CN110804175B - Antibacterial polyamino acid derivative or copolymer with alternating structure and preparation method thereof - Google Patents
Antibacterial polyamino acid derivative or copolymer with alternating structure and preparation method thereof Download PDFInfo
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- CN110804175B CN110804175B CN201911085707.6A CN201911085707A CN110804175B CN 110804175 B CN110804175 B CN 110804175B CN 201911085707 A CN201911085707 A CN 201911085707A CN 110804175 B CN110804175 B CN 110804175B
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- polyamino acid
- reacting
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- 239000002253 acid Substances 0.000 title claims abstract description 135
- 229920001577 copolymer Polymers 0.000 title claims abstract description 74
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 32
- -1 amino acid small molecules Chemical class 0.000 claims abstract description 4
- 125000006239 protecting group Chemical group 0.000 claims description 37
- 239000000243 solution Substances 0.000 claims description 34
- 238000010511 deprotection reaction Methods 0.000 claims description 33
- 239000000047 product Substances 0.000 claims description 31
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 238000006116 polymerization reaction Methods 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000000502 dialysis Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 239000012948 isocyanate Substances 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- AMGNHZVUZWILSB-UHFFFAOYSA-N 1,2-bis(2-chloroethylsulfanyl)ethane Chemical compound ClCCSCCSCCCl AMGNHZVUZWILSB-UHFFFAOYSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 10
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical class N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 9
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 7
- 239000012351 deprotecting agent Substances 0.000 claims description 7
- 238000001704 evaporation Methods 0.000 claims description 7
- 239000012044 organic layer Substances 0.000 claims description 7
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 6
- 235000019439 ethyl acetate Nutrition 0.000 claims description 6
- 238000004108 freeze drying Methods 0.000 claims description 6
- 239000013067 intermediate product Substances 0.000 claims description 6
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 5
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 4
- 239000010410 layer Substances 0.000 claims description 4
- 239000011347 resin Substances 0.000 claims description 4
- 229920005989 resin Polymers 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 4
- 229960004319 trichloroacetic acid Drugs 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 150000003141 primary amines Chemical class 0.000 claims description 3
- BAYAKMPRFGNNFW-UHFFFAOYSA-N 2,4-dimethylpentan-3-ol Chemical compound CC(C)C(O)C(C)C BAYAKMPRFGNNFW-UHFFFAOYSA-N 0.000 claims description 2
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 2
- XMLJCSFKQSJZLS-UHFFFAOYSA-L [K+].[K+].OC.[O-]C([O-])=O Chemical compound [K+].[K+].OC.[O-]C([O-])=O XMLJCSFKQSJZLS-UHFFFAOYSA-L 0.000 claims description 2
- XYBHGJNPHFDGGU-UHFFFAOYSA-L [Na+].[Na+].OC.[O-]C([O-])=O Chemical compound [Na+].[Na+].OC.[O-]C([O-])=O XYBHGJNPHFDGGU-UHFFFAOYSA-L 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 2
- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000000643 oven drying Methods 0.000 claims description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 2
- 229910001415 sodium ion Chemical group 0.000 claims description 2
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical group [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical group [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims 1
- 229910001414 potassium ion Inorganic materials 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 22
- 150000001413 amino acids Chemical class 0.000 abstract description 12
- 238000001727 in vivo Methods 0.000 abstract description 6
- 230000015556 catabolic process Effects 0.000 abstract description 4
- 238000006731 degradation reaction Methods 0.000 abstract description 4
- 230000000593 degrading effect Effects 0.000 abstract description 4
- 239000012634 fragment Substances 0.000 abstract description 2
- 230000003252 repetitive effect Effects 0.000 abstract description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 14
- 210000002950 fibroblast Anatomy 0.000 description 10
- 239000012153 distilled water Substances 0.000 description 8
- 150000003862 amino acid derivatives Chemical class 0.000 description 7
- 231100000956 nontoxicity Toxicity 0.000 description 7
- 239000002504 physiological saline solution Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 230000009471 action Effects 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 5
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 5
- RIEVCJDAGDYFEP-UHFFFAOYSA-N 2,2,2-trifluoro-n-(4-oxobutyl)acetamide Chemical compound FC(F)(F)C(=O)NCCCC=O RIEVCJDAGDYFEP-UHFFFAOYSA-N 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 150000002513 isocyanates Chemical group 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- VKKQFBPNSYOXJX-UHFFFAOYSA-N N-carbamimidoyl-2,2,2-trifluoro-N-(4-oxobutyl)acetamide Chemical compound C(CC=O)CN(C(=O)C(F)(F)F)C(=N)N VKKQFBPNSYOXJX-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000010539 anionic addition polymerization reaction Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- QVOUTJXSGTXBRK-UHFFFAOYSA-N benzyl n-(4-oxobutyl)carbamate Chemical compound O=CCCCNC(=O)OCC1=CC=CC=C1 QVOUTJXSGTXBRK-UHFFFAOYSA-N 0.000 description 1
- DQUTUODQTCRDGQ-UHFFFAOYSA-N benzyl n-(5-oxopentyl)carbamate Chemical compound O=CCCCCNC(=O)OCC1=CC=CC=C1 DQUTUODQTCRDGQ-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000007777 multifunctional material Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- YLLIGHVCTUPGEH-UHFFFAOYSA-M potassium;ethanol;hydroxide Chemical compound [OH-].[K+].CCO YLLIGHVCTUPGEH-UHFFFAOYSA-M 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
- C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
- A01N37/46—N-acyl derivatives
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- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Wood Science & Technology (AREA)
- Environmental Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Zoology (AREA)
- Plant Pathology (AREA)
- Agronomy & Crop Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Polyamides (AREA)
Abstract
The invention discloses an antibacterial polyamino acid derivative or copolymer with an alternate structure and a preparation method thereof. The polyamino acid derivatives or copolymers have alternating structural units and the same conformation. In the alternate repeating structural unit, one is basic amino acid or a derivative of the basic amino acid, and the polyamino antibacterial material with different hydrophilicity and hydrophobicity, material strength, degradation rate and antibacterial activity is obtained by changing the type of the other amino acid. Meanwhile, the small molecular fragments obtained by degrading the polyamino acid derivatives or the copolymers synthesized by the method in vivo have the same conformation and are still repetitive units with an alternative structure, and finally the amino acid small molecules are obtained by degrading by a human body.
