Structure of 1,12-Dibromododecane
CAS No.: 3344-70-5
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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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Marshall S. Padilla ; Kaitlin Mrksich ; Yiming Wang ; Rebecca M. Haley ; Jacqueline J. Li ; Emily L. Han , et al.
Abstract: Lipid nanoparticles (LNPs) are the preeminent non-viral drug delivery vehicle for mRNA-based therapies. Immense effort has been placed on optimizing the ionizable lipid (IL) structure, which contains an amine core conjugated to lipid tails, as small molecular adjustments can result in substantial changes in the overall efficacy of the resulting LNPs. However, despite some advancements, a major barrier for LNP delivery is endosomal escape. Here, we develop a platform for synthesizing a class of branched ILs that improve endosomal escape. These compounds incorporate terminally branched groups that increase hepatic mRNA and ribonucleoprotein complex delivery and gene editing efficiency as well as T cell transfection compared to non-branched lipids. Through an array of complementary experiments, we determine that our lipid architecture induces greater endosomal penetration and disruption. This work provides a scheme to generate a class of ILs for both mRNA and protein delivery.
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CAS No. : | 3344-70-5 |
Formula : | C12H24Br2 |
M.W : | 328.13 |
SMILES Code : | BrCCCCCCCCCCCCBr |
MDL No. : | MFCD00000226 |
InChI Key : | ZJJATABWMGVVRZ-UHFFFAOYSA-N |
Pubchem ID : | 18766 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 11 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 75.54 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
4.04 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
6.91 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
5.68 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
5.28 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
5.66 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
5.51 |
Log S (ESOL):? ESOL: Topological method implemented from |
-5.5 |
Solubility | 0.00103 mg/ml ; 0.00000315 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-6.72 |
Solubility | 0.0000623 mg/ml ; 0.00000019 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-6.42 |
Solubility | 0.000126 mg/ml ; 0.000000384 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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
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) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-3.4 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
1.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
1.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
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) |
3.76 |
* 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 |
---|---|---|
85% | 1,12-Dibromododecane (0.20 g, 0.61 mmol) was dissolved in 4-methyl-2- pentanone (2.0 ml) and <strong>[1802-20-6]3-pentylpyridine</strong> (0.20 g, 1.34 mmol) was added. The mixture was 5 stirred at reflux for 20 h under a nitrogen atmosphere, and the solvent was removed under reduced pressure. The crude was triturated with Et2O (8 x 10 ml), and the solvent was removed under reduced pressure. The residue was purified by Al2O3 chromatography <n="32"/>(neutral, activity H-III)5 using gradient elution (starting with CHCl3/MeOH = 2 % to 10 %). The residue was passed down a column of Lewatit MP-64 anion resin (Cl"), eluting with EtOH. The resulting fractions were combined and the solvent removed under reduced pressure to give the above compound as a light yellow waxy oil (0.28 g, 85 %).5 1H NMR (300 MHz, CDCl3): delta 9.55 (4H, m, CH(2',6')), 8.20 (2H, d, J= 6.5 Hz, CH(4')), 8.07 (2H3 m, CH(3')), 5.00 (4H5 m5 CH2(I)), 3.10 (4H5 m, CH2(I")), 2.89 (4H5 m, CH2(2"))5 2.06 (4H5 m5 CH2(2))5 1.72 (4H5 m5 CH2(3"))5 1.33 (12H5 m, CH2(354,4")), 1.33 (8H5 m, CH2(5,6)), 0.96 (6H, m, CH3(5")). 13C NMR (300 MHz, CDCl3): 164.2, 144.2, 128.5, 61.2, 35.6, 32.2, 31.4, 29.5, 29.4, 29.1, 26.2, 22.4, 13.3, 1 signal obscured or io overlapping. MS: m/z ESI (positive ion) 233 [M-2C1"]2+ (18 %), 465 [M-2Cl"-H+]+ (10). Found [M-2C1"]2+ 233.2136, [C16H27N]2+ requires 233.2144. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In DMF (N,N-dimethyl-formamide); for 168h; | 4- (DIMETHYLAMINO) phenyldiphenylphosphine (1.73 mmoles, 0.529 g) and 1,12-dibromododecane (1.73 mmoles, 0.569 g) were dissolved in DMF (1 ml) and shaken for 1 week. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | General procedure: A solution of 8-T-cGMP (200 mM, 1 eq) and N.N-diisopropylethylamine (2 eq) in DMSO was added portionwise over 30 min to a solution of 1 , 12-dibromdodecane (1.5 M, 15 eq) in (0803) DMSO at 40 C. The reaction mixture was stirred until no further reaction progress was observed (< 10 % remaining starting material). The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in (0804) MeCN/water (8:1 , v/v), washed with petroleum ether (3 x) and the aqueous phase evaporated to dryness using a rotary evaporator. The crude product was dissolved in DMF (115 mM). 4,4"-Thiobisbenzenthiol (0.5 eq) and Nu,Nu-diisopropylethylamine (2.2 eq) were added successively. The reaction mixture was stirred until the starting material was completely consumed. The solvent was removed through high vacuum evaporation with a speedvac concentrator. The residue was dissolved in water (1 mL), washed with ethyl acetate (3 x 1 mL), subjected to preparative reversed phase hplc and desalted. (0805) Yield f Purity) :26 % (> 99 %). (0806) HPLC: (57 % MeCN, 30 mM NaH2PO* buffer, pH 6.8). (0807) UV-VIS: Amax = 275 nm (pH 7), epsilon = 24660 (est.). (0808) ESI- S (+): m/z calculated for C56H73N10O14P2S5 (P+H]+): 1337.39, found: 1337. (0809) ESS-MS (-): m/z calculated for C56H77N10O14P2S5 ([M-H] ): 1335.37, found: 1335. |