JPH04221395A - Peptide lipid - Google Patents
Peptide lipidInfo
- Publication number
- JPH04221395A JPH04221395A JP2333336A JP33333690A JPH04221395A JP H04221395 A JPH04221395 A JP H04221395A JP 2333336 A JP2333336 A JP 2333336A JP 33333690 A JP33333690 A JP 33333690A JP H04221395 A JPH04221395 A JP H04221395A
- Authority
- JP
- Japan
- Prior art keywords
- gly
- asp
- arg
- peptide
- amino acid
- 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.)
- Pending
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 49
- 150000002632 lipids Chemical class 0.000 title claims abstract description 21
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 21
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 12
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 claims abstract description 9
- 125000002252 acyl group Chemical group 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 239000004475 Arginine Substances 0.000 claims abstract description 3
- 239000004471 Glycine Substances 0.000 claims abstract description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims abstract description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 8
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 6
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 5
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 2
- 108010089975 arginyl-glycyl-aspartyl-serine Proteins 0.000 claims description 2
- 229960001230 asparagine Drugs 0.000 claims description 2
- 235000009582 asparagine Nutrition 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 claims description 2
- 239000004474 valine Substances 0.000 claims description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 abstract description 19
- 235000001014 amino acid Nutrition 0.000 abstract description 18
- -1 t-butyloxycarbonyl Chemical group 0.000 abstract description 10
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 239000012528 membrane Substances 0.000 abstract description 4
- 239000000693 micelle Substances 0.000 abstract description 4
- 125000006239 protecting group Chemical group 0.000 abstract description 4
- DMBKPDOAQVGTST-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylmethoxypropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)COCC1=CC=CC=C1 DMBKPDOAQVGTST-LBPRGKRZSA-N 0.000 abstract description 3
- 230000021164 cell adhesion Effects 0.000 abstract description 3
- 230000012292 cell migration Effects 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 abstract 1
- 235000003704 aspartic acid Nutrition 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 abstract 1
- 150000001718 carbodiimides Chemical class 0.000 abstract 1
- 239000006143 cell culture medium Substances 0.000 abstract 1
- 125000000524 functional group Chemical group 0.000 abstract 1