Description
Technical Field
The invention relates to the field of antibacterial materials. More particularly, relates to an antibacterial polyamino acid derivative or copolymer with an alternate structure and a preparation method thereof.
Background
With the increasing health consciousness and medical health level, the demand and requirement of people for antibacterial materials are also increasing, and the antibacterial materials need to have antibacterial performance and also need higher biological safety and environmental safety, for example, antibacterial medical instruments need to effectively inhibit the growth and reproduction of bacteria and also need good safety. At present, most of antibacterial materials are mainly materials capable of releasing antibacterial metal ions and antibacterial materials of quaternary ammonium salts. These materials all have strong antibacterial performance, but due to the defects of certain cytotoxicity to human bodies, drug resistance and the like, the development of antibacterial materials meeting the industrial requirements is urgently needed.
The antibacterial peptide serving as polyamino acid polypeptide can be degraded into amino acid micromolecules in vivo and absorbed or discharged by human bodies, is an ideal antibacterial material, and meets the biocompatibility and degradability in vivo. The polypeptide contains a large amount of basic amino acids, such as ornithine, lysine, arginine and histidine, and the obtained polyamino acid has a cationic group, such as amino or indolyl, on a side chain, and has a good antibacterial effect. At present, most polyamino acids are subjected to anionic polymerization to obtain a block copolymer consisting of two or more than two amino acid repeating units, different segments on any main chain of the polyamino acid copolymer obtained by the method have different amino acid repeating unit arrangement sequences, and the structure of the polyamino acid copolymer cannot be accurately adjusted by adding different amino acids, so that the properties of hydrophilicity and hydrophobicity, material strength, degradation rate, antibacterial activity, biological safety and the like of the polymer cannot be effectively controlled. When the polyamino acid copolymer obtained by the method is degraded in vivo or in vitro, the structures of the degraded segments are different, and the antibacterial mechanism of the polyamino acid copolymer cannot be explored.
Disclosure of Invention
The invention obtains polyamino acid derivatives or copolymers with different properties by accurately adjusting the structure, designs and synthesizes the polyamino acid derivative or copolymer material with the antibacterial function, the synthesis of the polyamino acid derivative or copolymer is to carry out polymerization reaction and deprotection reaction on aldehydes with protecting groups on terminal amino groups, primary amines and isocyanates by a Ugi's 4CC method, and the polyamino acid derivative or copolymer with an alternating structure and rich amino groups in the structure is obtained, and the polyamino acid derivative or copolymer has alternating structural units and the same conformation. In the alternate repeating structural unit, one is basic amino acid or a derivative of the basic amino acid, and the polyamino antibacterial material with different hydrophilicity and hydrophobicity, material strength, degradation rate and antibacterial activity is obtained by changing the type of the other amino acid. Meanwhile, the small molecular fragments obtained by degrading the polyamino acid derivatives or the copolymers synthesized by the method in vivo have the same conformation and are still repetitive units with an alternative structure, and finally the amino acid small molecules are obtained by degrading by a human body.
An object of the present invention is to provide an antibacterial polyamino acid derivative or copolymer having an alternating structure, which has a well-defined adjustable structure, and simultaneously has a good antibacterial effect as well as biocompatibility and degradability.
Another object of the present invention is to provide a method for preparing the above polyamino acid derivative or copolymer having an alternating structure.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides an antibacterial polyamino acid derivative or copolymer of alternating structure, said polyamino acid derivative or copolymer having the structure:
Wherein A and B represent two kinds of repeating units of polyamino acid derivative or copolymer respectively; n is the number of repeating units of the AB repeating unit; n is a positive integer, and n is 2-10000.
A. The chemical structural formula of B is as follows:
A：
B：
further, in the repeating unit A, R1The end of the group contains an amino group, including but not limited to the following structures:
R2groups include, but are not limited to, the following structures:
as understood by those skilled in the art, when R is2When the group is-H, it corresponds to a polyamino acid copolymer, R2When the group is other than-H, it corresponds to a polyamino acid derivative.
The upper side chain of the repeating unit A is provided with free amino and positive charges, so that the antibacterial property of the polyamino acid derivative or copolymer material can be adjusted;
in the repeating unit B, R3Groups include, but are not limited to, the following structures: -H, -CH3，
R3The function of the group is to adjust the hydrophilicity and hydrophobicity, degradability, strength and the like of the polyamino acid derivative or copolymer material.
