Structure of 3,5-Dihydroxybenzaldehyde
CAS No.: 26153-38-8
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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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Lulu Xue ; Alex G. Hamilton ; Gan Zhao ; Zebin Xiao ; Rakan El-Mayta ; Xuexiang Han , et al.
Abstract: Lipid nanoparticles for delivering mRNA therapeutics hold immense promise for the treatment of a wide range of lung-associated diseases. However, the lack of effective methodologies capable of identifying the pulmonary delivery profile of chemically distinct lipid libraries poses a significant obstacle to the advancement of mRNA therapeutics. Here we report the implementation of a barcoded high-throughput screening system as a means to identify the lung-targeting efficacy of cationic, degradable lipid-like materials. We combinatorially synthesize 180 cationic, degradable lipids which are initially screened in vitro. We then use barcoding technology to quantify how the selected 96 distinct lipid nanoparticles deliver DNA barcodes in vivo. The top-performing nanoparticle formulation delivering Cas9-based genetic editors exhibits therapeutic potential for antiangiogenic cancer therapy within a lung tumor model in female mice. These data demonstrate that employing high-throughput barcoding technology as a screening tool for identifying nanoparticles with lung tropism holds potential for the development of next-generation extrahepatic delivery platforms.
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CAS No. : | 26153-38-8 |
Formula : | C7H6O3 |
M.W : | 138.12 |
SMILES Code : | O=CC1=CC(O)=CC(O)=C1 |
MDL No. : | MFCD00016611 |
InChI Key : | HAQLHRYUDBKTJG-UHFFFAOYSA-N |
Pubchem ID : | 94365 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 35.88 |
TPSA ? Topological Polar Surface Area: Calculated from |
57.53 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.76 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.45 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.91 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.18 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.02 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.86 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.99 |
Solubility | 1.42 mg/ml ; 0.0103 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.26 |
Solubility | 0.752 mg/ml ; 0.00545 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.17 |
Solubility | 9.4 mg/ml ; 0.0681 mol/l |
Class? Solubility class: Log S scale |
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 |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
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) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.11 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 |
1.0 |
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<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.0 |
* 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 |
---|---|---|
90% | With potassium carbonate; In acetone; at 0 - 40℃; for 12h;Inert atmosphere; | General procedure: To the stirred solution of phenolic aldehyde (2.00 mmol) in anhydrous acetone (10 mL) was added K2CO3 (3.00 mmol, 1.5 eq.) In a nitrogen atmosphere0 And cooled.Benzyl bromide (2.4 mmol, 1.2 eq.) Was slowly added,The mixture temperature was raised to 40 ,Stir for 12 hours.After completion of the reaction, the reaction mixture was cooled to room temperature,Filter through a Celite pad and concentrate in vacuo.The crude compound was purified by column chromatography (EtOAc / Hexane = 1/3) to give the pure aromatic aldehyde in which the benzyl group was protected [note: two equivalents of K2CO3 were used in the synthesis of compound 18, 2.4 equivalents of benzyl bromide and 4.0 equivalents of K2CO3 was used for the synthesis of Compound 19). |
82% | With potassium carbonate; potassium iodide; In acetone; at 20℃; for 4h;Inert atmosphere; | A stirred suspension of 3,5-dihydroxybenzaldehyde (690mg, 5mmol), potassium carbonate (3.46g, 25mmol) and potassium iodide (166.0mg, 1mmol) in acetone (15mL) was treated dropwise with benzyl bromide (1.18mL, 10mmol) and stirring continued for 4h at room temperature. The resulting suspension was concentrated under reduced pressure and the crude mass subjected to flash column chromatography (silica, 4:1 v/v hexane/ethyl acetate) and concentration of the relevant fractions (Rf=0.58 in 4:1 v/v hexane/ethyl acetate) afforded the title compound as a white powder (1.3g, 82%) m.p. 80-81C. (0031) 1H NMR (DMSO-d6, 500MHz): delta 9.91 (s, 1H), 7.48-7.44 (m, 4H), 7.43-7.38 (m, 4H), 7.37-7.32 (m, 2H), 7.17 (d, J=2.3Hz, 2H), 7.01 (t, J=2.3Hz, 1H), 5.17 (s, 4H) ppm. 13C NMR (DMSO-d6, 126MHz): delta 192.6, 159.9, 138.3, 136.6, 128.4, 127.9, 127.7, 108.2, 108.1, 69.6ppm. IR (diamond cell, neat) numax: 1686, 1591, 1447, 1381, 1349, 1296, 1170, 1048, 829, 739, 719, 694, 675, 629cm-1. LRMS (+ESI) m/z: 319 [(M+H)+, 100%] |
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