Structure of Fmoc-N-Me-Arg(pbf)-OH
CAS No.: 913733-27-4
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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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Nα-Methylation of arginine: Implications for cell-penetrating peptides
Calabretta, Lindsey O. ; Yang, Jinyi ; Raines, Ronald T. ;
Abstract: The field of cell-penetrating peptides is dominated by the use of oligomers of arginine residues. Octanol-water partitioning in the presence of an anionic lipid is a validated proxy for cell-penetrative efficacy. Here, we add one, two, or three N-Me groups to Ac-Arg-NH2 and examine the effects on octanol-water partitioning. In the absence of an anionic lipid, none of these arginine derivatives can be detected in the octanol layer. In the presence of sodium dodecanoate, however, increasing N-methylation correlates with increasing partitioning into octanol, which is predictive of higher cell-penetrative ability. We then evaluated fully Nα-methylated oligoarginine peptides and observed an increase in their cellular penetration compared with canonical oligoarginine peptides in some contexts. These findings indicate that a simple modification, Nα-methylation, can enhance the performance of cell-penetrating peptides.
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Keywords: guanidino group ; octanol-water partitioning ; peptoid ; topological polar surface area
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Purchased from AmBeed: 154445-77-9 ; 913733-27-4 ; 74-79-3 ; 12135-22-7 ; 3849-21-6 ; 88530-28-3 ; 58107-60-1
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Guanidinium Compounds: Synthesis, Oxoanion Binding, and Cellular Delivery
Orgren Calabretta, Lindsey ;
Abstract: The delivery of biological molecules into cells has been an issue of importance in both chemical biology and drug discovery. One method used to transport biologics into cells is the cellpenetrating peptide (CPP). This arginine-rich peptide forms strong interactions with the cell surface through bidentate guanidinium–oxoanion hydrogen bonds. Depending on conditions, this interaction guides the uptake of the CPP and its cargo through direct translocation or endocytosis. In Chapter 1, I summarize literature that is relevant to this thesis. In Chapter 2, I describe the synthesis and characterization of a small molecule, 1- guanidino-8-amino-2,7-diazacarbazole dichloride (GADAC), that displays a high binding affinity to a carboxylate, phosphate, and sulfate in water. GADAC is also fluorescent and displays an increase in quantum yield mediated by pH. The uptake and fluorescence of GADAC is observed in human melanoma cells via epifluorescent microscopy. Thus, the GADAC scaffold shows promise as a potential cell-uptake promoter and fluorescent reporter of biologics. In Chapters 3 and 4, I explore alternative amino acids for use in CPPs. I studied the ability of canavanine, a -oxa-analog of arginine, to partition into octanol in the presence of anionic lipids as a proxy for its cell-penetration ability. I observed that canavanine is worse at partitioning than arginine, indicating it may not be an effective CPP alternative. In contrast, I synthesized and performed anion-mediated partitioning on Nα-methylated arginine derivatives and observed increased octanol uptake compared to unmethylated arginine. This increased uptake is correlates with a decrease in topological polar surface area (TPSA) and indicates that an Nα-methylated CPP could be a cell-uptake promoter with increased efficacy. Lastly, in Chapter 4, I describe the synthesis of biaryl-bisguanidines. These guanidines are inspired by axially constrained organometallic catalyst ligands and have applications in oxoanion binding as dications and organometallic catalysts as dianions. I detail initial forays into determining the binding affinities of the guanidines to oxoanions through NMR titration experiments, which were hampered by changing ionic strength of the solutions. Appendices describe the synthesis of photocaged phosphinothioesters for the traceless Staudinger ligation and attempts to install a diazo moiety site-selectively at the N-terminus of a peptide or protein.
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CAS No. : | 913733-27-4 |
Formula : | C35H42N4O7S |
M.W : | 662.80 |
SMILES Code : | O=C(O)[C@H](CCCNC(NS(=O)(C1=C(C)C(C)=C(OC(C)(C)C2)C2=C1C)=O)=N)N(C(OCC3C4=C(C5=C3C=CC=C5)C=CC=C4)=O)C |
MDL No. : | MFCD02094401 |
InChI Key : | MEGKXARLCPKZHJ-LJAQVGFWSA-N |
Pubchem ID : | 122129466 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 47 |
Num. arom. heavy atoms | 18 |
Fraction Csp3 | 0.4 |
Num. rotatable bonds | 14 |
Num. H-bond acceptors | 8.0 |
Num. H-bond donors | 4.0 |
Molar Refractivity | 180.2 |
TPSA ? Topological Polar Surface Area: Calculated from |
166.5 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
3.46 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
5.66 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
6.32 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.79 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
5.04 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
4.66 |
Log S (ESOL):? ESOL: Topological method implemented from |
-6.87 |
Solubility | 0.0000885 mg/ml ; 0.000000133 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
Log S (Ali)? Ali: Topological method implemented from |
-8.92 |
Solubility | 0.000000795 mg/ml ; 0.0000000012 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-9.88 |
Solubility | 0.0000000882 mg/ml ; 0.0000000001 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
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) |
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) |
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) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.32 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
2.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
2.0 |
Egan? Egan (Pharmacia) filter: implemented from |
2.0 |
Muegge? Muegge (Bayer) filter: implemented from |
3.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.17 |
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<3.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
5.77 |
Tags: 913733-27-4 synthesis path| 913733-27-4 SDS| 913733-27-4 COA| 913733-27-4 purity| 913733-27-4 application| 913733-27-4 NMR| 913733-27-4 COA| 913733-27-4 structure
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