In a second aspect, the invention provides a preparation method of a degradable antibacterial polyamino acid derivative or copolymer with an alternate structure, which comprises two steps of polymerization reaction and deprotection reaction, and comprises the following steps:
1) polymerisation reaction
Reacting a primary amine
And aldehydes
Adding the mixture into an organic solvent W, and reacting for 0.1 to 120 hours at the temperature of between 0 and 100 ℃ to obtain an intermediate product F containing carbon-nitrogen double bonds; intermediate product F, isocyanate
Dissolving with strong acid Y in solvent X, reacting at 0-100 deg.C for 0.1-240 hr to obtain amino protecting group R4And R5The polyamino acid derivative of (a);
wherein R is1The terminal group contains an amino group, and an amino-protecting group R4And R1The nitrogen atom on the terminal amino group is connected;
2) deprotection reaction:
reacting an amino-containing protecting group R4And R5Is derived from polyamino acidsThe compound reacts for 0.1 to 150 hours at the temperature of between 0 and 120 ℃ by using a deprotection agent P, and then R is removed4Radical, to obtain R-free4Polyamino acid derivatives of groups;
alternatively, the step 2) further comprises:
the obtained product is free of R4Reacting polyamino acid derivative with deprotection agent Q at 0-120 deg.C for 0.1-150 hr to remove R5And (4) obtaining the polyamino acid copolymer.
It is understood by those skilled in the art that only R is eliminated4The protecting group is obtained as a polyamino acid derivative, in which case R corresponds to2In the case where R is other than-H2And R5The consistency is achieved; continue to remove R5The protecting group gives a polyamino acid copolymer, in which case R corresponds to2Is the case of-H.
Alternatively, in the preparation of polyamino acid copolymers, R4Group and R5The groups need to be removed, and the order of removing the groups can be interchanged. That is, in the case of preparing the polyamino acid copolymer, step 2) includes:
reacting an amino-containing protecting group R4And R5Reacting the polyamino acid derivative with a deprotection agent Q at the temperature of 0-120 ℃ for 0.1-150 hours, and then removing R5Radical, to obtain R-free5Polyamino acid copolymers of groups; the obtained product is free of R5Reacting the polyamino acid copolymer of the group with a deprotection agent P at the temperature of 0-120 ℃ for 0.1-150 hours to remove R4And (4) obtaining the polyamino acid copolymer.
Preferably, the polymerization reaction of step 1) can also be a one-pot process comprising the steps of:
reacting a primary amine
Strong acid Y, isocyanate
And aldehydes
Adding a solventIn X, reacting for 0.1-360 hours at the temperature of 0-100 ℃ to obtain the amino-containing protecting group R4And R5Polyamino acid derivatives of the group.
Preferably, in step 1), the primary amine
Strong acid Y, isocyanate
And aldehydes
In a molar ratio of (1-3): (1-3): (1-3): (1-3); preferably 1: 1: 1: 1.
preferably, in step 2), the aldehyde
The molar ratio of deprotection agent P to deprotection agent P is 1: (1-10), preferably 1: 3; the primary amine
And deprotecting agent Q in a molar ratio of 1: (1-10), preferably 1: 3.
Preferably, the primary amine
In, R5Including but not limited to the following structures:
preferably, the amino protecting group R4Including but not limited to the following structures: benzyloxycarbonyl, tert-butoxycarbonyl, fluorenyl-methoxycarbonyl, trifluoroacetyl;
preferably, an isocyanate
Wherein M is an alkali metal cation including but not limited to potassium, sodiumIons.
Preferably, the organic solvent W includes, but is not limited to, one or a mixture of two or more of tetrahydrofuran, ethyl acetate, toluene, dichloromethane, chloroform, n-butanol, and acetone.
Preferably, the solvent X includes but is not limited to one or a mixture of more than two of methanol, water, N-dimethylformamide, 2, 4-dimethyl-3-pentanol, isopropanol and o-chlorophenol.
Preferably, the strong acid Y comprises but is not limited to one or a mixture of more than two of hydrofluoric acid, fluorosulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, pentafluoroacetic acid, heptafluoropropionic acid, ethanesulfonic acid and methyl phenyl sulfide.
Preferably, the step 1) further comprises, after the polymerization reaction is finished: for the amino-protecting group R obtained4And R5The polyamino acid derivative of (a) is purified by a method including, but not limited to, the following methods:
the method comprises the following steps: adding water to extract the product, purifying the water layer, and freeze-drying to obtain the purified amino-containing protecting group R4And R5The polyamino acid derivative of (a);
the method 2 comprises the following steps: adding water to extract the product, drying the organic layer, removing water, evaporating the solvent, and oven drying the obtained product to obtain purified amino-protecting group R4And R5The polyamino acid derivative of (1).
In the case of using less organic solvent for the polymerization reaction in step 1), those skilled in the art understand that, for the purpose of smooth extraction and improved yield, part of the organic solvent is generally added at the same time as the water is added for extraction, and preferably, in the method 1 and the method 2, the organic solvent Z is added at the same time as the water is added; the organic solvent Z comprises but is not limited to one or a mixture of more than two of chloroform, ethyl acetate, toluene, n-butanol and dichloromethane; the purification treatment includes, but is not limited to, dialysis bag treatment or anion resin treatment.
