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Chemical Structure| 913733-27-4 Chemical Structure| 913733-27-4

Structure of Fmoc-N-Me-Arg(pbf)-OH
CAS No.: 913733-27-4

Chemical Structure| 913733-27-4

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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.

Keywords: guanidino group ; octanol-water partitioning ; peptoid ; topological polar surface area

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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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Product Details of [ 913733-27-4 ]

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

Safety of [ 913733-27-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 913733-27-4 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

166.5 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.46
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

5.66
Log Po/w (WLOGP)?

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

6.32
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.

2.79
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

5.04
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

4.66

Water Solubility

Log S (ESOL):?

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

-6.87
Solubility 0.0000885 mg/ml ; 0.000000133 mol/l
Class?

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

Poorly soluble
Log S (Ali)?

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

-8.92
Solubility 0.000000795 mg/ml ; 0.0000000012 mol/l
Class?

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

Poorly 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

-9.88
Solubility 0.0000000882 mg/ml ; 0.0000000001 mol/l
Class?

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

Poorly soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
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

Yes
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

Yes
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.32 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

2.0
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

2.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

2.0
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

3.0
Bioavailability Score?

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

0.17

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

2.0 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<3.0
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)

5.77
 

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