- 239000002502 liposome Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 147
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 70
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 239000000243 solution Substances 0.000 description 36
- 238000000034 method Methods 0.000 description 32
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 23
- 229920006395 saturated elastomer Polymers 0.000 description 23
- 239000011734 sodium Substances 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 22
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 18
- 229940024606 amino acid Drugs 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 16
- 239000003480 eluent Substances 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 150000003463 sulfur Chemical class 0.000 description 11
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 7
- SCCPDJAQCXWPTF-VKHMYHEASA-N Gly-Asp Chemical group NCC(=O)N[C@H](C(O)=O)CC(O)=O SCCPDJAQCXWPTF-VKHMYHEASA-N 0.000 description 7
- 238000009833 condensation Methods 0.000 description 7
- 230000005494 condensation Effects 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- SOHLZANWVLCPHK-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-4-phenylmethoxybutanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC(=O)OCC1=CC=CC=C1 SOHLZANWVLCPHK-LBPRGKRZSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- SZAZMWQINJVVDZ-UHFFFAOYSA-N [2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl] 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate Chemical compound CC(C)(C)OC(=O)NCC(=O)OC(=O)CNC(=O)OC(C)(C)C SZAZMWQINJVVDZ-UHFFFAOYSA-N 0.000 description 4
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 210000003705 ribosome Anatomy 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- ZERWDZDNDJBYKA-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O ZERWDZDNDJBYKA-UHFFFAOYSA-N 0.000 description 2
- FHOAKXBXYSJBGX-YFKPBYRVSA-N (2s)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CO)C(O)=O FHOAKXBXYSJBGX-YFKPBYRVSA-N 0.000 description 2
- XXCXRVNSUQAYMM-UHFFFAOYSA-N 3,7,11-trimethyldodecanoic acid Chemical compound CC(C)CCCC(C)CCCC(C)CC(O)=O XXCXRVNSUQAYMM-UHFFFAOYSA-N 0.000 description 2
- 101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 2
- 102000016359 Fibronectins Human genes 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 108010038807 Oligopeptides Proteins 0.000 description 2
- 102000015636 Oligopeptides Human genes 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- LUFPJJNWMYZRQE-UHFFFAOYSA-N benzylsulfanylmethylbenzene Chemical compound C=1C=CC=CC=1CSCC1=CC=CC=C1 LUFPJJNWMYZRQE-UHFFFAOYSA-N 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- CRDAMVZIKSXKFV-FBXUGWQNSA-N (2-cis,6-cis)-farnesol Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C/CO CRDAMVZIKSXKFV-FBXUGWQNSA-N 0.000 description 1
