CN108659059A - 一种血型抗原a及其类似物的合成方法及应用 - Google Patents
一种血型抗原a及其类似物的合成方法及应用 Download PDFInfo
- Publication number
- CN108659059A CN108659059A CN201710212712.3A CN201710212712A CN108659059A CN 108659059 A CN108659059 A CN 108659059A CN 201710212712 A CN201710212712 A CN 201710212712A CN 108659059 A CN108659059 A CN 108659059A
- Authority
- CN
- China
- Prior art keywords
- catalyst
- silicone grease
- reaction
- trifluoromethanesulfonic acid
- blood group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000008280 blood Substances 0.000 title claims abstract description 62
- 210000004369 blood Anatomy 0.000 title claims abstract description 56
- 239000000427 antigen Substances 0.000 title claims abstract description 41
- 102000036639 antigens Human genes 0.000 title claims abstract description 41
- 108091007433 antigens Proteins 0.000 title claims abstract description 41
- 238000010189 synthetic method Methods 0.000 title claims abstract description 13
- 210000002966 serum Anatomy 0.000 claims abstract description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 238000001514 detection method Methods 0.000 claims abstract description 11
- 208000014951 hematologic disease Diseases 0.000 claims abstract description 10
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 7
- 229940124589 immunosuppressive drug Drugs 0.000 claims abstract description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 30
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical group OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 239000004519 grease Substances 0.000 claims description 25
- 229920001296 polysiloxane Polymers 0.000 claims description 25
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 24
- 239000011324 bead Substances 0.000 claims description 23
- 101710098119 Chaperonin GroEL 2 Proteins 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 229910015900 BF3 Inorganic materials 0.000 claims description 12
- OEGAMYZOUWNLEO-UHFFFAOYSA-N [butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical group CCCC[Si](C)(C)OS(=O)(=O)C(F)(F)F OEGAMYZOUWNLEO-UHFFFAOYSA-N 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 6
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 6
- RBWNDBNSJFCLBZ-UHFFFAOYSA-N 7-methyl-5,6,7,8-tetrahydro-3h-[1]benzothiolo[2,3-d]pyrimidine-4-thione Chemical compound N1=CNC(=S)C2=C1SC1=C2CCC(C)C1 RBWNDBNSJFCLBZ-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 6
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- KBYOBAICCHNMNJ-UHFFFAOYSA-L diperchloryloxymercury Chemical compound [Hg+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O KBYOBAICCHNMNJ-UHFFFAOYSA-L 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 6
- NGYIMTKLQULBOO-UHFFFAOYSA-L mercury dibromide Chemical group Br[Hg]Br NGYIMTKLQULBOO-UHFFFAOYSA-L 0.000 claims description 6
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 6
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 6
- 235000011150 stannous chloride Nutrition 0.000 claims description 6
- 239000001119 stannous chloride Substances 0.000 claims description 6
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 235000014121 butter Nutrition 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- OBHWOLDGXCOBAK-UHFFFAOYSA-N [F].CS(O)(=O)=O Chemical compound [F].CS(O)(=O)=O OBHWOLDGXCOBAK-UHFFFAOYSA-N 0.000 claims description 4
- -1 azido, hydroxyl Chemical group 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- JREZQKBMXWQVON-UHFFFAOYSA-N carbonic acid;mercury Chemical compound [Hg].OC(O)=O JREZQKBMXWQVON-UHFFFAOYSA-N 0.000 claims description 4
