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Structure of 13406-29-6

Chemical Structure| 13406-29-6

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Keyes, Robert F. ; McAllister, Donna ; Dwinell, Michael B. ; Smith, Brian C. ;

Abstract: Triphenylphosphonium (TPP+) compounds like mito-metformin (MMe) target cancer cells by exploiting their hyperpolarized mitochondrial membrane potential. Here, we present a protocol for synthesizing TPP+ analogs with selectivity for mammalian cancer cells, reduced toxicity, and quantifiability using fluorine-19 NMR (19F-NMR). We describe steps for treating mammalian cells with mitochondria-targeted compounds, treating and preparing mouse tissue with these compounds, and 19F-NMR detection of MMe analogs in cells and tissue. TPP+-conjugated metformin analogs include para-methoxy (pMeO-MMe) and para-trifluoromethyl MMe (pCF3-MMe) and meta-trifluoromethyl MMe (mCF3-MMe).

Purchased from AmBeed: ; ; ;

Mahmoud AbuEid ; Robert F. Keyes ; Donna McAllister ; Francis Peterson ; Ishaque Pulikkal Kadamberi ; Daniel J. Sprague , et al.

Abstract: Triphenylphosphonium (TPP+) conjugated compounds selectively target cancer cells by exploiting their hyperpolarized mitochondrial membrane potential. To date, studies have focused on modifying either the linker or the cargo of TPP+-conjugated compounds. Here, we investigated the biological effects of direct modification to TPP+ to improve the efficacy and detection of mito-metformin (MMe), a TPP+-conjugated probe we have shown to have promising preclinical efficacy against solid cancer cells. We designed, synthesized, and tested trifluoromethyl and methoxy MMe analogs (pCF3-MMe, mCF3-MMe, and pMeO-MMe) against multiple distinct human cancer cells. pCF3-MMe showed enhanced selectivity toward cancer cells compared to MMe, while retaining the same signaling mechanism. Importantly, pCF3-MMe allowed quantitative monitoring of cellular accumulation via 19F-NMR in vitro and in vivo. Furthermore, adding trifluoromethyl groups to TPP+ reduced toxicity in vivo while retaining anti-tumor efficacy, opening an avenue to de-risk these next-generation TPP+-conjugated compounds.

Purchased from AmBeed: ;

Alternative Products

Product Details of [ 13406-29-6 ]

CAS No. :13406-29-6
Formula : C21H12F9P
M.W : 466.28
SMILES Code : FC(C1=CC=C(P(C2=CC=C(C(F)(F)F)C=C2)C3=CC=C(C(F)(F)F)C=C3)C=C1)(F)F
MDL No. :MFCD00058883
InChI Key :PXYCJKZSCDFXLR-UHFFFAOYSA-N
Pubchem ID :139448

Safety of [ 13406-29-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335-H413
Precautionary Statements:P261-P273-P305+P351+P338

Computational Chemistry of [ 13406-29-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 31
Num. arom. heavy atoms 18
Fraction Csp3 0.14
Num. rotatable bonds 6
Num. H-bond acceptors 9.0
Num. H-bond donors 0.0
Molar Refractivity 100.15
TPSA ?

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

13.59 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

4.08
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

7.26
Log Po/w (WLOGP)?

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

9.96
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.

7.61
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

8.61
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

7.5

Water Solubility

Log S (ESOL):?

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

-7.34
Solubility 0.0000214 mg/ml ; 0.0000000459 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.

-7.37
Solubility 0.0000199 mg/ml ; 0.0000000426 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

-10.06
Solubility 0.0000000407 mg/ml ; 0.0000000001 mol/l
Class?

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

Insoluble

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

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.

-3.99 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

1.0
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

1.0
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

2.0
Bioavailability Score?

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

0.55

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

1.0 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)

3.96

Application In Synthesis of [ 13406-29-6 ]

* 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 [ 13406-29-6 ]

