CN112961091A - Amino lipide compound and preparation method and application thereof - Google Patents
Amino lipide compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an amino lipide compound, a compound shown in a chemical formula I, or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt and a prodrug thereof,
also disclosed are methods for the preparation of the compounds and their use as components for the delivery of therapeutic agents and in the preparation of medicaments.
Description
Technical Field
The invention relates to an amino lipid compound, in particular to an amino lipid compound which can be used for delivering genes into cells, and a preparation method and application thereof.
Background
Gene therapy is the artificial delivery of genes with specific genetic information to target cells, and the expressed target proteins have the effects of regulating, treating and even curing diseases caused by congenital or acquired gene defects. Both nucleic acid and cell membrane have negative charge, so that naked nucleic acid is difficult to directly introduce into cell, and is easily degraded by nucleic acid degrading enzyme in cytoplasm, and can not reach the action of gene introduction and gene therapy, so that it can implement gene transfer by means of external force or carrier. Genetic vectors are generally classified into viral vectors and non-viral vectors. The viral vector has extremely high transfection efficiency in vivo and in vitro, but has a plurality of defects such as high toxicity, strong immune response, small gene capacity, poor targeting property, complex preparation process and the like. Non-viral vectors have gained increasing attention and application due to their ease of preparation, transport, and storage, safety, efficacy, lack of immunogenicity, and the like.
However, gene delivery currently faces two problems during therapy relative to gene delivery at the cellular level. First, free RNA is susceptible to nuclease digestion in plasma. A frequently used solution is to introduce into the nanoparticles phosphonate ester loaded with PEG chains, which extend at the outermost layer of the micelle during self-assembly. Because the PEG layer has the characteristics of electric neutrality, protein adsorption resistance, no functional group at the end group and the like, the PEG layer can reduce the cytotoxicity of the nano carrier in vivo and prolong the cycle time. Second, after endocytosis of the cell, the gene vector can be transported into endosomal/lysosomal vesicles, where the gene is readily degraded by enzymes or acidic materials that are abundant in the lysosome. Therefore, the ability of nucleic acids to escape from endosomes/lysosomes into the cytoplasm is an important link for gene delivery in non-viral vectors. In the endosomal/lysosomal pathway, the nanocomplex undergoes a process of acidity reduction from pH 5-6 in late endosomes to lysosomes at pH about 4.5, which are rich in lysosomal enzymes and highly susceptible to degradation of the nanocomplex, and commonly used non-viral vectors have very low efficiency of endosomal/lysosomal escape and inefficient gene delivery.
Disclosure of Invention
Aiming at the existing defects, the invention provides an amino lipid compound for delivering genes into cells, and a preparation method and application thereof.
The technical scheme adopted by the invention for solving the technical problems is as follows: an aminolipidated compound, a compound of formula I, or a stereoisomer, or a tautomer thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof:
wherein:
R1-R2independently of each other, selected from the following structures:
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl structure containing from 6 to 24 carbon atoms, wherein in the substituted alkyl structure the substituent group is a hydrocarbon group containing from 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkenyl structure containing from 6 to 24 carbon atoms, wherein in the substituted alkenyl structure the substituent group is a hydrocarbon group containing from 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkynyl structure containing 6 to 24 carbon atoms, wherein in the substituted alkynyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted acyl structure containing from 4 to 24 carbon atoms, wherein in the substituted acyl structure the substituent group is a hydrocarbyl group containing from 1 to 6 carbon atoms;
R3-R4independently of each other, selected from the following structures:
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl structure containing 1 to 12 carbon atoms, wherein in the substituted alkyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkenyl structure containing 2 to 12 carbon atoms, wherein in the substituted alkenyl structure, the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkynyl structure containing 2 to 12 carbon atoms, wherein in the substituted alkynyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms; (ii) a
R3And R4A 4 to 10 membered heterocyclic ring formed in combination with each other, said heteroatoms being one or more of nitrogen, sulfur and oxygen, said heterocyclic ring being optionally substituted with 1 to 6 heteroatoms;
l is selected from the following structures:
a linear or branched, saturated or unsaturated alkylene structure containing 1 to 12 carbon atoms, the substituent group being one or more of alkyl, carboxyl, acyl, alkoxy;
linear or branched, saturated or unsaturated alkenylene structure containing 2 to 12 carbon atoms, the substituent group being one or more of alkyl, carboxyl, acyl, alkoxy;
linear or branched, saturated or unsaturated alkynylene structures containing 2 to 12 carbon atoms, said substituent groups being one or more of hydrocarbyl, carboxyl, acyl, alkoxy;
a 4 to 10 membered heterocyclic ring structure, the heteroatom being one or more of nitrogen, sulfur and oxygen, the heterocyclic ring being optionally substituted with 1 to 6 heteroatoms;
n is 1 or 2;
x is selected from C, N, O, S, S ═ O, S (═ O)2And S-S.