- 239000000260 (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol Substances 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- VGALFAWDSNRXJK-VIFPVBQESA-N L-aspartic acid beta-benzyl ester Chemical compound OC(=O)[C@@H](N)CC(=O)OCC1=CC=CC=C1 VGALFAWDSNRXJK-VIFPVBQESA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 235000021360 Myristic acid Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- WBAXJMCUFIXCNI-WDSKDSINSA-N Ser-Pro Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(O)=O WBAXJMCUFIXCNI-WDSKDSINSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- PLZVEHJLHYMBBY-UHFFFAOYSA-N Tetradecylamine Chemical compound CCCCCCCCCCCCCCN PLZVEHJLHYMBBY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000011173 biocomposite Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- MQYQOVYIJOLTNX-UHFFFAOYSA-N dichloromethane;n,n-dimethylformamide Chemical compound ClCCl.CN(C)C=O MQYQOVYIJOLTNX-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940043259 farnesol Drugs 0.000 description 1
- 229930002886 farnesol Natural products 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- VHNBNECUVQXBQA-UHFFFAOYSA-N methylsulfanylbenzene;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CSC1=CC=CC=C1 VHNBNECUVQXBQA-UHFFFAOYSA-N 0.000 description 1
- HNTDJKLSENGQMG-UHFFFAOYSA-N methylsulfanylbenzene;trifluoromethanesulfonic acid Chemical compound CSC1=CC=CC=C1.OS(=O)(=O)C(F)(F)F HNTDJKLSENGQMG-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- ABCVHPIKBGRCJA-UHFFFAOYSA-N nonyl 8-[(8-heptadecan-9-yloxy-8-oxooctyl)-(2-hydroxyethyl)amino]octanoate Chemical compound OCCN(CCCCCCCC(=O)OC(CCCCCCCC)CCCCCCCC)CCCCCCCC(=O)OCCCCCCCCC ABCVHPIKBGRCJA-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
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- 230000002250 progressing effect Effects 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- 238000001953 recrystallisation Methods 0.000 description 1
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- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、Ａｒｇ−Ｇｌｙ−Ａｓｐのトリペプチド単位
を有する、リボソームあるいはミセル等の分子集合体を
形成するのに最適なペプチド脂質に関する。
〔従来の技術〕
フィブロネクチンは細胞−細胞外基質の接着に関与する
タンパク質であり、血小板凝集やガン転移にも関与して
いると考えられている。これらの相互作用は一連の細胞
表面のレセプターにより仲介されること、これらのレセ
プターが、分子量約２５万の巨大分子であるフィブロネ
クチンのアルギニン−グリシン−アスパラギン酸（Ａｒ
ｇ−Ｇｌｙ−ＡｓｐまたはＲＧＤ）配列を特異的に認識
することが明らかにされ、レセプターとの相互作用に重
要なものであることが報告されている（ネイチャー（Ｎ
ａｔｕｒｅ）、第３０９巻、３０頁、１９８４年）。
以来、Ａｒｇ−Ｇｌｙ−Ａｓｐ配列を有するオリゴある
いはポリペプチドを用いる研究が進められている。
例えば、Ａｒｇ−Ｇｌｙ−Ａｓｐ配列を有する種々の鎖
状および環状のオリゴペプチドを用いて血小板凝集を阻
害する方法（高分子学会予稿集（ＰｏｌｙｍｅｒＰｒｅ
ｐｒｉｎｔｓ，Ｊａｐａｎ）、第３８巻、３１４９頁、
１９８９年、特開平２−１７４７９７号）、Ａｒｇ−Ｇ
ｌｙ−Ａｓｐ配列を有するペプチドを細胞移動抑制剤と
して用いる方法（特開平２−４７１６号）、Ａｒｇ−Ｇ
ｌｙ−Ａｓｐを固定化したＰＭＭＡ膜を細胞接着膜とし
て用いる方法（高分子学会予稿集（Ｐｏｌｙｍｅｒ Ｐ
ｒｅｐｒｉｎｔｓ，Ｊａｐａｎ）、第３７巻、７０５頁
、１９８８年）が報告されている。さらに、ポリマーに