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 4
- ZBZJXHCVGLJWFG-UHFFFAOYSA-N trichloromethyl(.) Chemical compound Cl[C](Cl)Cl ZBZJXHCVGLJWFG-UHFFFAOYSA-N 0.000 claims description 4
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 210000002615 epidermis Anatomy 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 150000004676 glycans Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 230000008629 immune suppression Effects 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000002772 monosaccharides Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000012188 paraffin wax Substances 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 229910052709 silver Inorganic materials 0.000 claims 2
- 239000004332 silver Substances 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 abstract description 3
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 abstract description 3
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 abstract description 3
- 125000003147 glycosyl group Chemical group 0.000 abstract description 2
- 230000028993 immune response Effects 0.000 abstract description 2
- 210000000056 organ Anatomy 0.000 abstract description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 abstract description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 abstract 1
- 125000000837 carbohydrate group Chemical group 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 238000012986 modification Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 210000003743 erythrocyte Anatomy 0.000 description 5
- 239000006249 magnetic particle Substances 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 239000002122 magnetic nanoparticle Substances 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000002102 nanobead Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 150000001720 carbohydrates Chemical group 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- FLZWAAFMRTZQGV-ULZIYQADSA-N n-[(2r,3r,4r,5r,6r)-4,5-dihydroxy-6-(hydroxymethyl)-2-[(2r,3s,4s,5r)-4,5,6-trihydroxy-1-oxo-2-[(2s,3s,4r,5s,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyhexan-3-yl]oxyoxan-3-yl]acetamide Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@@H](C=O)[C@H]([C@@H](O)[C@H](O)CO)O[C@@H]1[C@H](NC(C)=O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 FLZWAAFMRTZQGV-ULZIYQADSA-N 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- HXBYBCASAVUYKF-YTQLPXDHSA-N (4r,5s,6s,7r)-4,5,6,7,8-pentahydroxyoctane-2,3-dione Chemical compound CC(=O)C(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO HXBYBCASAVUYKF-YTQLPXDHSA-N 0.000 description 1
- PQUXFUBNSYCQAL-UHFFFAOYSA-N 1-(2,3-difluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1F PQUXFUBNSYCQAL-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 0 CCO[C@]1[C@]2OC(*C)OCC2*C(*)C1OC Chemical compound CCO[C@]1[C@]2OC(*C)OCC2*C(*)C1OC 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical class CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical group OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- HBEQXAKJSGXAIQ-UHFFFAOYSA-N oxopalladium Chemical compound [Pd]=O HBEQXAKJSGXAIQ-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940047670 sodium acrylate Drugs 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
- G01N33/54326—Magnetic particles
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
- G01N33/54346—Nanoparticles
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Biotechnology (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- Medicinal Chemistry (AREA)
- Food Science & Technology (AREA)
