Structure of 13406-29-6
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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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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).
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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.
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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 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335-H413 |
Precautionary Statements: | P261-P273-P305+P351+P338 |
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 |
13.59 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
4.08 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
7.26 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
9.96 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
7.61 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
8.61 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
7.5 |
Log S (ESOL):? ESOL: Topological method implemented from |
-7.34 |
Solubility | 0.0000214 mg/ml ; 0.0000000459 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
Log S (Ali)? Ali: Topological method implemented from |
-7.37 |
Solubility | 0.0000199 mg/ml ; 0.0000000426 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-10.06 |
Solubility | 0.0000000407 mg/ml ; 0.0000000001 mol/l |
Class? Solubility class: Log S scale |
Insoluble |
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) |
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 |
-3.99 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
1.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
1.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
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) |
3.96 |
* 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 |
---|---|---|
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. |
Yield | Reaction Conditions | Operation 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). |