Ａｒｇ−Ｇｌｙ−Ａｓｐを必須構成単位とするペプチド
を共有結合させ動物細胞培養基体、生体複合人工臓器用
基体として用いる方法（特開平１−３０９６８２号、特
開平１−３０５９６０号）、Ａｒｇ−Ｇｌｙ−Ａｓｐ−
Ｓｅｒ配列を有するポリペプチドを体外血液用血小板保
護剤として用いる方法が開示されている（特開昭６４−
６２１７号）。
また、Ａｒｇ−Ｇｌｙ−Ａｓｐ配列を有するオリゴペプ
チドあるいはその繰り返し構造を有するポリペプチドを
用いて、ガン転移を抑制する方法が知られている（イン
ターナショナル・ジャーナル・オブ・バイオロジカル・
マクロモレキュルズ（Ｉｎｔ．Ｊ．Ｂｉｏｌ．Ｍａｃｒ
ｏｍｏｌ．）、第１１巻、２３頁、１９８９年、同誌、
第１１巻、２２６頁、１９８９年、ジャパン・ジャーナ
ル・オブ・キャンサー・リサーチ（Ｊｐｎ．Ｊ．Ｃａｎ
ｃｅｒ Ｒｅｓ．）第６０巻、７２２頁、１９８９年）
。
一方、リボソームやミセル等の分子集合体をドラッグキ
ャリアーとして用いる方法が多数検討されている（例え
ば、リボソーム、２４５頁〜２７１頁、南江堂、１９８
８年、キャンサー・リサーチ（Ｃａｎｃｅｒ Ｒｅｓ．
）第４３巻、５３２８頁、１９８３年、ジャーナル・オ
ブ・コントロールド．リリース（Ｊ．Ｃｏｎｔｒｏｌｌ
ｅｄ Ｒｅｌｅａｓｅ）２６９頁、１９９０年）。
しかし、リボソーム等の分子集合体形成脂質にＡｒｇ−
Ｇｌｙ−Ａｓｐ配列を有するペプチド脂質を用いた例は
知られていない。
〔発明が解決しようとする課題〕
本発明の目的は、Ａｒｇ−Ｇｌｙ−Ａｓｐのトリペプチ
ド単位を有する、リボソームあるいはミセル等の分子集
合体を形成するのに最適なペプチド脂質誘導体及びその
合成法を提供することである。
〔課題を解決するための手段〕
本発明の化合物は下記、一般式〔Ｉ〕で示される合成ペ
プチド脂質またはその塩である。
Ｒ１−（〔Ｘ〕−Ａｒｇ−Ｇｌｙ−Ａｓｐ−〔Ｙ〕）ｎ
−Ｚ−Ｒ２…〔Ｉ〕式中、Ａｒｇ、Ｇｌｙ、Ａｓｐはそ
れぞれアルギニン、グリシン、アスパラギン酸残基を示
す。
〔Ｘ〕、〔Ｙ〕は、存在するかあるいは存在しないアミ
ノ酸残基または、二つあるいは三つのアミノ酸残基から
なるペプチド残基を示す。存在する場合には〔Ｘ〕〔Ｙ
〕は、Ｓｅｒ、Ｇｌｙ、Ｖａｌ、Ａｓｎ、Ｐｒｏ、Ｃｙ
ｓ、Ｔｈｒから選択されるアミノ酸残基または、これら
のアミノ酸残基の組み合わせにより構成されるペプチド
残基が好ましい。特に〔Ｙ〕はＳｅｒであることが好ま
しい。また、〔Ｘ〕、〔Ｙ〕が共に存在しない場合も特
に好ましい。さらに、〔Ｘ〕はＧｌｙ、〔Ｙ〕はＳｅｒ
−Ｐｒｏであることも特に好ましい。Ｓｅｒ、Ｖａｌ、
Ａｓｎ、Ｐｒｏ、Ｃｙｓ、Ｔｈｒはそれぞれセリン、バ
リン、アスパラギン、プロリン、システイン、トレオニ
ン残基を示す。
ｎは１〜５の整数を示し、特に１〜３が好ましい。
Ｚは−Ｏ−または−ＮＨ−を示す。
本発明において、アミノ酸はＬ−、Ｄ−、ラセミ体いず
れでもよいが、Ｌ−アミノ酸が好ましい。
Ｒ１は炭素数８〜２４の直鎖または分岐のアシル基であ
り、置換基、不飽和基を有していてもよい。好ましくは
炭素数１２〜１８である。例えばミリストイル基、パル
ミトイル基、ステアロイル基、３，７，１１，１５−テ
トラメチルヘキサデカノイル基、３，７，１１−トリメ
チルドデカノイル基が好ましい例として示される。
Ｒ２は炭素数８〜２４の直鎖または分岐のアルキル基で
あり、置換基、不飽和基を有していてもよい。好ましく
は炭素数１２〜１８である。例えばミリスチル基、パル
ミチル基、ステアリル基、フィチル基３，７，１１，１
５−テトラメチルヘキサデシル基、３，７，１１−トリ
メチルドデシル基が好ましい例として示される。
好ましい塩の例として、トリフルオロ酢酸塩、塩酸塩、
酢酸塩、硫酸塩、乳酸塩があげられる。
以下に本発明の好ましい具体例を物性値とともに示すが
、本発明はこれらに限定されるものではない。
ペプチド脂質−１
Ｃ１３Ｈ２７ＣＯ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−Ｏ−Ｃ１
４Ｈ２９ＦＡＢ−ＭＳ（Ｐｏｓ．）（Ｍ＋Ｎａ）＋７７
５（Ｍ＋Ｈ）＋７５３ＦＡＢ−ＭＳ（Ｎｅｇ．）（Ｍ＋
Ｎａ）−７７５（Ｍ−Ｈ）−７５１アミノ酸分析：Ａｒ
ｇ ０．９６，Ｇｌｙ ０．９７，Ａｓｐ ０．９６，
ペプチド脂質−２
Ｃ１５Ｈ３１ＣＯ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−Ｓｅｒ−
Ｏ−Ｃ１６Ｈ３３ＦＡＢ−ＭＳ（Ｐｏｓ．）（Ｍ＋Ｎａ
）＋９１８（Ｍ＋Ｈ）＋８９６ＦＡＢ−ＭＳ（Ｎｅｇ．
）（Ｍ＋Ｎａ）−９１８（Ｍ−Ｈ）−８９４アミノ酸分
析：Ａｒｇ ０．９９，Ｇｌｙ １．０１，Ａｓｐ ０
．９５，Ｓｅｒ ０．７９
ペプチド脂質−３
Ｃ８Ｈ１７ＣＯ−Ｇｌｙ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−Ｓ
ｅｒ−Ｏ−Ｃ１０Ｈ２１ＦＡＢ−ＭＳ（Ｐｏｓ．）（Ｍ
＋Ｎａ）＋７９３（Ｍ＋Ｈ）＋７７１ＦＡＢ−ＭＳ（Ｎ
ｅｇ．）（Ｍ＋Ｎａ）−７９３（Ｍ−Ｈ）−７６９アミ
ノ酸分析：Ａｒｇ ０．９８，Ｇｌｙ ２．１７，Ａｓ
ｐ ０．９２，Ｓｅｒ ０．７６
ペプチド脂質−４
Ｃ１７Ｈ３５ＣＯ−Ｃｙｓ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−
Ｃｙｓ−Ｏ−Ｃ１８Ｈ３７ＦＡＢ−ＭＳ（Ｐｏｓ．）（
Ｍ＋Ｎａ）＋１０９３（Ｍ＋Ｈ）＋１０７１ＦＡＢ−Ｍ
Ｓ（Ｎｅｇ．）（Ｍ＋Ｎａ）−１０９３（Ｍ−Ｈ）−１
０６９アミノ酸分析：Ａｒｇ ０．９７，Ｇｌｙ ０．
９２，Ａｓｐ ０．８２，Ｃｙｓ １．７１
ペプチド脂質−５
Ｃ８Ｈ１７ＣＯ−Ｇｌｙ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−Ｔ
ｈｒ−Ｏ−Ｃ２０Ｈ４１ＦＡＢ−ＭＳ（Ｐｏｓ．）（Ｍ
＋Ｎａ）＋９４７（Ｍ＋Ｈ）＋９２５ＦＡＢ−ＭＳ（Ｎ
ｅｇ．）（Ｍ＋Ｎａ）−９４７（Ｍ−Ｈ）−９２３アミ
ノ酸分析：Ａｒｇ ０．９３，Ｇｌｙ １．９４，Ａｓ
ｐ ０．９７，Ｔｈｒ ０．７４
ペプチド脂質−６
Ｃ１３Ｈ２７ＣＯ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−ＮＨ−Ｃ
１４Ｈ２９ＦＡＢ−ＭＳ（Ｐｏｓ．）（Ｍ＋Ｎａ）＋７