- Analytical Chemistry (AREA)
- Microbiology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Genetics & Genomics (AREA)
- Cell Biology (AREA)
- Nanotechnology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
本发明提供了一种血型抗原A及其类似物的合成方法，糖基部分为半乳糖、2‑乙酰胺基半乳糖、岩藻糖或是糖环中的氧原子被硫原子所取代的相对应的硫代糖，建立高效的通用合成方法，为后续的更广泛的研究提供基础；同时，本发明公开的血型抗原A及其类似物应用于免疫抑制药物、医疗器械及血液疾病的检测试剂，有望在输血、器官移植、血液疾病检测中去除各种血清抗体，减少免疫反应发生，有巨大潜在的临床应用价值。
Description
技术领域
本发明属于化学与医药技术领域，具体涉及血型抗原A及其类 似物的合成方法，在制备抗器官移植排斥、抗输血排斥的免疫抑制药 物和医疗器械以及制备血液疾病相关的检测试剂方面的应用。
背景技术
人体血液根据红细胞膜表面抗原的不同可分为不同的血型。人 类第一个血型系统是由Landsteiner发现的ABO系统，截至到目前， 已经发现并被国际输血协会承认的血型系统有30多个，目前为人们 普遍接受的主要是ABO血型系统。中国人中A型血占30％、B型血占28％、AB型血占10％、O型血占32％。
不同血型的血液中具有不同的抗原和抗体。A型血的红细胞上 带有A抗原，血清中有B抗体；B型血的红细胞上带有B抗原，血 清中有A抗体；AB型血的红细胞上既有A抗原也有B抗原，血清 中没有其抗体；O型血的红细胞上A抗原和B抗原都没有，血清中 相应的抗体同时存在。这就使不同血型的血液相互输血时，因为抗原 和抗体的凝聚作用而发生溶血现象，进而可能危及人的生命安全。
血型抗原是由糖蛋白和糖脂组成，而血型抗原和抗体的特异性 识别主要是通过血型抗原上的糖链进行识别。血型抗原三糖是血型抗 原的特异性所在，血型抗原A的主要特征是糖链终末端的N-乙酰半 乳糖胺。
发明内容
本发明的目的是通过对血型抗原A及其类似物的合成，建立高 效的通用合成方法，为后续的更广泛的研究提供基础；本发明的另一 目的是提供血型抗原A及其类似物在制备抗器官移植排斥、抗输血 排斥的免疫抑制药物和医疗器械以及制备血液疾病相关的检测试剂 方面的用途。
本发明的目的是这样实现的：式1血型抗原A及其类似物，
其中，X表示氧原子或硫原子；
R2表示乙酰基、苯甲酰基或苄基；
Y表自Cl、Br、OAc、SEt、SPh、OC(NH)CCl3,；
R1表示取代基，选自3～17个碳的饱和烷基链、末端甲基带有卤 素、叠氮基、羟基、酯基、羧基的3～17个碳的直链烷烃、其他单糖 或多糖。
本发明的血型抗原A及其类似物的合成方法包括以下步骤：
(1)以半乳糖为反应底物，催化剂作用下与醇反应偶联反应， 该反应式为：
(2)步骤(1)产物脱保护，该反应式为：
(3)步骤(2)产物与苯甲醛反应，该反应为：
(4)步骤(3)的产物与新戊酰氯反应，该反应为：
(5)以步骤(4)的产物为反应受体，与供体在催化剂作用下反 应得到偶联产物，该反应的反应式为：
(6)步骤(5)的偶联产物脱保护反应，该反应式为：
(7)以步骤(6)的脱保护产物为受体，与供体在催化剂作用下 反应得到偶联产物，该反应式为：
(8)步骤(7)的偶联产物脱保护，该反应式为：
(9)步骤(8)中产物和乙酰氯反应得乙酰化产物，该反应式为：
(10)步骤(9)乙酰化产物经脱保护得到最终产物血型抗原A 及其类似物，该反应式为：
进一步地，所述步骤(1)～(10)反应都是在有机溶剂中进行的。
进一步地，所述步骤(1)半乳糖中：当Y为Cl、Br时，催化 剂为碳酸钾、碳酸银、碳酸铯、碳酸汞、高氯酸银、高氯酸汞或三氟 甲磺酸银；当Y为OAc时，催化剂为二溴化汞、三氯化铁、四氯化 钛、二氯化锡或四氯化锡；当Y为SEt、SPh时，催化剂为三氟甲磺 酸、三氟化硼乙醚、三氟甲磺酸三甲基硅脂、三氟甲磺酸三乙基硅脂 或叔丁基二甲硅基三氟甲磺酸酯；当Y为OC(NH)CCl3时，催化剂为 三氟化硼乙醚、三氟甲磺酸三甲基硅脂、三氟甲磺酸三乙基硅脂或叔 丁基二甲硅基三氟甲磺酸酯。
进一步地，所述步骤(2)中，R2为乙酰基、苯甲酰基时，脱保 护的反应条件为甲醇钠、碳酸钾或氢氧化钠的碱性条件，R2为苄基时， 脱保护的反应条件为氢气/钯碳、氢气/氢氧化钯。
进一步地，所述步骤(5)中，当Y为Cl、Br时，催化剂为碳 酸钾、碳酸银、碳酸铯、碳酸汞、高氯酸银、高氯酸汞或三氟甲磺酸 银；当Y为OAc时，催化剂为二溴化汞、三氯化铁、四氯化钛、二 氯化锡或四氯化锡；当Y为SEt、SPh时，催化剂为三氟甲磺酸、三 氟化硼乙醚、三氟甲磺酸三甲基硅脂、三氟甲磺酸三乙基硅脂或叔丁 基二甲硅基三氟甲磺酸酯；当Y为OC(NH)CCl3时，催化剂为三氟化 硼乙醚、三氟甲磺酸三甲基硅脂、三氟甲磺酸三乙基硅脂或叔丁基二 甲硅基三氟甲磺酸酯。
进一步地，所述步骤(7)中，当Y为Cl、Br时，催化剂为碳 酸钾、碳酸银、碳酸铯、碳酸汞、高氯酸银、高氯酸汞或三氟甲磺酸 银；当Y为OAc时，催化剂为二溴化汞、三氯化铁、四氯化钛、二 氯化锡或四氯化锡；当Y为SEt、SPh时，催化剂为三氟甲磺酸、三 氟化硼乙醚、三氟甲磺酸三甲基硅脂、三氟甲磺酸三乙基硅脂或叔丁 基二甲硅基三氟甲磺酸酯；当Y为OC(NH)CCl3时，催化剂为三氟 化硼乙醚、三氟甲磺酸三甲基硅脂、三氟甲磺酸三乙基硅脂或叔丁基 二甲硅基三氟甲磺酸酯。
本发明的血型抗原A及其类似物用于制备抗器官移植排斥、抗 输血排斥的免疫抑制药物和医疗器械以及制备血液疾病相关的检测 试剂的用途。
进一步地，所述的免疫抑制药物、医疗器械和检测试剂包括血型 抗原A及其类似物连接的纳米磁珠，所述纳米磁珠磁性内核被硅胶 化表皮包裹，外层修饰了血清抗原A及类似物。这种纳米磁珠可提 取溶液中的抗血清抗原A抗体。
进一步地，所述纳米磁珠应用于制备抗器官移植排斥和抗输血排 斥的免疫抑制药物和医疗器械以及应用于制备血液疾病相关的检测 试剂。
本发明的有益效果是：在血型抗原三糖A及其类似物的合成方 法中，糖基部分为半乳糖、2-乙酰胺基半乳糖、岩藻糖或是糖环中 的氧原子被硫原子所取代的相对应的硫代糖，并在R1的位置替换各 种各样的取代基得到了其类似物，为获得血型抗原三糖A及其类似 物提供了高效、通用的合成方法，为后续的更广泛的研究提供基础。
同时，本发明公开的血型抗原A及其类似物应用于免疫抑制药 物、医疗器械以及血液疾病相关的检测试剂，有望在输血、器官移植 和血液疾病检测中可去除各种血清抗体，较少免疫反应发生，有巨 大潜在的临床应用价值。
附图说明
图1为本发明血型抗原A及其类似物合成路线图；
图2为本发明应用血型抗原A及其类似物制备具有免疫抑制作 用的纳米磁珠的路线图；
图3为本发明Fe3O4MNPs、硅胶包裹的磁性纳米颗粒、炔基修 饰的磁性纳米颗粒、糖基化纳米磁珠、硅胶化纳米磁珠的扫描电镜图 像
图4为血清抗原A修饰的纳米磁珠、炔基化得磁性颗粒、血清 抗原A单体的傅里叶红外光谱图；
图5为血清抗原A修饰的纳米磁珠、炔基化的磁性颗粒的热重 分析图；
图6为不同浓度血清抗原A修饰的纳米磁珠分离抗A抗体的效 率对比图。
具体实施方式
下面结合实施例和实例中的附图，对本发明的技术方案进行清 楚、完整的描述，但本发明要求的保护范围并不局限于实施例表述的 范围。
实施例1：血型抗原A类似物式1的合成
合成路线图如图1所示：
(1)化合物3的合成：
温氮气保护下，将全乙酰半乳糖Schmidt试剂和4-氯-1-丁醇溶 于DCM中，加入三氟化硼乙醚，室温反应2h后，三乙胺淬灭，柱 层析得到中间体3，产率为63.4％。
1H-NMR(400MHz,CDCl3)δ:5.37(s,1H),5.29(s,1H),5.18(t, J＝8.0Hz,1H),5.00(d,J＝8.0Hz,1H),4.44(d,J＝8.0Hz,1H),4.19-4.08(m, 2H),3.95-3.87(m,2H),3.55-3.48(m,3H),2.14(s,3H),2.04(d, J＝8.0Hz,6H),1.97(s,3H),1.85-1.78(m,2H),1.75-1.71(m,2H).