Preferably, when R is4When the group is benzyloxycarbonyl, the R4The group deprotecting agent P is an acidic agent, including but not limited toOne or more of trifluoroacetic acid/33% hydrobromic acid in acetic acid, trichloroacetic acid, benzenesulfonic acid, methanesulfonic acid, phenylthiomethane, dichlorodicyanobenzoquinone and acetic acid;
when R is4When the group is tert-butyloxycarbonyl, the R4Group deprotecting agents P include, but are not limited to, TFA or 50% TFA (TFA: CH)2Cl21:1, v/v), HCl/dioxane, HCl/EtOAc (methanol as solvent), Me3SiI CHCl3Or CH3CN solution;
when R is4When the group is fluorenyl methoxycarbonyl, R4Group deprotecting agents P include, but are not limited to, 20% piperidine solution or concentrated ammonia, dioxane/4M NaOH (30:9:1), and 50% CH with piperidine, ethanolamine, cyclohexylamine, morpholine, pyrrolidone, DBU, and like amines2Cl2Solution of Bu4N+F-DMF solution;
when R is4When the group is trifluoroacetyl, the R4The group deprotection agent P is alkaline solution, including but not limited to sodium hydroxide aqueous solution, sodium hydroxide ethanol aqueous solution, potassium hydroxide ethanol aqueous solution, piperidine solution, potassium carbonate methanol aqueous solution, sodium carbonate methanol aqueous solution;
the R is5The group deprotection agent Q comprises one or a mixture of more than two of trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, methanesulfonic acid, phenylthiomethane, dichlorodicyano benzoquinone and acetic acid.
Further, R is eliminated4After the reaction of the protecting group is completed, and/or R is removed5After the reaction of the protecting group is finished, the obtained product is further purified, and the purification method comprises but is not limited to the following methods:
the method comprises the following steps: adding a large amount of solvent U into the solution to precipitate a product, washing, purifying, and freeze-drying to obtain a polyamino acid derivative or copolymer;
the method 2 comprises the following steps: purifying the solution, and freeze-drying to obtain polyamino acid derivatives or copolymers;
the solvent U may be an ether or alkane solvent, including but not limited to: methyl tert-butyl ether, ethanol; the purification treatment includes, but is not limited to, dialysis bag treatment, anion resin treatment.
The invention has the following beneficial effects:
(1) the polyamino acid derivative or polyamino acid copolymer has good compatibility and antibacterial performance, can be degraded into amino acid monomers in vivo, and has no toxic or side effect.
(2) The invention prepares the multifunctional material with definite and adjustable structure, antibacterial function, good biocompatibility, degradation performance and the like by changing the factors such as the types, the proportions and the like of isocyanate, amine and aldehyde.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
FIG. 1 shows the structural formula of the polyamino acid derivative or copolymer of the present invention.
FIG. 2 shows the relative molecular weight test results for the polyamino acid copolymer prepared in example 1.
FIG. 3 shows the antibacterial ratio against Staphylococcus aureus of the polyamino acid copolymer prepared in example 1.
FIG. 4 shows the antibacterial ratio against E.coli of the polyamino acid copolymer prepared in example 1.
FIG. 5 shows the relative survival rate of the polyamino acid copolymer prepared in example 1 against mouse fibroblast cells L929.
Detailed Description
In order to make the technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in detail with reference to the accompanying drawings.
The structure diagram of the antibacterial polyamino acid derivative or copolymer with an alternate structure provided by the invention is shown in figure 1; abbreviated as [ A ]B]n(ii) a Wherein A and B represent two kinds of repeating units of polyamino acid derivative or copolymer respectively; n is the number of repeating units of the AB repeating unit; n is a positive integer, and n is 2-10000.
A. The chemical structural formula of B is as follows: a:
B：
several exemplary preparations and corresponding products are provided below.
Example 1
This example prepares a degradable antibacterial polyamino acid copolymer with an alternating structure
1) Polymerization reaction: 0.01moL of 5- (benzyloxycarbonylamino) pentanal and 0.01moL of benzylamine were added in this order to 10mL of tetrahydrofuran and reacted at room temperature. After stirring for 3 days, the solution was distilled under reduced pressure to remove the solvent to give a yellow oily intermediate. 0.01moL of potassium isocyanate was dissolved in 5mL of methanol at 0 ℃ and 0.01moL of hydrofluoric acid and a yellow oily intermediate were sequentially added. The mixture was warmed to room temperature and stirred for 4 days, and the reaction was stopped. Adding distilled water, and extracting purified water layer to obtain amino acid derivative with protecting group.
2) Deprotection reaction: dissolving the polyamino acid derivative containing the benzyloxycarbonyl protecting group with 20mL of trifluoroacetic acid, adding 5mL of 33% hydrobromic acid acetic acid solution, reacting at 25 ℃ for 4 hours, precipitating the product with methyl tert-butyl ether, washing with ethanol for three times, dialyzing with a 1000-molecular-weight dialysis bag for 3 days, and obtaining the polyamino acid derivative with the benzyloxycarbonyl protecting group removed.
Dissolving the obtained polyamino acid derivative with 5mL methanesulfonic acid, reacting at 100 ℃ for 2 days, precipitating the product with methyl tert-butyl ether, washing with ethanol for three times, and dialyzing in a 1000 molecular weight dialysis bag for 3 days to obtain the polyamino acid copolymer.