Preferably, R is1Is one of N6, N7, N8, N9, N10, N11, N12, N13, N14, N15, N16, N18, N19, N20 selected from:
N6:CH3(CH2)5-；N7:CH3(CH2)6-；N8:CH3(CH2)7-；
N9:CH3(CH2)8-；N10：CH3(CH2)9-；N11:CH3(CH2)10-；
N12:CH3(CH2)11-；N13:CH3(CH2)12-；N14:CH3(CH2)13-；
N15:CH3(CH2)14-；N16:CH3(CH2)15-；N18:CH3(CH2)17-；
the R is2Is one of A6, a7, A8, a9, a10, a11, a12, a13, a14, a15, a16, a18, a19, a20 selected from:
A6:CH3(CH2)4-；A7:CH3(CH2)5-；A8:CH3(CH2)6-；
A9:CH3(CH2)7-；A10：CH3(CH2)8-；A11:CH3(CH2)9-；
A12:CH3(CH2)10-；A13:CH3(CH2)11-；A14：CH3(CH2)12-；
A15:CH3(CH2)13-；A16:CH3(CH2)14-；A18:CH3(CH2)16-；
-X-L-N(R3)(R4) Is any one of O1, O2, O3, O4, O5, O6, O7, O8, O9, O10, D1, D2, D3, D4, D5, D6, D7, D8, D9 and D10 selected from the following group:
preferably, R is1-R2Independently of each other, selected from the following structures:
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl structure containing from 6 to 24 carbon atoms, wherein in the substituted alkyl structure the substituent group is a hydrocarbon group containing from 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkenyl structure containing from 6 to 24 carbon atoms, wherein in the substituted alkenyl structure the substituent group is a hydrocarbon group containing from 1 to 6 carbon atoms;
R3-R4independently of each other, selected from the following structures:
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl structure containing 1 to 12 carbon atoms, wherein in the substituted alkyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
R3and R4A 4 to 10 membered heterocyclic ring structure formed in combination with each other, said heteroatoms being one or more of nitrogen, sulfur and oxygen, said heterocyclic ring being optionally substituted with 1 to 6 heteroatoms;
x is N or O.
Preferably, L is a linear or branched, saturated or unsaturated, substituted or unsubstituted alkylene structure containing 1 to 4 carbon atoms, wherein in the substituted alkylene structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms.
A method for preparing amino lipid compound comprises the following steps:
s1, reacting compound NH2-R1And R2-CHO is stirred in solvent for reaction, then cyclic acid anhydride is added after the solvent is removed by distillation, the compound (II) is obtained after temperature rise reaction and purification, the structural formula is as follows,
s2, reacting the compound (II) with
The alcohol or amine is reacted in the presence of a condensing agent to obtain the compound (I), the structural formula is as follows,
wherein:
R1-R2independently of each other, selected from the following structures:
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl structure containing from 6 to 24 carbon atoms, wherein in the substituted alkyl structure the substituent group is a hydrocarbon group containing from 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkenyl structure containing from 6 to 24 carbon atoms, wherein in the substituted alkenyl structure the substituent group is a hydrocarbon group containing from 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkynyl structure containing 6 to 24 carbon atoms, wherein in the substituted alkynyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted acyl structure containing from 4 to 24 carbon atoms, wherein in the substituted acyl structure the substituent group is a hydrocarbyl group containing from 1 to 6 carbon atoms;
R3-R4independently of each other, selected from the following structures:
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl structure containing 1 to 12 carbon atoms, wherein in the substituted alkyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkenyl structure containing 2 to 12 carbon atoms, wherein in the substituted alkenyl structure, the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkynyl structure containing 2 to 12 carbon atoms, wherein in the substituted alkynyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms; (ii) a
R3And R4A 4 to 10 membered heterocyclic ring formed in combination with each other, said heteroatoms being one or more of nitrogen, sulfur and oxygen, said heterocyclic ring being optionally substituted with 1 to 6 heteroatoms;
l is selected from the following structures:
a linear or branched, saturated or unsaturated alkylene structure containing 1 to 12 carbon atoms, the substituent group being one or more of alkyl, carboxyl, acyl, alkoxy;
linear or branched, saturated or unsaturated alkenylene structure containing 2 to 12 carbon atoms, the substituent group being one or more of alkyl, carboxyl, acyl, alkoxy;
linear or branched, saturated or unsaturated alkynylene structures containing 2 to 12 carbon atoms, said substituent groups being one or more of hydrocarbyl, carboxyl, acyl, alkoxy;
a 4 to 10 membered heterocyclic ring structure, the heteroatom being one or more of nitrogen, sulfur and oxygen, the heterocyclic ring being optionally substituted with 1 to 6 heteroatoms;
n is 1 or 2;
x is selected from C, N, O, S, S ═ O, S (═ O)2And S-S.
Use of an aminolipidated compound as a medicament for any one of gene therapy, gene vaccination, antisense therapy, interfering RNA therapy, and nucleic acid transfer, wherein when n ═ 1, X is not O as a medicament for nucleic acid transfer
Preferably, the nucleic acid is any one of RNA, mRNA, antisense oligonucleotide, DNA, plasmid, rRNA, miRNA, tRNA, siRNA, and snRNA.