(2)化合物4的合成：
将中间体3溶于四氢呋喃和水混合溶剂中，加入氢氧化钠溶液 (0.1eq)，反应2h后，酸性树脂酸化，过滤旋干得到中间体4，产率 98％。
(3)化合物5的合成：
中间体4溶于甲醇中，加入苯甲醛和三氟甲磺酸，室温下反应 2h，反应液浓缩，柱层析分离得到中间体5，产率为92.3％。
1H-NMR(400MHz,MeOD)δ:7.55-7.53(m,2H),7.35-7.34(m,3H), 5.60(s,1H),4.31(s,1H),4.20(d,J＝12.0Hz,2H),4.14(d,J＝12.0Hz,1H), 3.97-3.92(m,1H),3.64-3.58(m,5H),3.54(s,1H),1.93-1.88(m,2H), 1.82-1.76(m,2H)。
(4)化合物6的合成：
中间体5溶于DCM中，加入新戊酰氯和咪唑，室温下反应2h， 反应液浓缩，柱层析分离，得到中间体6，产率为91.5％。
1H-NMR(400MHz,MeOD)δ:7.48-7.47(m,2H),7.35-7.34(m,3H), 5.56(s,1H),4.82(dd,J＝12.0Hz,4.0Hz,1H),4.41-4.37(m,2H),4.18(dd, J＝32.0Hz,12.0Hz,2H),3.98-3.93(m,1H),3.80(t,J＝8.0Hz,1H), 3.65-3.59(m,4H),1.92-1.87(m,2H),1.82-1.77(m,2H),1.20(s,9H).
(5)化合物8的合成：
室温氮气保护下，将中间体6和苄基保护的岩藻糖Schmidt试剂 溶于DCM中，加入三氟甲磺酸三甲基硅脂，室温反应3h，三乙胺淬 灭，柱层析分离，得到中间体8，产率为63.2％。
1H-NMR(400MHz,CDCl3)δ:7.49-7.27(m,20H),5.48(s,1H),4.30(d, J＝4.0Hz,1H),5.08(dd,J＝12.0Hz,4.0Hz,1H),4.99(d,J＝8.0Hz,1H), 4.78(d,J＝12.0Hz,2H),4.70(dd,J＝16.0Hz,12.0Hz,2H),4.61(d, J＝12.0Hz,1H),4.53(d,J＝8.0Hz,1H),4.45(d,J＝2.8Hz,1H),4.37(q, J＝6.4Hz,1H),4.33-4.24(m,2H),4.11-4.04(m,2H),3.99-3.94(m,2H), 3.71(s,1H),3.50-3.45(m,4H),1.81-1.78(m,2H),1.73-1.67(m,2H), 1.13(s,3H),1.11(s,9H).
(6)化合物9的合成：
将中间体8溶解到甲醇中，加甲醇钠溶液，反应过夜，加入酸性 树脂，搅拌0.5小时，浓缩反应液，柱层析分离，得到中间体9，产 率为84.8％。
1H-NMR(400MHz,CDCl3)δ:7.55-7.53(m,2H),7.40-7.22(m,18H), 5.56(s,1H),5.24(d,J＝4.0Hz,1H),4.97(d,J＝12.0Hz,1H),4.83-4.74(m, 4H),4.66(d,J＝12.0Hz,1H),4.36(s,1H),4.30(d,J＝12.0Hz,1H),4.21(s, 1H),4.15(q,J＝8.0Hz,1H),4.07(d,J＝12.0Hz,2H),3.98-3.91(m,2H), 3.85(d,J＝4.0Hz,2H),3.69(s,1H),3.54-3.46(m,3H),3.42(s,1H), 1.85-1.82(m,2H),1.74-1.73(m,2H),1.12(d,J＝8.0Hz,3H).