７４（Ｍ＋Ｈ）＋７５２ＦＡＢ−ＭＳ（Ｎｅｇ．）（Ｍ
＋Ｎａ）−７７４（Ｍ−Ｈ）−７５０アミノ酸分析：Ａ
ｒｇ ０．９９，Ｇｌｙ ０．９５，Ａｓｐ ０．９１
，ペプチド脂質−７
Ｃ１５Ｈ３１ＣＯ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−Ｓｅｒ−
ＮＨ−Ｃ１６Ｈ３３ＦＡＢ−ＭＳ（Ｐｏｓ．）（Ｍ＋Ｎ
ａ）＋９１７（Ｍ＋Ｈ）＋８９５ＦＡＢ−ＭＳ（Ｎｅｇ
．）（Ｍ＋Ｎａ）−９１７（Ｍ−Ｈ）−８９３アミノ酸
分析：Ａｒｇ ０．９７，Ｇｌｙ ０．９８，Ａｓｐ
０．８８，Ｓｅｒ ０．７５
ペプチド脂質−８
Ｃ１７Ｈ３５ＣＯ−Ｇｌｙ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−
Ｔｈｒ−ＮＨ−Ｃ１８Ｈ３７ＦＡＢ−ＭＳ（Ｐｏｓ．）
（Ｍ＋Ｎａ）＋１０４３（Ｍ＋Ｈ）＋１０２２ＦＡＢ−
ＭＳ（Ｎｅｇ．）（Ｍ＋Ｎａ）−１０４３（Ｍ−Ｈ）−
１０２０アミノ酸分析：Ａｒｇ ０．９４，Ｇｌｙ １
．８４，Ａｓｐ ０．９２，Ｔｈｒ ０．７２
ペプチド脂質−９
ＦＡＢ−ＭＳ（Ｐｏｓ．）（Ｍ＋Ｎａ）＋９４３（Ｍ＋
Ｈ）＋９２１ＦＡＢ−ＭＳ（Ｎｅｇ．）（Ｍ＋Ｎａ）−
９４３（Ｍ−Ｈ）−９１９アミノ酸分析：Ａｒｇ ０．
９９，Ｇｌｙ ０．９５，Ａｓｐ ０．９６，ペプチド
脂質−１０
Ｃ１７Ｈ３５ＣＯ（Ａｒｇ−Ｇｌｙ−Ａｓｐ）２−Ｏ−
Ｃ１８Ｈ３７ＦＡＢ−ＭＳ（Ｐｏｓ．）（Ｍ＋Ｎａ）＋
１２１５（Ｍ＋Ｈ）＋１１９３ＦＡＢ−ＭＳ（Ｎｅｇ．
）（Ｍ＋Ｎａ）−１２１５（Ｍ−Ｈ）−１１９１アミノ
酸分析：Ａｒｇ １．９９，Ｇｌｙ １．９４，Ａｓｐ
１．９２，ペプチド脂質−１１
Ｃ１３Ｈ２７ＣＯ−（Ａｒｇ−Ｇｌｙ−Ａｓｐ−Ｓｅｒ
）２−ＮＨ−Ｃ１４Ｈ２９ＦＡＢ−ＭＳ（Ｐｏｓ．）（
Ｍ＋Ｎａ）＋１２７６（Ｍ＋Ｈ）＋１２５４ＦＡＢ−Ｍ
Ｓ（Ｎｅｇ．）（Ｍ＋Ｎａ）−１２７６（Ｍ−Ｈ）−１
２５２アミノ酸分析：Ａｒｇ １．９２，Ｇｌｙ １．
９５，Ａｓｐ １．７９，Ｓｅｒ １．５３
ペプチド脂質−１２
Ｃ１５Ｈ３１ＣＯ−（Ａｒｇ−Ｇｌｙ−Ａｓｐ）３−Ｏ
−Ｃ１６Ｈ３３ＦＡＢ−ＭＳ（Ｐｏｓ．）（Ｍ＋Ｎａ）
＋１４８７（Ｍ＋Ｈ）＋１４６５ＦＡＢ−ＭＳ（Ｎｅｇ
．）（Ｍ＋Ｎａ）−１４８７（Ｍ−Ｈ）−１４６３アミ
ノ酸分析：Ａｒｇ ３．０３，Ｇｌｙ ２．８１，Ａｓ
ｐ ３．０１，ペプチド脂質−１３
Ｃ９Ｈ１９ＣＯ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−Ｓｅｒ−Ｐ
ｒｏ−ＮＨ−Ｃ１０Ｈ２１ＦＡＢ−ＭＳ（Ｐｏｓ．）（
Ｍ＋Ｈ）＋８２５ＦＡＢ−ＭＳ（Ｎｅｇ．）（Ｍ＋Ｈ）
−８２３ペプチド脂質−１４
ＦＡＢ−ＭＳ（Ｐｏｓ．）（Ｍ＋Ｈ）＋１０２２ＦＡＢ
−ＭＳ（Ｎｅｇ．）（Ｍ＋Ｈ）−１０２０本発明の化合
物は、たとえば次の４段階の工程により合成することが
できる。
■保護アミノ酸と、Ｒ２−Ｚ−Ｈとの縮合（Ｒ２は相当
するアルキル基、Ｚは−Ｏ−または−ＮＨ−を示す、）
■保護アミノ酸の逐次延伸
■Ｒ１−Ｗとの縮合
（Ｒ１は相当するアシル基を示す。Ｗは水酸基またはハ
ロゲン原子を示す。）
■脱保護、精製
以下、各段階の工程について詳細に説明する。
■一般式〔Ｉ〕で示される化合物の場合、Ｙで示される
アミノ酸の保護体またはＹが存在しない場合はＡｓｐの
保護体と相当するＲ２−Ｚ−Ｈとを縮合し、エステルあ
るいはアミドとする。
縮合に関しては、ＤＣＣ法、ＤＣＣ−ａｄｄｉｔｉｖｅ
法、ＣＤＩ法等一般の手法が採用される。
■保護アミノ酸を逐次伸長する方法としては、既知の方
法、すなわら泉屋ら編「ペプチド合成の基礎と実験」（
丸善）やＢｏｄａｎｓｚｋｙ著“ＰＲＩＮＣＩＰＬＥＳ
ＯＦ ＰＥＰＴＩＤＥ ＳＹＮＴＨＥＳＩＳ“ＴＨＥ
ＰＲＡＣＴＩＣＥ ＯＦ ＰＥＰＴＩＤＥ ＳＹＮＴＨ
ＳＩＳ”（ＳｐｒｉｎｇｅｒＶｅｒｌａｇ，Ｎｅｗ Ｙ
ｏｒｋ）に記載されている方法がいずれも有効である。
縮合反応の段階では、ＤＣＣ法、ＤＣＣ−ａｄｄｉｔｉ
ｖｅ法、アジド法、ＣＤＩ法、混合酸無水物法、活性化
エステル法のいずれを採用してもよいが、１−ヒドロキ
シベンゾトリアゾール（ＨＯＢｔ）とＤＣＣを併用する
ＤＣＣ−ＨＯＢｔ法が好ましい。
■相当するＲ１−ＯＨと（〔Ｘ〕−Ａｒｇ−Ｇｌｙ−Ａ
ｓｐ−〔Ｙ〕）ｎ−Ｚ−Ｒ２とを縮合する方法としては
、ＤＣＣ法、ＤＣＣ−ａｄｄｉｔｉｖｅ法、ＣＤＩ法、
いずれを採用してもよい。
また、Ｒ１−ＯＨをＲ１−Ｃｌ等の酸クロライドに変え
てアミド化を行ってもよい。
尚、アミノ酸残基の多いペプチド脂質に関しては、Ｒ１
−、Ｒ２−Ｚ−両端からペプチド逐次伸長を行い、フラ
グメント縮合を行うのが好ましい。この縮合法は、上記
■の方法に従う。
■保護基を脱保護するのに用いられる条件は、用いた保
護基の種類に大きく依存する。通常使用される脱保護方
法は、加水素分解、トリフルオロ酢酸、無水フッ化水素
、トリフルオロメタンスルホン酸−チオアニソール混合
系、トリフルオロ酢酸−チオアニソール混合系等である
が、保護基の種類によってはさらに多様な手段が可能で
ある。
以下に、本発明のペプチド脂質−２、ペプチド脂質−６
及びペプチド脂質−１０の合成例を示すが、本発明の合
成法はこれらに限定されるものではない。
また、本発明の化合物の好ましい具体例で示したペプチ
ド脂質（１）￣（１２）は、アミノ酸側鎖をベンジルエ
ーテル、ベンジルチオエーテルあるいはベンジルエステ
ルで保護した相当するＢｏｃ−アミノ酸と相当するＲ１
−ＯＨおよび相当するＲ２−ＯＨあるいはＲ２−ＮＨ２
を用いて、以下に示す合成例と同様にして合成できる。
実施例１
ペプチド脂質−２の合成
Ｂｏｃ−セリンベンジルエーテル５．９ｇ、ヘキサデシ
ルアルコール（カテコール６０、花王品）４．８ｇ、ジ
シクロヘキシルカルボジイミド４．６ｇ、ジメチルアミ
ノピリジン０．２４ｇ、をジクロロメタンに溶解し１０
℃で一昼夜撹拌した。反応液をろ過し、ろ液を減圧濃縮
してシリカゲルクロマトグラフィーにて精製（溶離液ク
ロロホルム）し、Ｂｏｃ−Ｓｅｒ（Ｂｚｌ）−ＯＣ１６
Ｈ３３ １０．３ｇを得た。
次に、Ｂｏｃ−Ｓｅｒ（Ｂｚｌ）−ＯＣ１６Ｈ３３ １
０．３ｇをジクロロメタン、トリフルオロ酢酸混合液（
２０ｍｌ／２０ｍｌ）に溶解し３０分間撹拌した。
溶媒を減圧留去した後、クロロホルムに溶解し、飽和炭
酸水素ナトリウム水溶液で処理して有機層をボウ硝乾燥