The reaction formula is as follows:
the relative molecular weight test results of the polyamino acid copolymer prepared in this example are shown in FIG. 2, wherein W is mass and M is weight average molecular weight; as can be seen from FIG. 2, the polyamino acid copolymer obtained in this example had a number average molecular weight of 2835 and a weight average molecular weight of 13434.
The product was formulated with sterilized distilled water to four concentrations of 200ppm, 100ppm, 50ppm and 25ppm, respectively. 4mL of 0.03mmoL/L sterile PBS solution, 0.5mL of polymer-containing solution, and 0.5mL of Staphylococcus aureus solution (concentration: 1.5X 10)6CFU/mL), three replicates per group were done simultaneously. The blank was not loaded with any drug, and 4.5mL of 0.03mmoL sterile PBS and 0.5mL of bacterial suspension were added to make three replicates. And unscrewing the centrifugal tube covers, putting the centrifugal tube covers into a constant-temperature oscillation box, oscillating the centrifugal tube covers at 37 ℃, taking out the centrifugal tube covers after one day, and diluting each sample by four gradients of ten times, hundred times, thousand times and ten thousand times by using physiological saline. Respectively sucking 1mL of solution, adding the solution into culture dishes, adding a proper amount of PCA culture medium, shaking up, cooling, and recording the number of colonies growing in each culture dish after one-day inverted culture.
The antibacterial efficiency against Staphylococcus aureus at the concentrations of polyamino acid copolymer of 20ppm, 10ppm, 5ppm, and 2.5ppm, respectively, is shown in FIG. 3. When the concentration is more than 10ppm, the antibacterial rate is 100%, when the concentration is 5ppm, the antibacterial rate is 96.75%, and when the concentration is 2.5ppm, the antibacterial rate is 63.46%.
The antibacterial activity against E.coli at the concentrations of the polyamino acid copolymer of 20ppm, 10ppm, 5ppm and 2.5ppm, respectively, is shown in FIG. 4. When the concentration is more than 10ppm, the antibacterial rate is 100%, and when the concentration is 5ppm, the antibacterial rate is 87.53%. When the concentration was 2.5ppm, the antibacterial ratio was 38.19%.
Add 100. mu.L of 5X 10 concentration per well in 96-well plates5CFU/mL mouse fibroblast cells L929, carbon dioxide biochemical incubator. The polymer solution was prepared with the culture solution to have four concentrations of 20ppm, 10ppm, 5ppm and 2.5 ppm. One day later, the original cell culture solution in the 96-well plate was aspirated, and the freshly prepared culture solutions 100 containing polymers at different concentrations were added to the wellsmu.L, culture medium was also added to the zero-adjusted group (without cells) and the control group, six replicates were made, 10uL of CCK-8 reagent was added to each well after one day of culture, and the culture was continued for 2 h. Detecting the light absorption value A of each hole at the wavelength of 450 nm by using a microplate reader, and calculating the relative survival rate of the cells according to the formula as follows: relative cell survival rate (%) ═ a1-A2)/(A3-A1) X is 100%; in the above formula A1Represents the absorbance of the solution at a polymer concentration of not 0 ppm; a. the2Represents the absorbance of the culture and CCK-8; a. the3Represents the absorbance of the solution at a polymer concentration of 0 ppm.
The relative survival rates of mouse fibroblast cells L929 at polyamino acid copolymer concentrations of 20ppm, 10ppm, 5ppm, and 2.5ppm are shown in FIG. 5. 86.24%, 100.25%, 101.63% and 104.27%, respectively. When the concentration is less than 10ppm, the composition has no toxicity to mouse fibroblasts.
Example 2
This example prepares a degradable antibacterial polyamino acid copolymer with an alternating structure
1) Polymerization reaction: adding 0.01moL of 4-methoxybenzylamine, 0.01moL of methanesulfonic acid, 0.01moL of potassium isocyanate and 0.01moL of 4- (benzyloxycarbonylamino) butyraldehyde into 5mL of tetrahydrofuran at 0 ℃ in sequence, heating the mixture to room temperature, stirring for 15 days, stopping the reaction, adding distilled water, and extracting a purified water layer to obtain the amino acid derivative with the protecting group.
2) Deprotection reaction: dissolving the polyamino acid derivative containing the benzyloxycarbonyl protecting group with 5mL of methanesulfonic acid, reacting at 50 ℃ for 3 days, precipitating the product with methyl tert-butyl ether, washing with ethanol for three times, and dialyzing in a 1000-molecular-weight dialysis bag for 3 days to obtain the polyamino acid derivative without the protecting group.
The reaction formula is as follows:
the polyamino acid derivative obtained in this example has a number average molecular weight of 23758 and a weight concentration of 2%1.0X 10 in physiological saline5After 24 hours of action of staphylococcus aureus with cfu/mL concentration, the bacterial concentration is reduced by more than 50 percent, and the staphylococcus aureus has no toxicity on mouse fibroblast L929; the experimental procedure is as in example 1.