(7)化合物11的合成：
室温氮气保护下，将中间体9和全乙酰2-叠氮半乳糖Schmidt试 剂溶于DCM中，加入三氟甲磺酸三甲基硅脂，室温反应2h，三乙胺 淬灭，浓缩，柱层析分离，得到中间体11，产率为59.6％。
1H-NMR(400MHz,CDCl3)δ:7.56-7.24(m,20H),5.55(s,1H),5.45(d, J＝4.0Hz,1H),5.31(d,J＝4.0Hz,1H),5.25(dd,J＝12.0Hz,4.0Hz,1H), 5.18(d,J＝4.0Hz,1H),5.10(d,J＝12.0Hz,1H),4.91(dd,J＝20.0Hz,12.0Hz, 2H),4.76(dd,J＝16.0Hz,12.0Hz,2H),4.62(d,J＝12.0Hz,1H), 4.41-4.32(m,4H),4.25(dd,J＝8.0Hz,3.2Hz,1H),4.17-4.08(m,3H), 4.00(dd,J＝12.0Hz,4.0Hz,1H),3.97-3.92(m,1H),3.87(dd,J＝8.0Hz, 4.0Hz,1H),3.80(dd,J＝12.0Hz,4.0Hz,1H),3.71(d,J＝1.2Hz,1H), 3.59-3.47(m,4H),3.39(s,1H),3.31(dd,J＝12.0Hz,4.0Hz,1H),2.09(s, 3H),2.04(s,3H),1.96(s,3H),1.84-1.79(m,2H),1.73-1.68(m,2H), 1.13(d,J＝8.0Hz,3H).
(8)化合物12的合成：
将中间体11溶于甲醇中，加入钯碳，通入氢气，反应4h，反应 体系过滤，浓缩，得到中间体12，产率为98.2％。
(9)化合物13的合成：
将中间体12溶于吡啶中，室温下滴加乙酰氯，反应1h，浓缩反 应液，柱层析分离，得到中间体，产率为60.1％。将中间体溶于DMF 中，加入叠氮化钠和碘化钠，冷凝回流2h,反应液萃取，旋干，柱层 析分离，得到中间体13。
1H-NMR(400MHz,CDCl3)δ:6.25(d,J＝8.0Hz,1H),5.49(d,J＝4.0Hz, 1H),5.41(s,1H),5.36(d,J＝4.0Hz,1H),5.32(dd,J＝12.0Hz,4.0Hz,1H), 5.26(s,1H),5.21(dd,J＝12.0Hz,4.0Hz,2H),4.97(dd,J＝12.0Hz,4.0Hz, 1H),4.52-4.44(m,2H),4.37(d,J＝8.0Hz,1H),4.23(t,J＝4.0Hz,1H), 4.14-4.04(m,4H),3.91-3.78(m,4H),3.60-3.56(m,1H),3.34-3.31(m,2H), 2.15(s,3H),2.13(s,3H),2.11(s,6H),2.05(s,3H),2.02(s,3H),1.98(s,3H), 1.96(s,3H),1.94(s,3H),1.69(s,4H),1.10(d,J＝4.0Hz,3H).
(10)化合物14的合成：
室温下将中间体13溶于甲醇中，加入甲醇钠溶液，调节PH＝9， 反应2h，酸性树脂酸化，体系过滤，得到终产物14，产率为98.0％。
1H-NMR(400MHz,D2O)δ:5.31(d,J＝4.0Hz,1H),5.16(d,J＝4.0Hz, 1H),4.52(d,J＝8.0Hz,1H),4.43(q,J＝8.0Hz,1H),4.24-4.20(m,3H), 3.98-3.93(m,3H),3.89(d,J＝12.0Hz,1H),3.81-3.69(m,9H),3.64(d, J＝4.0Hz,1H),3.34(d,J＝8.0Hz,2H),2.02(s,3H),1.66-1.62(m,4H), 1.21(d,J＝4.0Hz,3H).