した後、クロロホルムを減圧留去してＳｅｒ（Ｂｚｌ）
−ＯＣ１６Ｈ３３ ９．３ｇを得た。
Ｂｏｃ−アスパラギン酸−β−ベンジルエステル７．１
ｇ、Ｓｅｒ（Ｂｚｌ）−ＯＣ１６Ｈ３３ ９．３ｇ、１
−ヒドロキシベンゾトリアゾール３．７ｇのジクロロメ
タン、ジメチルホルムアミド混合液６０ｍｌにジシクロ
ヘキシルカルボジイミド４．９ｇを加え一昼夜攪拌した
。
反応液をろ過し、ろ液を減圧留去した後、クロロホルム
に溶解した。飽和炭酸水素ナトリウム−水溶液で有機層
を洗いボウ硝乾燥した後、クロロホルムを減圧留去し、
残留物をシリカゲルクロマトグラフィーにて精製（溶離
液ヘキサン／酢酸エチル＝６／４）してＢｏｃ−Ａｓｐ
（ＯＢｚｌ）−Ｓｅｒ（Ｂｚｌ）−ＯＣ１６Ｈ３３ １
４．２ｇを得た。
次に、Ｂｏｃ−Ａｓｐ（ＯＢｚｌ）−Ｓｅｒ（Ｂｚｌ）
−ＯＣ１６Ｈ３３ １４．２ｇをジクロロメタン、トリ
フルオロ酢酸混合液（２０ｍｌ／２０ｍｌ）に溶解し３
０分間撹拌した。
溶媒を減圧留去した後、クロロホルムに溶解し飽和炭酸
水素ナトリウム水溶液で処理して有機層をボウ硝乾燥し
た後、クロロホルムを減圧留去してＡｓｐ（ＯＢｚｌ）
−Ｓｅｒ（Ｂｚｌ）−ＯＣ１６Ｈ３３ １３．５ｇを得
た。
Ａｓｐ（ＯＢｚｌ）−Ｓｅｒ（Ｂｚｌ）−ＯＣ１６Ｈ３
３ １３．５ｇをジクロロメタン５０ｍｌに溶解し、Ｂ
ｏｃ−グリシン無水物８．７ｇを加え一昼夜攪拌した、
反応液を飽和炭酸水素ナトリウム水溶液で洗い、ボウ硝
乾燥した後、ジクロロメタンを減圧留去し、残留物をシ
リカゲルクロマトグラフィーにて精製（溶離液ジクロロ
メタン／酢酸エチル＝６／４）して
Ｂｏｃ−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）−Ｓｅｒ（Ｂｚｌ
）−ＯＣ１６Ｈ３３ １１．８ｇを得た。
次に、Ｂｏｃ−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）−Ｓｅｒ（
Ｂｚｌ）−ＯＣ１６Ｈ３３１１．８ｇをジクロロメタン
、トリフルオロ酢酸混合液（２０ｍｌ／２０ｍｌ）に溶
解し３０分間撹拌した。
溶媒を減圧留去した後、クロロホルムに溶解し飽和炭酸
水素ナトリウム水溶液で処理して有機層をボウ硝乾燥し
た後、クロロホルムを減圧留去してＧｌｙ−Ａｓｐ（Ｏ
Ｂｚｌ）−Ｓｅｒ（Ｂｚｌ）−ＯＣ１６Ｈ３３ １０．
２ｇを得た。
Ｂｏｃ−Ａｒｇ（Ｚ）２ ８．４ｇ、１−ヒドロキシベ
ンゾトリアゾール２．４ｇ，Ｇｌｙ−Ａｓｐ（ＯＢｚｌ
）−Ｓｅｒ（Ｂｚｌ）−ＯＣ１６Ｈ３３ １０．２ｇの
ジクロロメタン、ジメチルホルムアミド混合液６０ｍｌ
にジシクロヘキシルカルボジイミド３．２ｇのジクロロ
メタン溶液２０ｍｌを加え、一昼夜撹拌した。
反応液をろ過し、ろ液を減圧留去した後、クロロホルム
に溶解した。飽和炭酸水素ナトリウム水溶液で有機層を
洗いボウ硝乾燥した後、クロロホルムを減圧留去し、残
留物をシリカゲルクロマトグラフィーにて精製（溶離液
ジクロロメタン／酢酸エチル＝６／４）した後、酢酸エ
チルで再結晶しＢｏｃ−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓ
ｐ（ＯＢｚｌ）−Ｓｅｒ（Ｂｚｌ）−ＯＣ１６Ｈ３３６
．６ｇを得た。
Ｂｏｃ−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）
−Ｓｅｒ（Ｂｚｌ）−ＯＣ１６Ｈ３３２．０ｇジクロロ
メタン、トリフルオロ酢酸混合液（２０ｍｌ／２０ｍｌ
）に溶解し３０分間撹拌した。
溶媒を減圧留去した後、クロロホルムに溶解し飽和炭酸
水素ナトリウム水溶液で処理して有機層をボウ硝乾燥し
た後、クロロホルムを減圧留去してＡｒｇ（Ｚ）２−Ｇ
ｌｙ−Ａｓｐ（ＯＢｚｌ）−Ｓｅｒ（Ｂｚｌ）−ＯＣ１
６Ｈ３３ １．５ｇを得た。
パルミチン酸０．５６ｇ、ジシクロヘキシルカルボジイ
ミド０．２３ｇをジクロロメタン５０ｍｌに溶解し、室
温で一時間攪拌した後に、Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａ
ｓｐ（ＯＢｚｌ）−Ｓｅｒ（Ｂｚｌ）ＯＣ１６Ｈ３３
１．１ｇのジクロロメタン溶液３０ｍｌを加え、一昼夜
攪拌した。
反応液をろ過し、ろ液を飽和炭酸水素ナトリウム水溶液
で洗いボウ硝乾燥した後、ジクロロメタンを減圧留去し
た。残留物をシリカゲルクロマトグラフィーにて精製（
溶離液クロロホルム／酢酸エチル＝５／５）した後、ク
ロロホルム、酢酸エチルで再結晶し、Ｃ１５Ｈ３１ＣＯ
−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）−Ｓｅ
ｒ（Ｂｚｌ）−ＯＣ１６Ｈ３３ １．３ｇを得た。
Ｃ１５Ｈ３１Ｃｏ−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓｐ（
ＯＢｚｌ）−Ｓｅｒ（Ｂｚｌ）−ＯＣ１６Ｈ３３ ５０
０ｍｇを酢酸７０ｍｌに溶解し二酸化白金１５０ｍｇを
加え加水素分解を５０℃で行った。
反応液をセライトにてろ過し、ろ液を減圧濃縮した。残
留物を酢酸、酢酸エチルにて再結晶し、Ｃ１５Ｈ３１Ｃ
Ｏ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−Ｓｅｒ−ＯＣ１６Ｈ３３
２６０ｍｇを得た。
実施例２
ペプチド脂質−６の合成
Ｂｏｃ−アスパラギン酸−β−ベンジルエステル６．５
ｇ、１−テトラデシルアミン４．３ｇ、１−ヒドロキシ
ベンゾトリアゾール３．１ｇ、ジシクロヘキシルカルボ
ジイミド４．６ｇ、ジメチルアミノピリジン０．２４ｇ
、をジクロロメタンに溶解し１０℃で一昼夜撹拌した。
反応液をろ過し、ろ液を減圧濃縮してシリカゲルクロマ
トグラフィーにて精製（溶離液クロロホルム）し、Ｂｏ
ｃ−Ａｓｐ（ＯＢｚｌ）−ＮＨ−Ｃ１４Ｈ２９ ９．７
ｇを得た。
次に、Ｂｏｃ−Ａｓｐ（ＯＢｚｌ）−ＮＨ−Ｃ１４Ｈ２
９ ９．７ｇをジクロロメタン、トリフルオロ酢酸混合
液（２０ｍｌ／２０ｍｌ）に溶解し３０分間攪拌した。
溶媒を減圧留去した後、クロロホルムに溶解し、飽和炭
酸水素ナトリウム水溶液で処理して有機層をボウ硝乾燥
した後、クロロホルムを減圧留去してＡｓｐ（ＯＢｚｌ
）−ＮＨ−Ｃ１４Ｈ２９ ９．３ｇを得た。
Ａｓｐ（ＯＢｚｌ）−ＮＨ−Ｃ１４Ｈ２９ ９．３ｇを
ジクロロメタン４０ｍｌに溶解し、Ｂｏｃ−グリシン無
