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Xuexiang Han ; Mohamad-Gabriel Alameh ; Ningqiang Gong , et al. Nat. Chem.,2024,16,1687-1697. DOI: 10.1038/s41557-024-01557-2 PubMed ID: 38982196
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Abstract: Lipid nanoparticles (LNPs) are widely used for mRNA delivery, with cationic lipids greatly afecting biodistribution, cellular uptake, endosomal escape and transfection efciency. However, the laborious synthesis of cationic lipids limits the discovery of efcacious candidates and slows down scale-up manufacturing. Here we develop a one-pot, tandem multi-component reaction based on the rationally designed amine-thiol-acrylate conjugation, which enables fast (1?h) and facile room-temperature synthesis of amidine-incorporated degradable (AID) lipids. Structure-activity relationship analysis of a combinatorial library of 100 chemically diverse AID-lipids leads to the identifcation of a tail-like amine-ring-alkyl aniline that generally afords efcacious lipids. Experimental and theoretical studies show that the embedded bulky benzene ring can enhance endosomal escape and mRNA delivery by enabling the lipid to adopt a more conical shape. The lead AID-lipid can not only mediate local delivery of mRNA vaccines and systemic delivery of mRNA therapeutics, but can also alter the tropism of liver-tropic LNPs to selectively deliver gene editors to the lung and mRNA vaccines to the spleen.
Purchased from AmBeed: 143-28-2 ; 4097-89-6 ; 506-43-4 ; 4097-88-5
CAS No. : | 506-43-4 | MDL No. : | MFCD00056667 |
Formula : | C18H34O | Boiling Point : | - |
Linear Structure Formula : | H(CH2)5CHCHCH2CHCH(CH2)8OH | InChI Key : | JXNPEDYJTDQORS-HZJYTTRNSA-N |
M.W : | 266.46 | Pubchem ID : | 5365682 |
Synonyms : |
cis,cis-Octadeca-9,12-dienol;Linoleic Alcohol
|
Chemical Name : | (9Z,12Z)-Octadeca-9,12-dien-1-ol |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
80% | With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0℃; | In a round bottom flask was introduced triphenylphosphine (1.90 g, 7.3 mmol), carbon tetrabromide (2.16 g, 6.5 mmol), and dichloromethane (DCM) (15 mL) was added at 0C, the mixture is let stirred for 10 minutes (orange solution), then (9Z, 12Z)-octadecadien-1-ol (965.9 mg, 3.6 mmol) in DCM (10 mL) was transferred on the mixture via cannula at 0C. A white precipitate was formed. The reaction mixture was let warm up overnight; then it was filtered over celite and concentrated under reduced pressure. The product was purified by a column chromatography on SiO2 (petroleum ether/ ethyl acetate (9:1), Rf = 0.90). mpure = 0.96 g. Aspect: colorless oil. Yield: 80%. 1H NMR (500 MHz, CDCl3) delta (ppm): 5.42-5.34 (m, 4H), 3.43 (t, 2H, J = 6.9 Hz), 2.79 (m, 2H), 2.07 (m, 4H), 1.88 (m, 2H), 1.45 (m, 2H), 1.39-1.31 (m, 14H), 0.92 (t, 3H, J = 7.0 Hz) 13C {1H} NMR (126 MHz, CDCl3) delta (ppm): 130.20, 130.10, 128.01, 63.07, 32.81, 31.52, 29.64, 29.48, 29.39, 29.34, 29.22, 27.20, 25.73, 25.63, 22.55, 14.03. One C is missing. HRMS calcd for C18H32Br [M-H]+ 327.1681, found 327.1682. |
66% | With N-Bromosuccinimide; triphenylphosphine; In dichloromethane; at 0 - 20℃; | To a solution of (9Z, 12Z)-octadeca-9, 12-dien- l -ol (5 g, 1 8.76 mmol) and PPh3 (5.22 g, 19.89 mmol) in DCM (60 mL) at 0 C, was added NBS (3.87 g, 21 .77 mmol) in one portion. The reaction mixture was allowed to stir at 0 C for 1 hour and then allowed to slowly warm to room temperature and allowed to stir for 1 hour. 240 mL of hexanes was added to the reaction mixture, filtered through a silica gel plug and concentrated in vacuo. 200 mL of hexanes was added to the reaction mixture, filtered through a silica gel plug and concentrated in vacuo to afford (6Z,9Z)- 8-bromooctadeca-6,9-diene (4.06 g, 12.33 mmol, 66%). NMR (300 MHz, CDC13) delta: ppm 5.45-5.3 1 (br. m, 4H); 3.43 (t, 2H); 2.80 (m, 2H); 2.1 1 - 2.04 (br. m, 411); 1 .88 (m, 211); 1 .47-1 .33 (br. m, 1 H); 0.92 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Intermediate 12: Intermediate 11 (2.5 g, 10.11 mmol), EDC (5.8 g, 30.30 mmol), and DMAP (494 mg, 4.04 mmol) in an oven-dried flask (200 mE) with a magnetic bar was added anhydrous DCM (50 mE). The mixture was stirred at ambient temperature for 5 minutes to a clear solution. Einoleyl alcohol (6.5 g, 24.20 mmol) was then added and the mixture was stirred at room temperature overnight. The reaction was finally quenched with H20 (50 mE) and extracted with DCM twice (2x50 mE). Organic layers were combined, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The crude purified by flash chromatography purification system (80 g silica gel colunm) using a gradient of hexane for 2 mm, then 0-25% EtOAc/hexane for 15 mm, then 25% EtOAc/hexane for 5 mm, then 75% EtOAc/hexane for 5 mm under the flow rate at 60 mE/mm. The product fractions were collected and concentrated to yield Intermediate 12 (7.0 g, 93% yield) as a clear liquid. ?H mm (400 MHz, CDC13) oe: 5.38-5.3 1 (8H, m, CH=), 4.28 (1H, bs, NH), 4.08-4.05 (4H, m, OCH2), 2.78-2.75 (4H, m, rrrCHCH2CHrrr), 2.69-2.59 (4H, m, COCH2N), 2.06-2.02 (4H, m, CH2CH2CH), 1.62-1.58 (4H, m, CH2CH2O), 1.43 (9H, s, C(CH3)3), 1.35-1.26 (36H, m, CH2), 0.90-0.86 (6H, m, CH3). |