Example 3
This example prepares a degradable antibacterial polyamino acid copolymer with an alternating structure
1) Polymerization reaction: adding 0.01moL of 4-methoxybenzylamine, 0.01moL of methanesulfonic acid, 0.01moL of potassium isocyanate and 0.01moL of 4- (trifluoroacetylamino) butyraldehyde into 5mL of tetrahydrofuran at 0 ℃ in sequence, heating the mixture to room temperature, stirring for 15 days, stopping the reaction, adding distilled water, drying the organic layer, removing water, evaporating the solvent, drying and purifying the obtained product to obtain the amino acid derivative with the protecting group.
2) Deprotection reaction: dissolving the polyamino acid derivative containing the trifluoroacetyl protecting group by using 40mL of 1mol/L sodium hydroxide solution, reacting for 5 hours at 50 ℃, and dialyzing the product for 3 days by using a 1000-molecular-weight dialysis bag to obtain the polyamino acid derivative with the protecting group removed.
The polyamino acid derivative prepared in this example had a number average molecular weight of 10679 and a 4% weight concentration of 1.0X 10 polyamino acid copolymer material in physiological saline5After 24 hours of action of staphylococcus aureus with cfu/mL concentration, the bacterial concentration is reduced by more than 50 percent, and the staphylococcus aureus has no toxicity on mouse fibroblast L929; the experimental procedure is as in example 1.
Example 4
This example prepares a degradable antibacterial polyamino acid copolymer with an alternating structure
1) Polymerization reaction: adding 0.01moL of 4-methoxybenzylamine, 0.01moL of methanesulfonic acid, 0.01moL of potassium 2- (isocyano) propionate and 0.01moL of 4- (trifluoroacetylamino) butyraldehyde into 5mL of tetrahydrofuran at 0 ℃, heating the mixture to room temperature, stirring for 15 days, stopping the reaction, adding distilled water, drying the organic layer, removing water, evaporating the solvent, and drying and purifying the obtained product to obtain the amino acid derivative with the protecting group.
2) Deprotection reaction: dissolving the polyamino acid derivative containing the trifluoroacetyl protecting group by using 40mL of 1mol/L sodium hydroxide solution, reacting for 5 hours at 50 ℃, and dialyzing the product for 3 days by using a 1000-molecular-weight dialysis bag to obtain the polyamino acid derivative with the protecting group removed.
The polyamino acid derivative prepared in this example had a number average molecular weight of 13593 and a weight concentration of 4% of the polyamino acid copolymer material in physiological saline of 1.0X 105After 24 hours of action of staphylococcus aureus with cfu/mL concentration, the bacterial concentration is reduced by more than 50 percent, and the staphylococcus aureus has no toxicity on mouse fibroblast L929; the experimental procedure is as in example 1.
Example 5
This example prepares a degradable antibacterial polyamino acid copolymer with an alternating structure
1) Polymerization reaction: adding 0.01moL of 4-methoxybenzylamine, 0.01moL of methanesulfonic acid, 0.01moL of potassium 2- (isocyano) -3- (phenyl) propionate and 0.01moL of 4- (trifluoroacetylamino) butyraldehyde into 5mL of tetrahydrofuran at 0 ℃, heating the mixture to room temperature, stirring for 15 days, stopping the reaction, adding distilled water, drying the organic layer, removing water, evaporating the solvent, and drying and purifying the obtained product to obtain the amino acid derivative with the protecting group.
2) Deprotection reaction: dissolving the polyamino acid derivative containing the trifluoroacetyl protecting group by using 40mL of 1mol/L sodium hydroxide solution, reacting for 5 hours at 50 ℃, and dialyzing the product for 3 days by using a 1000-molecular-weight dialysis bag to obtain the polyamino acid derivative with the protecting group removed.
The polyamino acid derivative obtained in this example had a number average molecular weight of 37341 and a weight concentration of 5% of the polyamino acid copolymer material in physiological saline of 1.0X 105After 24 hours of action of staphylococcus aureus with cfu/mL concentration, the bacterial concentration is reduced by more than 50 percent, and the staphylococcus aureus has no toxicity on mouse fibroblast L929; the experimental procedure is as in example 1.
Example 6
This example prepares a degradable antibacterial polyamino acid copolymer with an alternating structure
1) Polymerization reaction: adding 0.01moL of allylamine, 0.01moL of methanesulfonic acid, 0.01moL of potassium isocyanate and 0.01moL of 4- (trifluoroacetylamino) butyraldehyde into 5mL of tetrahydrofuran at 0 ℃, heating the mixture to room temperature, stirring for 15 days, stopping the reaction, adding distilled water, drying the organic layer, removing water, evaporating the solvent, drying and purifying the obtained product to obtain the amino acid derivative with the protecting group.
2) Deprotection reaction: dissolving the polyamino acid derivative containing the trifluoroacetyl protecting group by using 40mL of 1mol/L sodium hydroxide solution, reacting for 5 hours at 50 ℃, and dialyzing the product for 3 days by using a 1000-molecular-weight dialysis bag to obtain the polyamino acid derivative with the protecting group removed.
The polyamino acid derivative prepared in this example had a number average molecular weight of 18764 and a weight concentration of 5% of the polyamino acid copolymer material in physiological saline of 1.0X 105After 24 hours of action of staphylococcus aureus with cfu/mL concentration, the bacterial concentration is reduced by more than 50 percent, and the staphylococcus aureus has no toxicity on mouse fibroblast L929; the experimental procedure is as in example 1.