水物１０．０ｇを加え一昼夜撹拌した。反応液を飽和炭
酸水素ナトリウム水溶液で洗いボウ硝乾燥した後、ジク
ロロメタンを減圧留去し、残留物をシリカゲルクロマト
グラフィーにて精製（溶離液ジクロロメタン／酢酸エチ
ル＝６／４）してＢｏｃ−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）
−ＮＨ−Ｃ１４Ｈ２９ ９．１ｇを得た。
次に、Ｂｏｃ−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）−ＮＨ−Ｃ
１４Ｈ２９ ９．１ｇをジクロロメタン、トリフルオロ
酢酸混合液（２０ｍｌ／２０ｍｌ）に溶解し３０分間攪
拌した。
溶媒を減圧留去した後、クロロホルムに溶解し飽和炭酸
水素ナトリウム水溶液で処理して有機層をボウ硝乾燥し
た後、クロロホルムを減圧留去してＧｌｙ−Ａｓｐ（Ｏ
Ｂｚｌ）−ＮＨ−Ｃ１４Ｈ２９ ８．８ｇを得た。
Ｂｏｃ−Ａｒｇ（Ｚ）２ ９．５ｇ、１−ヒドロキシベ
ンゾトリアゾール２．８ｇ、Ｇｌｙ−Ａｓｐ（ＯＢｚｌ
）−ＮＨ−Ｃ１４Ｈ２９８．８ｇのジクロロメタン、ジ
メチルホルムアミド混合液６０ｍｌにジシクロヘキシル
カルボジイミド３．７ｇのジクロロメタン溶液２０ｍｌ
を加え、一昼夜攪拌した。
反応液をろ過し、ろ液を減圧留去した後、クロロホルム
に溶解した。飽和炭酸水素ナトリウム水溶液で有機層を
洗いボウ硝乾燥した後、クロロホルムを減圧留去し、残
留物をシリカゲルクロマトグラフィーにて精製（溶離液
ジクロロメタン／酢酸エチル＝７／３）した後、酢酸エ
チルで再結晶しＢｏｃ−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓ
ｐ（ＯＢｚｌ）−ＮＨ−Ｃ１４Ｈ２９ １２．４ｇを得
た。
Ｂｏｃ−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）
−ＮＨ−Ｃ１４Ｈ２９ ２．０ｇをジクロロメタン、ト
リフルオロ酢酸混合液（２０ｍｌ／２０ｍｌ）に溶解し
３０分間攪拌した。
溶媒を減圧留去した後、クロロホルムに溶解し飽和炭酸
水素ナトリウム水溶液で処理して有機層をボウ硝乾燥し
た後、クロロホルムを減圧留去してＡｒｇ（Ｚ）２−Ｇ
ｌｙ−Ａｓｐ（ＯＢｚｌ）−ＮＨ−Ｃ１４Ｈ２９ １．
８ｇを得た。
ミリスチン酸０．４５ｇ、ジシクロヘキシルカルボジイ
ミド０．２３ｇをジクロロメタン５０ｍｌに溶解し、室
温で一時間撹拌した後にＡｒｇ（Ｚ）２−Ｇｌｙ−Ａｓ
ｐ（ＯＢｚｌ）−ＮＨ−Ｃ１４Ｈ２９ １．４ｇのジク
ロロメタン溶液３０ｍｌを加え、一昼夜攪拌した。
反応液をろ過し、ろ液を飽和炭酸水素ナトリウム水溶液
で洗いボウ硝乾燥した後、ジクロロメタンを減圧留去し
た。残留物をシリカゲルクロマトグラフィーにて精製（
溶離液ジクロロメタン／酢酸エチル＝６／４）した後、
クロロホルム、酢酸エチルで再結晶しＣ１３Ｈ２７ＣＯ
−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）−ＮＨ
−Ｃ１４Ｈ２９ １．７ｇを得た。
Ｃ１３Ｈ２７ＣＯ−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓｐ（
ＯＢｚｌ）−ＮＨ−Ｃ１４Ｈ２９５００ｍｇを酢酸７０
ｍｌに溶解し二酸化白金１５０ｍｇを加え加水素分解を
５０℃で行った。反応液をセライトにてろ過し、ろ液を
減圧濃縮した。残留物を酢酸、酢酸エチルにて再結晶し
、Ｃ１３Ｈ２７ＣＯ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−ＮＨ−
Ｃ１４Ｈ２９ ２２０ｍｇを得た。
実施例３
ペプチド脂質−１０の合成
（Ａｓｐ（ＯＢｚｌ）−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓ
ｐ（ＯＢｚｌ）−Ｏ−Ｃ１８Ｈ３７の合成）
Ｂｏｃ−アスパラギン酸−β−ベンジルエステル６．５
ｇ、オクタデシルアルコール５．４ｇ、ジシクロヘキシ
ルカルボジイミド４．６ｇ、ジメチルアミノピリジン０
．２４ｇ、をジクロロメタンに溶解し１０℃で一昼夜攪
拌した。反応液をろ過し、ろ液を減圧濃縮してシリカゲ
ルクロマトグラフィーにて精製（溶離液クロロホルム）
し、Ｂｏｃ−Ａｓｐ（ＯＢｚｌ）−Ｏ−Ｃ１８Ｈ３７
１０．３ｇを得た。
次に、Ｂｏｃ−Ａｓｐ（ＯＢｚｌ）−Ｏ−Ｃ１８Ｈ３７
１０．３ｇをジクロロメタン、トリフルオロ酢酸混合
液（２０ｍｌ／２０ｍｌ）に溶解し３０分間撹拌した。
溶媒を減圧留去した後、クロロホルムに溶解し、飽和炭
酸水素ナトリウム水溶液で処理して有機層をボウ硝乾燥
した後、クロロホルムを減圧留去してＡｓｐ（ＯＢｚｌ
）−Ｏ−Ｃ１８Ｈ３７ ８．２ｇを得た。
Ａｓｐ（ＯＢｚｌ）−Ｏ−Ｃ１８Ｈ３７ ８．２ｇジク
ロロメタン４０ｍｌに溶解し、Ｂｏｃ−グリシン無水物
１２．０ｇを加え一昼夜攪拌した。反応液を飽和炭酸水
素ナトリウム水溶液で洗いボウ硝乾燥した後、ジクロロ
メタンを減圧留去し、残留物をシリカゲルクロマトグラ
フィーにて精製（溶離液ジクロロメタン／酢酸エチル＝
６／４）してＢｏｃ−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）−Ｏ
−Ｃ１８Ｈ３７ １０．７ｇを得た。
次に、Ｂｏｃ−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）−Ｏ−Ｃ１
８Ｈ３７ １０．７ｇをジクロロメタン、トリフルオロ
酢酸混合液（２０ｍｌ／２０ｍｌ）に溶解し３０分間撹
拌した、。
溶媒を減圧留去した後、クロロホルムに溶解し飽和炭酸
水素ナトリウム水溶液で処理して有機層をボウ硝乾燥し
た後、クロロホルムを減圧留去してＧｌｙ−Ａｓｐ（Ｏ
Ｂｚｌ）−Ｏ−Ｃ１８Ｈ３７ ９．１ｇを得た。
Ｂｏｃ−Ａｒｇ（Ｚ）２ ９．１ｇ、１−ヒドロキシベ
ンゾトリアゾール２．５ｇ、Ｇｌｙ−Ａｓｐ（ＯＢｚｌ
）−Ｏ−Ｃ１８Ｈ３７ ８．８ｇのジクロロメタン、ジ
メチルホルムアミド混合液６０ｍｌにジシクロヘキシル
カルボジイミド３．４ｇのジクロロメタン溶液２０ｍｌ
を加え、一昼夜攪拌した。
反応液をろ過し、ろ液を減圧濃縮した後、クロロホルム
に溶解した。飽和炭酸水素ナトリウム水溶液で有機層を
洗いボウ硝乾燥した後、クロロホルムを減圧留去し、残