13C-NMR(100Hz,D2O)δ:174.93,101.52,98.56,91.47,75.98,75.02, 72.24,72.02,71.23,69.99,69.84,68.63,67.94,67.87,66.98,63.14, 61.47,61.11,51.01,49.62,26.43,25.10,22.07,15.4
实施例2：将血清抗原A修饰在磁性纳米珠上
制备路线图如图2所示：
(1)四氧化三铁磁性纳米珠的制备
乙二醇6mL和二聚乙二醇34mL超声脱氧15分钟，然后加入 丙烯酸钠3.0克和FeCl3·6H2O 1.08g，室温搅拌过夜，然后转移到有 聚四氟乙烯盖子的不锈钢抗压罐里205℃保持12h，冷却到室温。 磁性纳米珠用磁铁收集，甲醇洗三次，50℃真空干燥12小时。
(2)硅胶包裹的磁性纳米珠
步骤(1)制备的磁性纳米珠50毫克，水6毫升，甲醇40毫升， 超声脱氧15分钟，氨水2毫升慢慢滴入。注射器加入 Tetraethylorthosilicate(TEOS,0.4mL)，超生2.5小时。磁性纳米珠用 磁铁收集，甲醇洗三次，50℃真空干燥12小时。
(3)制备炔基化的磁性纳米珠
步骤(2)制备的硅胶包裹磁性纳米珠50毫克，水6毫升，甲醇 40毫升，超声脱氧15分钟，氨水1毫升慢慢滴入。注射器加入化合 物15，超声3小时。磁性纳米珠用磁铁收集，甲醇洗三次，50℃真 空干燥12小时。
(4)制备血清抗原A功能化的磁性纳米珠
步骤(3)制备炔基化的的硅胶包裹磁性纳米珠50毫克，水25 毫升，THF25毫升，超声脱氧15分钟，抗原A250毫克慢慢滴入。 加入sodium ascorbate 100mg和CuSO4 50mg，50℃超生48小时。 磁性纳米珠用磁铁收集，甲醇洗三次，50℃真空干燥12小时得到糖 化的磁性纳米颗粒。
如图3所示，扫描电镜图像显示制备的Fe3O4MNPs(a、b)的平均 分散颗粒大小为100纳米，而硅胶包裹的磁性纳米颗粒为120纳米左右 (c、d)，炔基修饰的磁性纳米颗粒(e、f)和糖基化得的纳米磁珠(g、h) 颗粒大小和硅胶化的纳米磁珠颗粒大小相同。
如图4所示，傅里叶红外光谱显示血清抗原A修饰的纳米磁珠的 红外谱图、对比炔基化得磁性颗粒和血清抗原A单体的红外谱图时同 时具备炔基化得磁性颗粒的at 588,1084,1411,1558cm-1峰和血清抗 原A单体的1714and 1629cm-1特征峰。而且血清抗原A单体上的叠氮 特征锋2100cm-1消失了，说明了click triazole的形成。
如图5所示，热重分析显示血清抗原A修饰的纳米磁珠和炔基化 的磁性颗粒的热分解失重为30.4％和22.1％，基于这个计算，血清抗 原A单体在纳米磁珠上的重量比为0.08mg/mg(carbohydrate antigens/MNPs)。
实施例3：糖基化纳米磁珠提取抗血清抗原A抗体
为了简化血液中其它有非专一性识别的蛋白质的干扰，我们用市 售的抗血清抗原A抗体(anti-A antibody)配置成固定浓度的溶液来 模拟血清(at 65μg/mL)，来检测我们制备的血清抗原A修饰的纳米 磁珠(glyco-MNPs)分离抗原A抗体的效率，我们用不同浓度的血 清抗原A修饰的纳米磁珠(the glyco-MNPs at 10,20,30,40,50,and 60 μg/mL)来提取溶液中的抗血清抗原A抗体，37℃匀速旋转200rpm 大约60分钟，然后用外部磁铁固定纳米磁珠，分离悬浮液。如图6 所示，从三个独立的提取实验显示，我们的最大纳米磁珠提取效率可 达到93％。
Claims (10)
1.式1血型抗原A及其类似物：
其中，X表示氧原子或硫原子；
R2表示乙酰基、苯甲酰基或苄基；
Y选自Cl、Br、OAc、SEt、SPh、OC(NH)CCl3,；
R1表示取代基，选自3～17个碳的饱和烷基链、末端甲基带有卤素、叠氮基、羟基、酯基、羧基的3～17个碳的直链烷烃、其他单糖或多糖。
2.权利要求1的血型抗原A及其类似物的合成方法，其特征在于，包括以下步骤：
(1)以半乳糖为反应底物，催化剂作用下与醇反应偶联反应，该反应式为：
(2)步骤(1)产物脱保护，该反应式为：
(3)步骤(2)产物与苯甲醛反应，该反应为：
(4)步骤(3)的产物与新戊酰氯反应，该反应为：
(5)以步骤(4)的产物为反应受体，与供体在催化剂作用下反应得到偶联产物，该反应的反应式为：
(6)步骤(5)的偶联产物脱保护反应，该反应式为：
(7)以步骤(6)的脱保护产物为受体，与供体在催化剂作用下反应得到偶联产物，该反应式为：
(8)步骤(7)的偶联产物脱保护，该反应式为：
(9)步骤(8)中产物和乙酰氯反应得乙酰化产物，该反应式为：
(10)步骤(9)乙酰化产物经脱保护得到最终产物血型抗原A及其类似物，该反应式为：
3.根据权利要求2所述的血型抗原A及其类似物的合成方法，其特征在于，所述步骤(1)～(10)反应都是在有机溶剂中进行的。
4.根据权利要求2所述的血型抗原A及其类似物的合成方法，其特征在于，所述步骤(1)半乳糖中：当Y为Cl、Br时，催化剂为碳酸钾、碳酸银、碳酸铯、碳酸汞、高氯酸银、高氯酸汞或三氟甲磺酸银；当Y为OAc时，催化剂为二溴化汞、三氯化铁、四氯化钛、二氯化锡或四氯化锡；当Y为SEt、SPh时，催化剂为三氟甲磺酸、三氟化硼乙醚、三氟甲磺酸三甲基硅脂、三氟甲磺酸三乙基硅脂或叔丁基二甲硅基三氟甲磺酸酯；当Y为OC(NH)CCl3时，催化剂为三氟化硼乙醚、三氟甲磺酸三甲基硅脂、三氟甲磺酸三乙基硅脂或叔丁基二甲硅基三氟甲磺酸酯。
5.根据权利要求2所述的血型抗原A及其类似物的合成方法，其特征在于，所述步骤(2)中，R2为乙酰基、苯甲酰基时，脱保护的反应条件为甲醇钠、碳酸钾或氢氧化钠的碱性条件，R2为苄基时，脱保护的反应条件为氢气/钯碳或氢气/氢氧化钯。
6.根据权利要求2所述的血型抗原A及其类似物的合成方法，其特征在于，所述步骤(5)中，当Y为Cl、Br时，催化剂为碳酸钾、碳酸银、碳酸铯、碳酸汞、高氯酸银、高氯酸汞或三氟甲磺酸银；当Y为OAc时，催化剂为二溴化汞、三氯化铁、四氯化钛、二氯化锡或四氯化锡；当Y为SEt、SPh时，催化剂为三氟甲磺酸、三氟化硼乙醚、三氟甲磺酸三甲基硅脂、三氟甲磺酸三乙基硅脂或叔丁基二甲硅基三氟甲磺酸酯；当Y为OC(NH)CCl3时，催化剂为三氟化硼乙醚、三氟甲磺酸三甲基硅脂、三氟甲磺酸三乙基硅脂或叔丁基二甲硅基三氟甲磺酸酯。
