL). A 20% solution of piperidine in DMF (3 mL) was added and themixture was agitated for 30 min. The resin was filtered and then washed with DMF (3 × 3 mL).Succinic anhydride (100 mg, 1.0 mmol), DMF (3mL) and DIPEA (150 muL, 0.9 mmol) were addedand the mixture was agitated overnight, filtered and then washed with DMF (3 × 4 mL). Asolution of TFA:iPr3SiH:H2O (95:2.5:2.5, 3 mL) was added and the mixture was agitatedovernight. The resin was filtered and washed with TFA (2 × 3 mL). The combined filtrate wasconcentrated and the residue was washed with ether (3 × 3 mL) to give suc-L-Phe-Gly-ACC aspale yellow solid (32 mg, 62%). Amino terminus of some peptides was capped as the acetylderivative. This was accomplished by premixing AcOH (5 equiv), HOBt (5 equiv) and DIC (5equiv) in DMF and adding the mixture to the resin. The resulting mixture was agitated for 5h,filtered, and then washed with DMF. For ACC-peptides 11-18, the amino terminus was coupledwith the corresponding dicarboxylic acid as follows: In a separate scintillation vial were addeddicarboxylic acid (5 equiv), HOBt (5 equiv), DMF and DIC (5 equiv). After a pre-activation time of5 min, the mixture was added to the resin and agitated overnight. The resin was filtered andwashed with DMF (3 × 4 mL). The purification of all ACC-peptides was performed either bysimply washing the solid thoroughly with ether or by reverse-phase HPLC (ACN/H2O-0.1% TFA,15 - 60% for 20 min, 20 mL/min, 254 nm detection for 22.5 min). Purity check for all ACCpeptideswas completed by analytical reverse-phase HPLC (ACN/H2O-0.1% TFA, 10 - 60% for20 min, 1 mL/min, 254 nm detection for 23 min). Retention times are indicated as tR. |
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