[ 13406-29-6 ] Synthesis Path-Downstream   1~35

  • 2
  • [ 62-53-3 ]
  • [ 13406-29-6 ]
  • [ 13406-18-3 ]
  • 3
  • [ 80-48-8 ]
  • [ 13406-29-6 ]
  • [ 120360-41-0 ]
  • 6
  • [ 13406-29-6 ]
  • Difluortris(p-trifluormethylphenyl)phosphoran [ No CAS ]
  • 11
  • [ 13406-29-6 ]
  • C21H12Br2F9P [ No CAS ]
  • 14
  • [ 198345-82-3 ]
  • [ 13406-29-6 ]
  • 15
  • [ 13406-29-6 ]
  • C21H12F9PS [ No CAS ]
  • 16
  • [ 13406-27-4 ]
  • [ 13406-29-6 ]
YieldReaction ConditionsOperation in experiment
88%Chromat. With [AlH3(triethylamine)]; In hexane; at 20℃; for 0.166667h;Inert atmosphere; Schlenk technique; General procedure: Triphenylphosphine oxide or sulfide (1 mmol), dry hexane (1 mL), and Ic (1 mmol) were added to a Schlenk tube under the atmosphere of nitrogen. The reaction was carried out at room temperature for 10 min and monitored by TLC. Upon completion of the process the reaction mixture was filtered by silica gel and washed several times with ethyl acetate. Ethyl acetate was evaporated and the residue purified by flash chromatography on silica gel with pure cyclohexane toafford the desired phosphine. The yield was determined by GC without additional purification.
  • 17
  • aqueous sodium chloride [ No CAS ]
  • [ 402-43-7 ]
  • [ 7719-12-2 ]
  • [ 13406-29-6 ]
YieldReaction ConditionsOperation in experiment
35% With hydrogenchloride; n-butyllithium; In diethyl ether; hexane; water; PREPARATION OF TRIS(4-TRIFLUOROMETHYLPHENYL)PHOSPHINE (R=4-trifluomethylphenyl) 8 grams of 4-bromobenzotrifluoride were dissolved in 45 milliliters of anhydrous diethylether at 0° C. under a nitrogen atmosphere. 14 milliliters of a 2.5 M solution of n-butyllithium in hexane were then added to the solution via syringe, with stirring, over a 10 minute period. The solution was stirred for 30 minutes at 0° C., and then a solution of 1 milliliter of phosphorous trichloride in 15 milliliters of diethylether was added to the solution dropwise over a 50 minute period. The resulting mixture was warmed to room temperature and stirred for 21/2 hours, then quenched with 50 milliliters of a 5 percent solution of hydrochloric acid. The organic phase of the mixture was washed with 50 milliliters of water, followed by 50 milliliters of aqueous sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered, and concentrated on a rotavap (rotary evaporator). The resulting product was a red-orange oil, yield 5.31 grams. The product included a triarylphosphine oxide side-product. The side-product was removed by precipitation by the addition of hexane, followed by filtration of the side product. The hexane solvent was removed on a rotavap, and the final product was an orange oil which crystallized upon standing. The triarylphosphine product was purified by recrystallization from methanol. The final yield of the triarylphosphine product was 1.95 grams (yield 35percent).
  • 18
  • ruthenium(III) chloride trihydrate [ No CAS ]
  • [ 542-92-7 ]
  • [ 13406-29-6 ]
  • [ 172220-60-9 ]
  • 19
  • cis-bis-(2,2′-bipyridine) dichlororuthenium(II) dihydrate [ No CAS ]
  • sodium perchlorate [ No CAS ]
  • [ 13406-29-6 ]
  • [ 112088-20-7 ]
  • 20
  • [ 7601-90-3 ]
  • cis-bis-(2,2′-bipyridine) dichlororuthenium(II) dihydrate [ No CAS ]
  • [ 13406-29-6 ]
  • [ 112088-20-7 ]
  • 21
  • carbido heptadecacarbonyl hexaruthenium [ No CAS ]
  • [ 13406-29-6 ]
  • Ru6C*16CO*P(C6H4CF3)3=Ru6C(CO)16{P(C6H4CF3)3} [ No CAS ]
  • 22
  • bis(acetylacetonato)palladium(II) [ No CAS ]
  • [ 13406-29-6 ]
  • {Pd(O,O-acac)(γ-C-acac)(P(Ph-p-CF3)3)} [ No CAS ]
  • 23
  • dicarbonyl(η5-indenyl)methyliron [ No CAS ]
  • [ 13406-29-6 ]
  • (C9H7)Fe(CO)(COCH3)(P(C6H4CF3)3) [ No CAS ]
  • 24
  • bis(acetonitrile)(chloranilato)palladium(II) [ No CAS ]
  • [ 13406-29-6 ]
  • [ 121354-22-1 ]
  • 25
  • (η(5)-methylcyclopentadienyl)Fe(CO)2Me [ No CAS ]
  • [ 13406-29-6 ]
  • [ 117228-43-0 ]
  • 26
  • dicarbonyl(cyclopentadienyl)methyliron(II) [ No CAS ]
  • [ 13406-29-6 ]
  • [ 117228-09-8 ]
  • 27
  • [ 494804-05-6 ]
  • [ 13406-29-6 ]
  • [ 114835-23-3 ]
  • 28
  • [ 87863-04-5 ]
  • [ 13406-29-6 ]
  • oxotrichlorobis(tris(p-(trifluoromethyl)phenyl)phosphine)rhenium(V) [ No CAS ]
  • 29
  • [ 12080-32-9 ]
  • [ 13406-29-6 ]
  • [ 92471-73-3 ]
  • 30
  • (1,2,5,6-η4-cycloocta-1,5-diene)bis(4-methoxyphenyl)platinum(II) [ No CAS ]
  • [ 13406-29-6 ]
  • cis-bis(4-methoxyphenyl)bis(tris{4-(trifluoromethyl)phenyl}phosphane)platinum(II) [ No CAS ]
  • 31
  • {(indenyl)dicarbonyl(isopropyl)iron(II)} [ No CAS ]
  • [ 13406-29-6 ]
  • (C9H7)Fe(CO)(COCH(CH3)2)(P(C6H4CF3)3) [ No CAS ]
  • 32
  • [ 10025-99-7 ]
  • [ 13406-29-6 ]
  • [ 92471-73-3 ]
  • 33
  • [ 34766-74-0 ]
  • [ 13406-29-6 ]
  • Os2(CO)6(μ-C4Ph4) [ No CAS ]
  • Os(CO)4P(p-F3CC6H4)3 [ No CAS ]
  • Os(CO)3(P(p-F3CC6H4)3)2 [ No CAS ]
  • Os2(CO)5(P(p-F3CC6H4)3)(μ-C4Ph4) [ No CAS ]
  • 34
  • Ru5C(CO)15 [ No CAS ]
  • [ 13406-29-6 ]
  • Ru5C(CO)15[P(C6H4CF3)3] [ No CAS ]
  • 35
  • [ 92269-93-7 ]
  • [ 13406-29-6 ]
  • [ 344800-64-2 ]
 

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