7.根据权利要求2所述的血型抗原A及其类似物的合成方法，其特征在于，所述步骤(7)中，当Y为Cl、Br时，催化剂为碳酸钾、碳酸银、碳酸铯、碳酸汞、高氯酸银、高氯酸汞或三氟甲磺酸银；当Y为OAc时，催化剂为二溴化汞、三氯化铁、四氯化钛、二氯化锡或四氯化锡；当Y为SEt、SPh时，催化剂为三氟甲磺酸、三氟化硼乙醚、三氟甲磺酸三甲基硅脂、三氟甲磺酸三乙基硅脂或叔丁基二甲硅基三氟甲磺酸酯；当Y为OC(NH)CCl3时，催化剂为三氟化硼乙醚、三氟甲磺酸三甲基硅脂、三氟甲磺酸三乙基硅脂或叔丁基二甲硅基三氟甲磺酸酯。
8.权利要求1的血型抗原A及其类似物用于制备抗器官移植排斥、抗输血排斥的免疫抑制药物和医疗器械以及制备血液疾病相关的检测试剂的用途。
9.根据权利要求8所述的用途，其特征在于，所述的免疫抑制药物、医疗器械和检测试剂包括血型抗原A及其类似物连接的纳米磁珠，所述纳米磁珠磁性内核被硅胶化表皮包裹，外层修饰了血清抗原A及类似物。
10.根据权利要求9所述的用途，其特征在于，所述纳米磁珠应用于制备抗器官移植排斥和抗输血排斥的免疫抑制药物和医疗器械以及应用于制备血液疾病相关的检测试剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710212712.3A CN108659059B (zh) | 2017-04-01 | 2017-04-01 | 一种血型抗原a及其类似物的合成方法及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710212712.3A CN108659059B (zh) | 2017-04-01 | 2017-04-01 | 一种血型抗原a及其类似物的合成方法及应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108659059A true CN108659059A (zh) | 2018-10-16 |
| CN108659059B CN108659059B (zh) | 2021-04-06 |
Family
ID=63783792
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710212712.3A Active CN108659059B (zh) | 2017-04-01 | 2017-04-01 | 一种血型抗原a及其类似物的合成方法及应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108659059B (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114410705A (zh) * | 2022-01-24 | 2022-04-29 | 武汉糖智药业有限公司 | 一种新型血型抗原及其酶法合成方法 |
| CN116868059A (zh) * | 2022-10-18 | 2023-10-10 | 天津德祥生物技术股份有限公司 | 血型抗原三糖偶联物在血型抗体检测中的应用 |
| WO2024082390A1 (zh) * | 2022-10-18 | 2024-04-25 | 天津德祥生物技术股份有限公司 | 血型抗原三糖偶联物在血型抗体检测中的应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007011696A2 (en) * | 2005-07-14 | 2007-01-25 | The Scripps Research Institute | Compositions and methods for coupling a plurality of compounds to a scaffold |
| WO2009035494A2 (en) * | 2007-07-30 | 2009-03-19 | The Scripps Research Institute | Methods for producing anti-glycan antibodies, vaccines and methods for treating cancer or infectious disease |
-
2017
- 2017-04-01 CN CN201710212712.3A patent/CN108659059B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007011696A2 (en) * | 2005-07-14 | 2007-01-25 | The Scripps Research Institute | Compositions and methods for coupling a plurality of compounds to a scaffold |
| WO2009035494A2 (en) * | 2007-07-30 | 2009-03-19 | The Scripps Research Institute | Methods for producing anti-glycan antibodies, vaccines and methods for treating cancer or infectious disease |
Non-Patent Citations (1)
| Title |
|---|
| JINFENG YE,ET AL.: "Diversity-Oriented Enzymatic Modular Assembly of ABO Histo-blood Group Antigens", 《ACS CATAL.》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114410705A (zh) * | 2022-01-24 | 2022-04-29 | 武汉糖智药业有限公司 | 一种新型血型抗原及其酶法合成方法 |
| CN116868059A (zh) * | 2022-10-18 | 2023-10-10 | 天津德祥生物技术股份有限公司 | 血型抗原三糖偶联物在血型抗体检测中的应用 |