"substituted" as referred to above is optional, i.e. one or more hydrogen atoms attached to the atom or group are independently unsubstituted or substituted with one or more substituents independently selected from: deuterium (D), halogen, -OH, mercapto, cyano, -CD3、C1-C6Alkyl (preferably C)1-C3Alkyl group), C2-C6Alkenyl radical, C2-C6Alkynyl, cycloalkyl (preferably C)3-C8Cycloalkyl), aryl, heterocyclyl (preferably 3-8 membered heterocyclyl), heteroaryl, aryl C1-C6Alkyl-, heteroaryl C1-C6Alkyl radical, C1-C6Haloalkyl, -OC1-C6Alkyl (preferably-OC)1-C3Alkyl), -OC2-C6Alkenyl, OC1-C6Alkyl phenyl, C1-C6alkyl-OH (preferably C)1-C4alkyl-OH), C1-C6alkyl-SH, C1-C6alkyl-O-C1-C6Alkyl, OC1-C6Haloalkyl, NH2、C1-C6alkyl-NH2(preferably C)1-C3alkyl-NH2)、-N(C1-C6Alkyl radical)2(preferably-N (C)1-C3Alkyl radical)2)、-NH(C1-C6Alkyl) (preferably-NH (C)1-C3Alkyl)), -N (C)1-C6Alkyl) (C1-C6Alkylphenyl), -NH (C)1-C6Alkylphenyl), nitro, -C (O) -OH, -C (O) OC1-C6Alkyl (preferably-C (O) OC1-C3Alkyl), -CONRiri (Ri and Rii are H, D or C1-C6Alkyl, preferably C1-C3Alkyl), -NHC (O) (C)1-C6Alkyl), -NHC (O) (phenyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl group C (O) (phenyl), -C (O) C1-C6Alkyl, -C (O) heteroaryl (preferably-C (O) -5-7 membered heteroaryl), -C (O) C1-C6Alkylphenyl, -C (O) C1-C6Haloalkyl, -OC (O) C1-C6Alkyl (preferably-OC (O) C)1-C3Alkyl), -S (O)2-C1-C6Alkyl, -S (O) -C1-C6Alkyl, -S (O)2-phenyl, -S (O)2-C1-C6Haloalkyl, -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH (phenyl), -NHS (O)2(C1-C6Alkyl), -NHS (O)2(phenyl) and-NHS (O)2(C1-C6Haloalkyl), wherein each of the alkyl, cycloalkyl, phenyl, aryl, heterocyclyl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of: halogen, -OH, -NH2Cycloalkyl, 3-8 membered heterocyclyl, C1-C4Alkyl radical, C1-C4Haloalkyl-, -OC1-C4Alkyl, -C1-C4alkyl-OH, -C1-C4alkyl-O-C1-C4Alkyl, -OC1-C4Haloalkyl, cyano, nitro, -C (O) -OH, -C (O) OC1-C6Alkyl, -CON (C)1-C6Alkyl radical)2、-CONH(C1-C6Alkyl), -CONH2、-NHC(O)(C1-C6Alkyl), -NH (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -SO2(C1-C6Alkyl), -SO2(phenyl), -SO2(C1-C6Haloalkyl), -SO2NH2、-SO2NH(C1-C6Alkyl), -SO2NH (phenyl), -NHSO2(C1-C6Alkyl), -NHSO2(phenyl) and-NHSO2(C1-C6Haloalkyl). In this case, when one atom or group is substituted with a plurality of substituents, the plurality of substituents may be the same or different.
Wherein "alkyl" refers to the residue of an aliphatic hydrocarbon after the loss of one hydrogen atom, and includes straight-chain or branched, saturated or unsaturated hydrocarbon groups, including alkyl, alkenyl and alkynyl groups,
wherein "acyl" refers to hydrocarbyl-carbonyl, preferably said acyl is C4-C24An acyl group.
Wherein "alkoxy" means alkyl-oxy, preferably said alkoxy is C1-C10An alkoxy group.
Wherein "heterocycle" refers to a saturated or unsaturated cyclic group containing a heteroatom selected from N, O, S, which heterocycle may be optionally substituted with one or more substituents.
The invention has the beneficial effects that: the compound of the invention is an aminolipidic compound containing long apolar residues, the resulting compound all having hydrophobic character and, due to the amino group, also hydrophilic character, this amphoteric character can be used to form lipid particles, at the same time it has a 5-oxopyrrolidine-or 6-oxopiperidine group, the introduction of which significantly increases the membrane fusion to enhance the release of mRNA, thus promoting a synergistic improvement of mRNA delivery, being stable during the in vivo circulation, being rapidly degraded in endosomes/lysosomes, with significantly enhanced delivery efficiency. The preparation method of the amino lipid compound has the advantages of easily available raw materials, mild reaction conditions, good reaction selectivity, high reaction yield, low requirements on instruments and equipment and simple operation, and can be used as a medicament to remarkably improve the gene delivery efficiency.
Drawings
FIG. 1 is a body fluid antibody titer resulting from the delivery of OVA mRNA by subcutaneous administration of a representative amino lipid compound of an embodiment of the invention;
Detailed Description
To more clearly illustrate the objects, technical solutions and advantages of the embodiments of the present invention, the present invention will be further described in detail with reference to the accompanying drawings and embodiments, and it is obvious that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without inventive step, are within the scope of the present invention.
Example 1: 1-dodecyl-5-oxo-2-undecylpyrrolidine-3-carboxylic acid
N-dodecylamine (1.85g,10mmol), n-dodecanal (1.84g,100mmol) and anhydrous methanol (100 mL) are sequentially added into a 250mL reaction flask, stirred at room temperature for reaction for 12 hours, the solvent is evaporated under reduced pressure, then xylene (150 mL) and succinic anhydride (1.00g,100mmol) are sequentially added, and the temperature is raised to 140 ℃ for reaction for 10 hours. After the solvent was evaporated to dryness under reduced pressure, 50mL of n-hexane was added, stirred, crystallized, filtered, washed with a small amount of n-hexane, and dried to give 1-dodecyl-5-oxo-2-undecylpyrrolidine-3-carboxylic acid (3.75g, 83%).
Example 2: synthesis of 1-hexadecyl-2-nonyl-6-oxopiperidine-3-carboxylic acid
Into a 250mL reaction flask were added n-hexadecylamine (2.42g,10mmol), n-decaldehyde (1.56g,100mmol) and anhydrous methanol (100 mL) in this order, and the mixture was stirred at room temperature for 12 hours, after the solvent was evaporated to dryness under reduced pressure, 150mL of xylene and glutaric anhydride (1.14g,100mmol) were added in this order, and the mixture was heated to 140 ℃ for 10 hours. After the solvent was evaporated to dryness under reduced pressure, 50mL of n-hexane was added, stirred, crystallized, filtered, washed with a small amount of n-hexane, and dried to give 1-hexadecyl-2-nonyl-6-oxopiperidine-3-carboxylic acid (3.51g, 71%).
Example 3: synthesis of ((Z) -octadecyl-9-en-1-yl) -5-oxo-2-undecylpyrrolidine-3-carboxylic acid
Oleylamine (2.68g,10mmol), n-decanal (1.56g,100mmol) and anhydrous methanol (100 mL) were added sequentially to a 250mL reaction flask, stirred at room temperature for 12 hours, the solvent was evaporated under reduced pressure, then xylene (150 mL) and succinic anhydride (1.00g,100mmol) were added sequentially, and the temperature was raised to 140 ℃ for reaction for 10 hours. After the solvent was evaporated under reduced pressure, 50mL of n-hexane was added, stirred, crystallized, filtered, washed with a small amount of n-hexane, and dried to give ((Z) -octadecyl-9-en-1-yl) -5-oxo-2-undecylpyrrolidine-3-carboxylic acid (4.54g, 85%).
Example 4: synthesis of 1-dodecyl-2- ((8Z, 11Z) -heptadecyl-8, 11-dien-1-yl) -5-oxopyrrolidine-3-carboxylic acid
N-dodecylamine (1.85g,10mmol), cis-9, 12-octadecadienal (2.64g,100mmol) and anhydrous methanol (100 mL) are sequentially added into a 250mL reaction flask, stirred at room temperature for reaction for 12 hours, after the solvent is evaporated to dryness under reduced pressure, xylene (150 mL) and succinic anhydride (1.00g,100mmol) are sequentially added, and the temperature is raised to 140 ℃ for reaction for 10 hours. After the solvent was evaporated to dryness under reduced pressure, 50mL of n-hexane was added, stirred, crystallized, filtered, washed with a small amount of n-hexane, and dried to give 1-dodecyl-2- ((8Z, 11Z) -heptadecyl-8, 11-dien-1-yl) -5-oxopyrrolidine-3-carboxylic acid (4.31g, 81%).
Example 5: synthesis of Compound N12A12C4O2
1-dodecyl-5-oxo-2-undecylpyrrolidine-3-carboxylic acid (903mg,2mmol), 3-dimethylamino-1-propanol (310mg,3mol), and 50mL of dichloromethane were sequentially added to a 250mL reaction flask, and after stirring and dissolution, dicyclohexylcarbodiimide (824mg,4mmol), 4-dimethylaminopyridine (5mg,0.04mmol) were added, reacted at room temperature for 2 hours, washed with water for 3 times, dried over anhydrous sodium sulfate, concentrated, and purified using a flash column chromatography system (dichloromethane: methanol ═ 20: 1 to 5: 1) to obtain compound N12a12C4O2(1.03g, 96%).1H NMR(400MHz,DMSO-d6)：δ4.15(m,2H)；3.94(m,1H)；3.18(m,2H)；2.90(m,1H),2.73(m,1H),2.62(m,1H),2.34(t,2H),2.16(s,6H),1.67(m,2H),1.39-1.18(m,40H),0.89(m,6H).ESI-MS calculated for C33H65N2O3 +[M+H]+537.5,found 537.7
Example 6: synthesis of Compound N16A10C5O10
1-hexadecyl-2-nonyl-6-oxypiperidine-3-carboxylic acid (988mg,2mmol), N-hydroxyethylpiperidine (387mg,3mol), and 50mL of methylene chloride were sequentially charged into a 250mL reaction flask, and after stirring and dissolution, dicyclohexylcarbodiimide (824mg,4mmol), 4-dimethylaminopyridine (5mg,0.04mmol) were further added and reacted at room temperature for 2 hours, washed with water for 3 times, dried over anhydrous sodium sulfate, and after concentration, purified using a flash column chromatography system (methylene chloride: methanol 20: 1 to 5: 1) to obtain the compound N16A10C5O10(1.03g, 96%).1H NMR(400MHz,DMSO-d6)：δ4.15(m,2H)；3.94(m,1H)；3.18(m,2H)；2.90(m,1H),2.73(m,1H),2.62(m,1H),2.34(t,2H),2.16(s,6H),1.67(m,2H),1.39-1.18(m,40H),0.89(m,6H).ESI-MS calculated for C33H65N2O3 +[M+H]+606.0,found 606.3
Example 7: synthesis of Compound N12A12C4D1
1-dodecyl-5-oxo-2-undecylpyrrolidine-3-carboxylic acid (903mg,2mmol), N, N-dimethylethylenediamine (353mg,4mol), and 50mL of dichloromethane were sequentially added to a 250mL reaction flask, and after stirring and dissolving, O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU,1.14g,3mmol) and N, N-diisopropylethylamine (516mg,4mmol) were added, and after completion of the TLC detection reaction, 200mL of dichloromethane was added, and after washing 3 times, the mixture was dried over anhydrous sodium sulfate and concentratedAfter condensation, purification using flash column chromatography system (dichloromethane: methanol ═ 20: 1 to 5: 1) gave compound N12a12C4D1(982mg, 94%).1H NMR(400MHz,DMSO-d6)：δ4.17(m,2H)；3.95(m,1H)；3.19(m,2H)；2.91(m,1H),2.72(m,1H),2.63(m,1H),2.34(t,2H),2.16(s,6H),1.67(m,2H),1.39-1.18(m,38H),0.89(m,6H).ESI-MS calculated for C32H64N3O2 +[M+H]+522.5,found522.9
Example 8: synthesis of Compound N12A20C4O10
1-dodecyl-5-oxo-2-undecylpyrrolidine-3-carboxylic acid (903mg,2mmol), N-hydroxyethylpiperidine (387mg,3mol), and 50mL of dichloromethane were sequentially added to a 250mL reaction flask, and after stirring and dissolution, dicyclohexylcarbodiimide (824mg,4mmol), 4-dimethylaminopyridine (5mg,0.04mmol) were added and reacted at room temperature for 2 hours, washed with water for 3 times, dried over anhydrous sodium sulfate, and concentrated and then purified using a flash column chromatography system (dichloromethane: methanol 20: 1 to 5: 1) to obtain the compound N12A20C4O10(1.03g, 96%).1H NMR(400MHz,DMSO-d6)：δ4.15(m,2H)；3.94(m,1H)；3.18(m,2H)；2.90(m,1H),2.73(m,1H),2.62(m,1H),2.34(t,2H),2.16(s,6H),1.67(m,2H),1.39-1.18(m,40H),0.89(m,6H).ESI-MS calculated for C33H65N2O3 +[M+H]+644.1,found 644.3
Example 9: evaluation of luciferase mRNA in vivo delivery Performance of lipid nanoparticles prepared from amino lipid Compound
The preparation method comprises the following steps: the mol ratio of the amino lipidic compound to DSPC, cholesterol and PEG2000-DMG is 50: 10: 38.5: 1.5 in the absolute ethanol. Luciferase mrna (fluc mrna) was dissolved in sodium acetate solution (50mM, pH 4.0). Two micro-syringe pumps were used, the ratio of ethanol solution to sodium acetate solution (50mM, pH 4.0) was controlled to 1: 3, preparing a crude solution of lipid nanoparticles in a micro-flow channel chip, dialyzing with a dialysis cartridge (Fisher, MWCO 20,000) at 1 XPBS and a controlled temperature of 4 ℃ for 6h, and filtering with a 0.22 μm microporous membrane before use. The mass ratio of aminolipid compound to luciferase mrna (fluc mrna) was about 10: 1.
animal preparation: selecting male BALB/c mice of 6 weeks old, weighing about 20g, and feeding in SPF-level feeding room, wherein animal experiments are strictly carried out according to the guidelines of the national health institution and the ethical requirements of animals.
In vivo delivery: 3 mice were randomly selected per group and intramuscular injection of lipid nanoparticles was used at a dose of 0.5 mg/kg. After 6 hours, 200. mu.L of 10mg/mL D-fluorescein potassium salt was injected into each mouse via the tail vein, and after 10 minutes, the mice were placed under an in vivo imaging system (IVIS-200, Xenogen), and the total fluorescence intensity of each mouse was observed and recorded by photographing. Table 1 shows that intramuscular administration of representative amino lipid compounds delivered the expression intensity of Fluc mRNA, and DLin-MC3 was used as a control, and a number of the amino lipids were similar to the expression intensity of MC3 and were significantly better than the positive control.
TABLE 1
Example 10: in vivo delivery of ovalbumin mRNA and evaluation of immunological properties of lipid nanoparticles prepared from amino lipid compounds
The preparation method comprises the following steps: the mol ratio of the amino lipidic compound to DSPC, cholesterol and PEG2000-DMG is 50: 10: 38.5: 1.5 in the absolute ethanol. Ovalbumin mrna (ova mrna) was dissolved in sodium acetate solution (50mM, pH 4.0). Two micro-syringe pumps were used, the ratio of ethanol solution to sodium acetate solution (50mM, pH 4.0) was controlled to 1: 3, preparing a crude solution of lipid nanoparticles in a micro-flow channel chip, dialyzing with a dialysis cartridge (Fisher, MWCO 20,000) at 1 XPBS and a controlled temperature of 4 ℃ for 6h, and filtering with a 0.22 μm microporous membrane before use. The mass ratio of aminolipid compound to ovalbumin mrna (ova mrna) was about 10: 1.
animal preparation: selecting male BALB/c mice of 6 weeks old, weighing about 20g, and feeding in SPF-level feeding room, wherein animal experiments are strictly carried out according to the guidelines of the national health institution and the ethical requirements of animals.
In vivo delivery: 3 mice were randomly selected per group and injected subcutaneously with lipid nanoparticles (Day 0) at a dose of 0.5 mg/kg. After 7 days, the same amount was used for another boost (Day 7). Tail vein bleeds were taken on day 21 for serological analysis.
Enzyme-linked immunosorbent assay (ELISA): flat bottom 96 well plates (Nunc) were pre-coated in 50mM carbonate buffer at a concentration of 0.5 μ g protein per well (pH 9.6) overnight at 4 ℃, then blocked with 5% glycine, antiserum obtained from immunized animals were diluted from 102 to 106 PBS-0.05% Tween (PBS-T), pH 7.4, and added to wells and incubated at room temperature for 1 hour at 37 ℃, horseradish peroxidase (HRP) conjugated goat anti-mouse IgG in PBS-T-1% BSA at 1: a dilution of 10,000 was labeled. After addition of the HRP substrate, absorbance at 450nm was measured in an optical density ELISA plate reader (Bio-Rad) at one wavelength. As shown in fig. 1, N12a12C4O2 was comparable to the IgG antibody titration generated by MC3, while the IgG antibody titration of N16a10C5O10, N12a12C4D1, N12a20C4O10 was significantly better than the MC3 control.
Thus, the amino lipid compound can be placed in an aqueous solution to produce nano-sized materials, i.e., lipid nanoparticles, i.e., liposomes used to encapsulate drugs in lipid bilayers or in the internal aqueous space of liposomes, where liposomes are vesicles composed of bilayers of amphiphilic molecules that encapsulate the aqueous compartments, such as lipid bilayers vesicles (liposomes), multilamellar vesicles, or micelles, where the lipid is placed in water to first form lipid vesicles and then a bilayer or series of bilayers, each separated by water molecules, can be formed by lipid vesicles in water by ultrasound, where the lipid bilayer is a thin film formed by two layers of lipid molecules, where micelles are aggregates of surfactant molecules dispersed in liquid colloids, where typical micelles in aqueous solutions form aggregates with the hydrophilic head regions when exposed to water, a hydrophobic single tail region in the center of the chelating micelle; lipid particles formed from lipid compounds in gene therapy introduce foreign genes into target cells to correct or compensate for diseases caused by defective and abnormal genes for therapeutic purposes, such as treatment of cancer and genetic diseases; the cancer is one or more of lung cancer, gastric cancer, liver cancer, esophageal cancer, colon cancer, pancreatic cancer, brain cancer, lymph cancer, blood cancer or prostate cancer, and the genetic disease is one or more of hemophilia, thalassemia and gaucher's disease; in vaccination, amino-lipid compounds are used to deliver antigens or nucleic acids encoding antigens that elicit immune responses against various antigens that are used to treat and/or prevent a variety of conditions, such as cancer, allergy, toxicity, and infection by pathogens (e.g., viruses, bacteria, fungi, and other pathogenic organisms); the nucleic acid in the nucleic acid transfer is any one of RNA, mRNA (messenger RNA), antisense oligonucleotide, DNA, plasmid, rRNA (ribosomal RNA), miRNA (microrna), tRNA (transfer RNA), siRNA (small inhibitory RNA), snRNA (small nuclear RNA), and can be used in gene therapy, gene vaccination, antisense therapy, or therapy by interfering RNA in a patient. The nucleic acid has a biological effect when introduced into a cell or host as a biologically active agent, for example, by stimulating an immune or inflammatory response, by exerting an enzymatic activity or by supplementing mutations or the like, the biologically active agent being in particular a nucleic acid, a peptide, a protein, an antibody and a small molecule, or a member selected from the group consisting of antineoplastic agents, antibiotics, immunomodulators, anti-inflammatory agents, agents acting on the central nervous system, polypeptides or polypeptides (polypeptoids); of course, the bioactive agent can also be an anti-tumor agent, an antibiotic, an immunomodulator, an anti-inflammatory agent, an agent acting on the central nervous system, an antigen or fragment thereof, a protein, a peptide, a polypeptide, a vaccine, a small molecule, or a mixture thereof; furthermore, one or more of a helper lipid, a sterol, a polyethylene glycol lipid may be added to the application of the amino-lipidic compound, such as the helper lipid being a non-cationic lipid, the sterol being cholesterol, the polyethylene glycol lipid being PEG2000-DMG ((1- (monomethoxypolyethylene glycol) -2,3 dimyristoyl glycerol), the non-cationic lipid may contain cationic functional groups (e.g., ammonium groups) but should contain anionic functional groups to at least neutralize the molecule, the totality of all functional groups in the lipid molecule should be non-cationic, liposomes consisting of a mixture of cationic amino lipids and non-cationic (neutral) phospholipids being most effective in delivering nucleic acids into cells, e.g., the non-cationic lipid is DOPE (dioleoylphosphatidylethanolamine) or DSPC (distearoylphosphatidylcholine), is a natural component in cell membranes that can be used to stabilize particles and aid in integration with cell membranes; polyethylene glycol lipids (PEG lipids) help protect the particles and their contents from degradation in vitro or in vivo, PEG forms a protective layer on the liposome surface and increases circulation time in vivo, and can be used in liposomal drug delivery (PEG-liposomes) which can thus be used to transfect multicellular tissues or organs, providing a novel therapeutic treatment for patients, which can be any mammal, preferably from humans, mice, rats, pigs, cats, dogs, horses, goats, cattle and monkeys, and/or others.
It will be understood that modifications and variations can be made by persons skilled in the art in light of the above teachings and all such modifications and variations are intended to be included within the scope of the invention as defined in the appended claims.
Claims (7)
1. An aminolipidic compound characterized by: a compound of formula I, or a stereoisomer, or a tautomer, or a pharmaceutically acceptable salt, prodrug, or solvate thereof:
wherein:
R1-R2independently of each other, selected from the following structures:
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl structure containing from 6 to 24 carbon atoms, wherein in the substituted alkyl structure the substituent group is a hydrocarbon group containing from 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkenyl structure containing from 6 to 24 carbon atoms, wherein in the substituted alkenyl structure the substituent group is a hydrocarbon group containing from 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkynyl structure containing 6 to 24 carbon atoms, wherein in the substituted alkynyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted acyl structure containing from 4 to 24 carbon atoms, wherein in the substituted acyl structure the substituent group is a hydrocarbyl group containing from 1 to 6 carbon atoms;
R3-R4independently of each other, selected from the following structures:
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl structure containing 1 to 12 carbon atoms, wherein in the substituted alkyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkenyl structure containing 2 to 12 carbon atoms, wherein in the substituted alkenyl structure, the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkynyl structure containing 2 to 12 carbon atoms, wherein in the substituted alkynyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms; (ii) a
R3And R4A 4 to 10 membered heterocyclic ring formed in combination with each other, said heteroatoms being one or more of nitrogen, sulfur and oxygen, said heterocyclic ring being optionally substituted with 1 to 6 heteroatoms;
l is selected from the following structures:
a linear or branched, saturated or unsaturated alkylene structure containing 1 to 12 carbon atoms, the substituent group being one or more of alkyl, carboxyl, acyl, alkoxy;
linear or branched, saturated or unsaturated alkenylene structure containing 2 to 12 carbon atoms, the substituent group being one or more of alkyl, carboxyl, acyl, alkoxy;
linear or branched, saturated or unsaturated alkynylene structures containing 2 to 12 carbon atoms, said substituent groups being one or more of hydrocarbyl, carboxyl, acyl, alkoxy;
a 4 to 10 membered heterocyclic ring structure, the heteroatom being one or more of nitrogen, sulfur and oxygen, the heterocyclic ring being optionally substituted with 1 to 6 heteroatoms;
n is 1 or 2;
x is selected from C, N, O, S, S ═ O, S (═ O)2And S-S.
2. The amino lipid compound according to claim 1, wherein: the R is1Is one of N6, N7, N8, N9, N10, N11, N12, N13, N14, N15, N16, N18, N19, N20 selected from:
N6:CH3(CH2)5-；N7:CH3(CH2)6-；N8:CH3(CH2)7-；
N9:CH3(CH2)8-；N10：CH3(CH2)9-；N11:CH3(CH2)10-；
N12:CH3(CH2)11-；N13:CH3(CH2)12-；N14:CH3(CH2)13-；
N15:CH3(CH2)14-；N16:CH3(CH2)15-；N18:CH3(CH2)17-；
N19:
N20:
the R is2Is one of A6, a7, A8, a9, a10, a11, a12, a13, a14, a15, a16, a18, a19, a20 selected from:
A6:CH3(CH2)4-；A7:CH3(CH2)5-；A8:CH3(CH2)6-；
A9:CH3(CH2)7-；A10：CH3(CH2)8-；A11:CH3(CH2)9-；
A12:CH3(CH2)10-；A13:CH3(CH2)11-；A14：CH3(CH2)12-；
A15:CH3(CH2)13-；A16:CH3(CH2)14-；A18:CH3(CH2)16-；
A19:
A20:
-X-L-N(R3)(R4) Is any one of O1, O2, O3, O4, O5, O6, O7, O8, O9, O10, D1, D2, D3, D4, D5, D6, D7, D8, D9 and D10 selected from the following group:
O1：
O2：
O3：
O4：
O5：
O6：
O7：
O8：
O9：
O10：
D1：
D2：
D3：
D4：
D5：
D6：
D7：
D8：
D9：
D10：
3. the amino lipid compound according to claim 1, wherein:
the R is1-R2Independently of each other, selected from the following structures:
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl structure containing from 6 to 24 carbon atoms, wherein in the substituted alkyl structure the substituent group is a hydrocarbon group containing from 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkenyl structure containing from 6 to 24 carbon atoms, wherein in the substituted alkenyl structure the substituent group is a hydrocarbon group containing from 1 to 6 carbon atoms;
R3-R4independent of each otherAnd (b) is selected from the following structures:
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl structure containing 1 to 12 carbon atoms, wherein in the substituted alkyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
R3and R4A 4 to 10 membered heterocyclic ring structure formed in combination with each other, said heteroatoms being one or more of nitrogen, sulfur and oxygen, said heterocyclic ring being optionally substituted with 1 to 6 heteroatoms;
x is N or O.
4. The amino lipid compound according to claim 1, wherein: the L is a linear or branched, saturated or unsaturated, substituted or unsubstituted alkylene structure containing 1 to 4 carbon atoms, wherein in the substituted alkylene structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms.
5. A method for preparing an amino lipid compound, comprising: the method comprises the following steps:
s1, reacting compound NH2-R1And R2-CHO is stirred in solvent for reaction, then cyclic acid anhydride is added after the solvent is removed by distillation, the compound (II) is obtained after temperature rise reaction and purification, the structural formula is as follows,
s2, reacting the compound (II) with
The alcohol or amine is reacted in the presence of a condensing agent to obtain the compound (I), the structural formula is as follows,
wherein:
R1-R2independently of each other, selected from the following structures:
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl structure containing from 6 to 24 carbon atoms, wherein in the substituted alkyl structure the substituent group is a hydrocarbon group containing from 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkenyl structure containing from 6 to 24 carbon atoms, wherein in the substituted alkenyl structure the substituent group is a hydrocarbon group containing from 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkynyl structure containing 6 to 24 carbon atoms, wherein in the substituted alkynyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted acyl structure containing from 4 to 24 carbon atoms, wherein in the substituted acyl structure the substituent group is a hydrocarbyl group containing from 1 to 6 carbon atoms;
R3-R4independently of each other, selected from the following structures:
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl structure containing 1 to 12 carbon atoms, wherein in the substituted alkyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkenyl structure containing 2 to 12 carbon atoms, wherein in the substituted alkenyl structure, the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms;
a linear or branched, saturated or unsaturated, substituted or unsubstituted alkynyl structure containing 2 to 12 carbon atoms, wherein in the substituted alkynyl structure the substituent group is a hydrocarbon group containing 1 to 6 carbon atoms; (ii) a
R3And R4A 4-to 10-membered heterocyclic ring formed by bonding to each other, the hetero atom being one of nitrogen, sulfur and oxygenOr a plurality of heteroatoms, said heterocycle being optionally substituted with 1 to 6 heteroatoms;
l is selected from the following structures:
a linear or branched, saturated or unsaturated alkylene structure containing 1 to 12 carbon atoms, the substituent group being one or more of alkyl, carboxyl, acyl, alkoxy;
linear or branched, saturated or unsaturated alkenylene structure containing 2 to 12 carbon atoms, the substituent group being one or more of alkyl, carboxyl, acyl, alkoxy;
linear or branched, saturated or unsaturated alkynylene structures containing 2 to 12 carbon atoms, said substituent groups being one or more of hydrocarbyl, carboxyl, acyl, alkoxy;
a 4 to 10 membered heterocyclic ring structure, the heteroatom being one or more of nitrogen, sulfur and oxygen, the heterocyclic ring being optionally substituted with 1 to 6 heteroatoms;
n is 1 or 2;
x is selected from C, N, O, S, S ═ O, S (═ O)2And S-S.
6. Use of an aminolipidic compound, characterized in that: a compound according to any one of claims 1 to 4, wherein X is not O when n is 1, as a medicament for nucleic acid transfer, as a medicament for any one of gene therapy, gene vaccination, antisense therapy, interfering RNA therapy, and nucleic acid transfer.
7. Use of an amino lipid compound according to claim 6, characterized in that: the nucleic acid is any one of RNA, mRNA, antisense oligonucleotide, DNA, plasmid, rRNA, miRNA, tRNA, siRNA and snRNA.
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Address after: 518000 floor 6, block B, Tsinghua information port, No. 1, songpingshan Xindong Road, songpingshan community, Xili street, Nanshan District, Shenzhen, Guangdong Applicant after: Shenzhen Xinxin Biotechnology Co.,Ltd. Address before: 518000 b515, building 7, Shenzhen Bay science and technology ecological park, 1819 Shahe West Road, high tech community, Yuehai street, Nanshan District, Shenzhen City, Guangdong Province Applicant before: Shenzhen Xinxin Biotechnology Co.,Ltd. |
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| GR01 | Patent grant | ||
| GR01 | Patent grant |