Example 7
This example prepares a degradable antibacterial polyamino acid copolymer with an alternating structure
1) Polymerization reaction: adding 0.01moL of 4-methoxybenzylamine, 0.01moL of methanesulfonic acid, 0.01moL of potassium isocyanate and 0.01moL of 4- (trifluoroacetylguanidino) butyraldehyde into 5mL of tetrahydrofuran at 0 ℃ in sequence, heating the mixture to room temperature, stirring for 15 days, stopping the reaction, adding distilled water, drying the organic layer, removing water, evaporating the solvent, drying and purifying the obtained product to obtain the amino acid derivative with the protecting group.
2) Deprotection reaction: dissolving the polyamino acid derivative containing the trifluoroacetyl protecting group by using 40mL of 1mol/L sodium hydroxide solution, reacting for 5 hours at 50 ℃, and dialyzing the product for 3 days by using a 1000-molecular-weight dialysis bag to obtain the polyamino acid derivative with the protecting group removed.
The polyamino acid derivative prepared in this example has a number average molecular weight of 25623, and a weight concentration of 2% polyamino acid copolymer material in physiological saline of 1.0X 105Bacterial concentration 24 hours after the action of Staphylococcus aureus in cfu/mL concentrationThe reduction is more than 50 percent, and the traditional Chinese medicine composition has no toxicity to mouse fibroblast L929; the experimental procedure is as in example 1.
It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention, and it will be obvious to those skilled in the art that other variations or modifications may be made on the basis of the above description, and all embodiments may not be exhaustive, and all obvious variations or modifications may be included within the scope of the present invention.
Claims (10)
1. An antibacterial polyamino acid derivative or copolymer of alternating structure, wherein said polyamino acid derivative or copolymer has the structure:
Wherein A is
B is
n is a positive integer, n is 2-10000;
R1contains an amino group at the terminal thereof;
R2comprises the following steps:
R3comprises the following steps:
-H，-CH3，
the preparation method comprises the following steps:
1) polymerisation reaction
Reacting a primary amine
And aldehydes
Adding the mixture into an organic solvent W, and reacting for 0.1 to 120 hours at the temperature of between 0 and 100 ℃ to obtain an intermediate product F containing carbon-nitrogen double bonds; intermediate product F, isocyanate
Dissolving with strong acid Y in solvent X, reacting at 0-100 deg.C for 0.1-240 hr to obtain amino protecting group R4And R5The polyamino acid derivative of (a);
wherein R is1The terminal group contains an amino group, and an amino-protecting group R4And R1The nitrogen atom on the terminal amino group is connected;
2) deprotection reaction:
reacting an amino-containing protecting group R4And R5Reacting polyamino acid derivative with deprotection agent P at 0-120 deg.C for 0.1-150 hr, and removing R4Radical, to obtain R-free4Polyamino acid derivatives of groups;
alternatively, the step 2) further comprises:
the obtained product is free of R4Reacting polyamino acid derivative with deprotection agent Q at 0-120 deg.C for 0.1-150 hr to remove R5Radical, obtaining a polyamino acid copolymer;
alternatively, step 2) comprises:
reacting an amino-containing protecting group R4And R5Reacting the polyamino acid derivative with a deprotection agent Q at the temperature of 0-120 ℃ for 0.1-150 hours, and then removing R5Radical, obtained is free ofR5Polyamino acid copolymers of groups; the obtained product is free of R5Reacting the polyamino acid copolymer of the group with a deprotection agent P at the temperature of 0-120 ℃ for 0.1-150 hours to remove R4And (4) obtaining the polyamino acid copolymer.
2. The antibacterial polyamino acid derivative or copolymer of alternating structure of claim 1, wherein R is1Comprises the following steps:
3. a method for preparing the antibacterial polyamino acid derivative or copolymer with the alternating structure of claim 1 or 2, which comprises the following steps:
1) polymerisation reaction
Reacting a primary amine
And aldehydes
Adding the mixture into an organic solvent W, and reacting for 0.1 to 120 hours at the temperature of between 0 and 100 ℃ to obtain an intermediate product F containing carbon-nitrogen double bonds; intermediate product F, isocyanate
Dissolving with strong acid Y in solvent X, reacting at 0-100 deg.C for 0.1-240 hr to obtain amino protecting group R4And R5The polyamino acid derivative of (a);
wherein R is1The terminal group contains an amino group, and an amino-protecting group R4And R1The nitrogen atom on the terminal amino group is connected;
2) deprotection reaction:
reacting an amino-containing protecting group R4And R5The deprotection agent P for polyamino acid derivatives is 0 to 120The R is removed after the reaction is carried out for 0.1 to 150 hours in the temperature range4Radical, to obtain R-free4Polyamino acid derivatives of groups;
alternatively, the step 2) further comprises:
the obtained product is free of R4Reacting polyamino acid derivative with deprotection agent Q at 0-120 deg.C for 0.1-150 hr to remove R5Radical, obtaining a polyamino acid copolymer;
alternatively, step 2) comprises:
reacting an amino-containing protecting group R4And R5Reacting the polyamino acid derivative with a deprotection agent Q at the temperature of 0-120 ℃ for 0.1-150 hours, and then removing R5Radical, to obtain R-free5Polyamino acid copolymers of groups; the obtained product is free of R5Reacting the polyamino acid copolymer of the group with a deprotection agent P at the temperature of 0-120 ℃ for 0.1-150 hours to remove R4And (4) obtaining the polyamino acid copolymer.
4. The method of claim 3, wherein the step 1) polymerization reaction comprises the steps of:
reacting a primary amine
Strong acid Y, isocyanate
And aldehydes
Adding into solvent X, reacting at 0-100 deg.C for 0.1-360 hr to obtain amino protecting group R4And R5Polyamino acid derivatives of the group.
5. The method according to claim 3, wherein in the step 1), the primary amine is used
Strong acid Y, isocyanate
And aldehydes
In a molar ratio of (1-3): (1-3): (1-3): (1-3);
in step 2), the aldehyde
The molar ratio of deprotection agent P to deprotection agent P is 1: (1-10); the primary amine
And deprotecting agent Q in a molar ratio of 1: (1-10).
6. The method according to claim 3, wherein the primary amine is
In, R5Comprises the following steps:
7. the process according to claim 3, wherein R is an amino-protecting group4Comprises the following steps: benzyloxycarbonyl, tert-butoxycarbonyl, fluorenyl-methoxycarbonyl, trifluoroacetyl;
the isocyanate
Wherein M is alkali metal cation, potassium ion or sodium ion;
the organic solvent W is one or a mixture of more than two of tetrahydrofuran, ethyl acetate, toluene, dichloromethane, chloroform, n-butanol and acetone;
the solvent X is one or a mixture of more than two of methanol, water, N-dimethylformamide, 2, 4-dimethyl-3-pentanol, isopropanol and o-chlorophenol;
the strong acid Y is one or a mixture of more than two of hydrofluoric acid, fluorosulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, pentafluoroacetic acid, heptafluoropropionic acid and ethanesulfonic acid.
8. The method according to claim 3, further comprising, after the polymerization reaction of step 1): for the amino-protecting group R obtained4And R5The purification method of the polyamino acid derivative comprises the following steps:
the method comprises the following steps: adding water to extract the product, purifying the water layer, and freeze-drying to obtain the purified amino-containing protecting group R4And R5The polyamino acid derivative of (a);
the method 2 comprises the following steps: adding water to extract the product, drying the organic layer, removing water, evaporating the solvent, and oven drying the obtained product to obtain purified amino-protecting group R4And R5The polyamino acid derivative of (a);
in the method 1 and the method 2, the organic solvent Z is added while water is added; the organic solvent Z comprises but is not limited to one or a mixture of more than two of chloroform, ethyl acetate, toluene, n-butanol and dichloromethane;
the purification treatment comprises dialysis bag treatment or anion resin treatment.
9. The method according to claim 3, wherein when R is4When the group is benzyloxycarbonyl, the deprotection agent P is one or a mixture of more than two of trifluoroacetic acid/33% hydrobromic acid solution in acetic acid, trichloroacetic acid, benzenesulfonic acid, methanesulfonic acid, phenylthiomethane, dichlorodicyano benzoquinone and acetic acid;
when R is4When the group is tert-butyloxycarbonyl, the deprotecting agent P is TFA or 50% TFA, HCl/dioxane, HCl/EtOAc, or,Me3SiI CHCl3Or CH3CN solution;
when R is4When the group is fluorenyl methoxycarbonyl, the deprotecting agent P is 20% piperidine solution or concentrated ammonia, dioxane/4M NaOH, or 50% CH with piperidine, ethanolamine, cyclohexylamine, morpholine, pyrrolidone or DBU amine2Cl2Of Bu or4N+F-DMF solution;
when R is4When the group is trifluoroacetyl, the deprotection agent P is sodium hydroxide aqueous solution, sodium hydroxide ethanol aqueous solution, potassium hydroxide solution, piperidine solution, potassium carbonate methanol aqueous solution or sodium carbonate methanol aqueous solution;
the deprotection agent Q is one or a mixture of more than two of trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, methanesulfonic acid, phenylthiomethane, dichlorodicyano benzoquinone and acetic acid.
10. The process according to claim 3, wherein R is eliminated4After the reaction of the protecting group is completed, and/or R is removed5After the reaction of the protecting group is finished, purifying the obtained product, wherein the purification method comprises the following steps:
the method comprises the following steps: adding a large amount of solvent U into the solution to precipitate a product, washing, purifying, and freeze-drying to obtain a polyamino acid derivative or copolymer;
the method 2 comprises the following steps: purifying the solution, and freeze-drying to obtain polyamino acid derivatives or copolymers;
the solvent U is methyl tert-butyl ether or ethanol; the purification treatment is dialysis bag treatment or anion resin treatment.
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| CN106750262A (en) * | 2016-11-30 | 2017-05-31 | 同济大学 | The synthesis of amphipathic block antibacterial peptide and its preparation method and application of assembly |
| CN106832260A (en) * | 2016-12-22 | 2017-06-13 | 苏州度博迈医疗科技有限公司 | A kind of degradable antibacterial polyaminoacid and preparation method thereof |
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| CN106750262A (en) * | 2016-11-30 | 2017-05-31 | 同济大学 | The synthesis of amphipathic block antibacterial peptide and its preparation method and application of assembly |
| CN106832260A (en) * | 2016-12-22 | 2017-06-13 | 苏州度博迈医疗科技有限公司 | A kind of degradable antibacterial polyaminoacid and preparation method thereof |
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