| CN117269516A (zh) * | 2022-10-18 | 2023-12-22 | 天津德祥生物技术股份有限公司 | 一种血型抗原三糖a类似物蛋白偶联物在血型抗体检测中的应用 |
| CN117269517A (zh) * | 2022-10-18 | 2023-12-22 | 天津德祥生物技术股份有限公司 | 一种血型抗原三糖b类似物蛋白偶联物在血型抗体检测中的应用 |
| CN116868059B (zh) * | 2022-10-18 | 2024-04-05 | 天津德祥生物技术股份有限公司 | 血型抗原三糖偶联物在血型抗体检测中的应用 |
| CN117269517B (zh) * | 2022-10-18 | 2024-04-16 | 天津德祥生物技术股份有限公司 | 一种血型抗原三糖b类似物蛋白偶联物在血型抗体检测中的应用 |
| WO2024082390A1 (zh) * | 2022-10-18 | 2024-04-25 | 天津德祥生物技术股份有限公司 | 血型抗原三糖偶联物在血型抗体检测中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108659059B (zh) | 2021-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7109182B2 (en) | Synthetic oligomannosides, preparation and uses thereof | |
| AU2005258281A1 (en) | Arrays with cleavable linkers | |
| CN108659059A (zh) | 一种血型抗原a及其类似物的合成方法及应用 | |
| JPH02174696A (ja) | シアル酸グリコシド，抗原，免疫吸着剤およびそれらの調整方法 | |
| Bhunia et al. | Design, Synthesis, and Evaluation of Novel 1, 2, 3‐Triazole‐Tethered Glycolipids as Vaccine Adjuvants | |
| Paul et al. | Temperature-switchable glycopolymers and their conformation-dependent binding to receptor targets | |
| WO2019072045A1 (zh) | 一种cd169高亲和力抗肿瘤化合物及其制备方法和应用 | |
| WO2021232718A1 (zh) | 一种缀合物及其制备方法和应用 | |
| Sarpe et al. | Expeditious synthesis of Mycobacterium tuberculosis sulfolipids SL-1 and Ac2SGL analogues | |
| US7208561B2 (en) | Saccharide residue-functional organopolysiloxanes and method for the preparation thereof | |
| CN106397522A (zh) | 3,7‑二（叔丁基二甲基硅基氧基）‑6‑烯‑5β‑胆烷‑24‑酸甲酯 | |
| ter Maat et al. | Organic modification and subsequent biofunctionalization of porous anodic alumina using terminal alkynes | |
| Despras et al. | Biotin sulfone tagged oligomannosides as immunogens for eliciting antibodies against specific mannan epitopes | |
| KR101768926B1 (ko) | 18ｆ 표지 화합물의 제조 방법 및 그 방법에 사용하는 고분자 화합물 | |
| US12324832B2 (en) | Application of heptoglycan-chain-containing oligosaccharide compounds in preparation of vaccine against Helicobacter pylori | |
| Chatterjee et al. | Synthesis and immunoreactivity of neoglycoproteins containing the trisaccharide unit of phenolic glycolipid I of Mycobacterium leprae | |
| Satapathy et al. | New classes of carborane-appended 5-thio-D-glucopyranose derivatives | |
| CN113358865B (zh) | 一种循环肿瘤细胞检测方法 | |
| CN117186259B (zh) | 一种分子结构明确的可消除化疗药毒副作用的多糖化合物 | |
| CN117264180A (zh) | 一种利用romp聚合和点击化学制备的侧链含缬氨酸和甘露糖聚合物及其制备方法 | |
| Borbás et al. | Replacement of carbohydrate sulfates by sugar C‐sulfonic acid derivatives | |
| CN109232690A (zh) | 一种正电子显像剂标准品前体及其制备方法 | |
| US20090042816A1 (en) | Synthetic Ligands For The Differentiation Of Closely Related Toxins And Pathogens | |
| CN101348514B (zh) | 一种从面包海星提取的海星皂苷类化合物的用途 | |
| EP0051593A1 (en) | Isolation of carbohydrates from cell tissue |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |