Compositions and methods for enhancing immune responses to vaccines
a technology of cationiclipids and immune responses, applied in the field of cationiclipids, can solve the problems of insufficient or suboptimal humoral response, insufficient immunogenicity to raise the antibody titer in the organism to sufficient levels, and polynucleotide-based vaccination, etc., and achieve the effect of enhancing the humoral immune response of a vertebra
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A. Synthesis of Compounds of the Present Invention
[0315]The following examples are offered to illustrate, but not to limit the claimed disclosure. The preparation of embodiments of the present disclosure is described in the following examples. Those of ordinary skill in the art will understand that the chemical reactions and synthesis methods provided may be modified to prepare many of the other compounds of the present disclosure. Where compounds of the present disclosure have not been exemplified, those of ordinary skill in the art will recognize that these compounds may be prepared by modifying synthesis methods presented herein, and by using synthesis methods known in the art.
example i
Synthesis of (±)—N-(3-aminopropyl)-N,N-dimethyl-2,3-bis(myristoleyloxy)-1-propanaminium bromide (GAP-DMORIE, Formula I)
[0316]Racemic 1-dimethylamino-2,3-propanediol (0.96 g; Janssen Chimica) was converted to the disodium salt in situ by treatment with sodium hydride (60% in oil, 0.8 g) in tetrahydrofuran (70 mL). Condensation with myristoleyl methane sulfonate (5.3 g; NuChek Prep) afforded crude (+)-N,N-dimethyl-(2,3-bis(myristoleyloxy))propylamine (DMOP-DMA). This material was purified to homogeneity by silica gel chromatography employing a step gradient of ether in hexane (from 10% to 50%), and finally neat ether, as the eluents. DMOP-DMA (2.4 g) was then treated with N-(3-bromopropyl)phthalimide (2.5 g) in dimethylformamide (15 mL) at elevated temperature (85° C., overnight) to effect quaternization of the amine. Removal of the dimethylformamide in vacuo followed by silica gel chromatography using a step gradient of methanol / chloroform as the eluent afforded TLC homogenous materi...
example ii
Synthesis of (±)—N-(3′-N′-propyl-N′,N′,N′-trimethylammonium)-N,N-dimethyl-2,3-bis(myristoleyloxy)-1-propanaminium dibromide (Trimethyl-GAP-DMORIE, Formula I)
[0317]GAP-DMORIE (0.64 g) was treated with 1 M NaOH (4.2 mL) and CH3I (3 mL) in methanol (20 mL) at 0° C. to room temperature overnight to effect quaternization of the primary amine. The solvent was removed in vacuo, and the residue was taken up in CHCl3 and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on neutral alumina using 78 / 20 / 2 / 0.5 CHCl3 / MeOH / H2O / 15% NH4OH as the eluent. The appropriate fractions were pooled and concentrated. The residue was taken up in CHCl3, washed with 1 M NaBr, dried (Na2SO4), and concentrated to afford the pure product.
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