留物をシリカゲルクロマトグラフィーにて精製（溶離液
ジクロロメタン／酢酸エチル＝７／３）した後、酢酸エ
チルで再結晶し、Ｂｏｃ−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａ
ｓｐ（ＯＢｚｌ）−Ｏ−Ｃ１８Ｈ３７ １３．７ｇを得
た。
Ｂｏｃ−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）
−Ｏ−Ｃ１８Ｈ３７ １３．７ｇをジクロロメタン、ト
リフルオロ酢酸混合液（２０ｍｌ／２０ｍｌ）に溶解し
３０分間攪拌した。
溶媒を減圧留去した後、クロロホルムに溶解し、飽和炭
酸水素ナトリウム水溶液で処理して有機層をボウ硝乾燥
した後、クロロホルムを減圧留去してＡｒｇ（Ｚ）２−
Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）−Ｏ−Ｃ１８Ｈ３７１２．
４ｇを得た。
Ｂｏｃ−アスパラギン酸−β−ベンジルエステル４．２
ｇ、Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）−Ｏ
−Ｃ１８Ｈ３７１２．４ｇ、１−ヒドロキシベンゾトリ
アゾール２．９ｇをジクロロメタン５０ｍｌに溶解した
後に、ジシクロヘキシルカルボジイミド３．９ｇを加え
、一昼夜攪拌した。
反応液をろ過し、ろ液を飽和炭酸水素ナトリウム水溶液
で洗いボウ硝乾燥した後、ジクロロメタンを減圧留去し
た。残留物をシリカゲルクロマトグラフィーにて精製（
溶離液クロロホルム／酢酸エチル＝６／４）してＢｏｃ
−Ａｓｐ−（ＯＢｚｌ）−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａ
ｓｐ（ＯＢｚｌ）−Ｏ−Ｃ１８Ｈ３７１３．９ｇを得た
。
Ｂｏｃ−Ａｓｐ（ＯＢｚｌ）−Ａｒｇ（Ｚ）２−Ｇｌｙ
−Ａｓｐ（ＯＢｚｌ）−Ｏ−Ｃ１８Ｈ３７１３．９ｇを
ジクロロメタン、トリフルオロ酢酸混合液（２０ｍｌ／
２０ｍｌ）に溶解し３０分間攪拌した。
溶媒を減圧留去した後、クロロホルムに溶解し、飽和炭
酸水素ナトリウム水溶液で処理して有機層をボウ硝乾燥
した後、クロロホルムを減圧留去してＡｓｐ（ＯＢｚｌ
）−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）−Ｏ
−Ｃ１８Ｈ３７を１２．２ｇ得た。
（Ｃ１７Ｈ３５−ＣＯ−Ａｒｇ（Ｚ）２−Ｇｌｙ−の合
成）ステアリン酸５．６ｇ、ジシクロロヘキシルカルボ
ジイミド４．２ｇ、をジクロロメタン１００ｍｌに溶解
し室温で攪拌した、Ｎ−ヒドロキシスクシンイミド２．
３ｇを加え一昼夜攪拌した。反応液をろ過し、ろ液を水
で洗い、ボウ硝乾燥した後、ジクロロメタンを減圧留去
した。残留物をシリカゲルクロマトグラフィーにて精製
（溶離液ヘキサン／酢酸エチル８／２）した。続いて、
酢酸エチル／ヘキサン系にて分別結晶を行ない縮合剤転
移生成物を除き、ステアリン酸−Ｎ−ヒドロキシスクシ
ンイミドエステルを２．７ｇ得た。
ステアリン酸−Ｎ−ヒドロキシスクシンイミドエステル
２．７ｇ、Ａｒｇ（Ｚ）２−Ｇｌｙ３．５ｇ、ジメチル
アミノピリジン０．２ｇをジクロロメタンに溶解して一
昼夜攪拌した。反応液を飽和炭酸水素ナトリウム水溶液
、クエン酸水溶液で洗った後、ボウ硝乾燥した。残留物
をジクロロメタン／酢酸エチル系で再結晶してＣ１７Ｈ
３５ＣＯ−Ａｒｇ（Ｚ）２−Ｇｌｙ５．８ｇを得た。
（Ｃ１７Ｈ３５ＣＯ−（Ａｒｇ−Ｇｌｙ−Ａｓｐ）２−
Ｏ−Ｃ１８Ｈ３７の合成）上記で得たＣ１７Ｈ３５ＣＯ
−Ａｒｇ（Ｚ）２−Ｇｌｙ０．７５ｇＡｓｐ（ＯＢｚｌ
）−Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓｐ（ＯＢｚｌ）−Ｏ
−Ｃ１８Ｈ３７１．１６ｇ、シンクロヘキシルカルボジ
イミド２．１ｇ、１−ヒドロキシベンゾトリアゾール１
．５３ｇ、ジメチルアミノピリジン０．３ｇをジクロロ
メタン−ＤＭＦ混合液１００ｍｌに溶解して一昼夜攪拌
した、反応液を減圧留去して、残留物にジクロロメタン
を加え有機層を飽和炭酸水素ナトリウム水溶液、クエン
酸水溶液で洗いボウ硝乾燥した。ジクロロメタンを減圧
留去して残留物をシリカゲルクロマトグラフィーにて精
製（溶離液クロロホルム／酢酸エチル−４／６）した後
、ジクロロメタン−酢酸エチル系で再結晶し、
Ｃ１７Ｈ３５ＣＯ−（Ａｒｇ（Ｚ）２−Ｇｌｙ−Ａｓｐ
（ＯＢｚｌ））２−Ｏ′−Ｃ１８Ｈ３７を０．８５ｇ得
た。
Ｃ１７Ｈ３５ＣＯ−（Ａｒｇ（Ｚ）２−Ｇｌｙ−ＡＳＰ
（ＯＢｚｌ））２−Ｏ−Ｃ１８Ｈ３７０．５ｇを酢酸４
０ｍｌに溶解し５％パラジウム炭素２００ｍｇ、二酸化
白金２００ｍｇを加え、加水素分解（６５℃）を行ない
、Ｃ１７Ｈ３５ＣＯ−（Ａｒｇ−Ｇｌｙ−Ａｓｐ）２−
Ｏ−Ｃ１８Ｈ３７を０．０８ｇ得た。
実施例４ペプチド脂質−１４の合成
ファルネソール５０ｇをエタノール３５０ｍｌに溶解し
、二酸化白金５００ｍｇを加えて１２時間加水素分解を
行った。反応液をセライトを用いてろ過し、ろ液を減圧
濃縮して定量的に３，７，１１−トリメチルドデシルア
ルコールを得た。
３，７，１１−トリメチルドデシルアルコール１０ｇを
アセトンに溶解し、室温攪拌下Ｊｏｎｅｓ試薬（オーガ
ニック．シンセシス（Ｏｒｇ．Ｓｙｎｔｈｅｓｅｓ）、
Ｃｏｌ．第４巻３１０頁）を滴下した。反応液に酢酸エ
チルを加え、有機層を飽和食塩水で洗い、ホウ硝乾燥し
て減圧濃縮した。残留物をシリカゲルカラムクロマトに
より精製し（溶出液ヘキサン／酢酸エチル９／１）、３
，７，１１−トリメチルドデカン酸８．６ｇを得た。
Ｂｏｃ−Ｐｒｏ ２１．５ｇ、ジシクロヘキシルカルボ
ジイミド（ＤＣＣ）２０．６ｇ、３，７，１１−トリメ
チルドデシルアルコール２２．８ｇ、トリエチルアミン
１０．１ｇを用いて実施例１と同様にＤＣＣ縮合を行っ
た。反応液をろ過し、ろ液を減圧濃縮した。残留物をジ
クロロメタン５０ｍｌに溶解し、トリフルオロ酢酸５０
ｍｌを加えて３０分間攪拌した。
反応液を減圧濃縮した。
続いて実施例１と同様にして、ＤＣＣ−ａｄｄｉｔｉｖ
ｅ法、対称酸無水物法によりＢｏｃ−Ｓｅｒ（Ｂｚｌ）
、Ｂｏｃ−Ａｓｐ（ＯＢｚｌ）、Ｂｏｃ−グリシン無水
物、Ｂｏｃ−Ａｒｇ（Ｚ）２、Ｂｏｃ−グリシン無水物
を用いてペプチドを伸長し、３，７，１１−トリメチル
ドデカン酸と縮合し、５％−パラジウム炭素を用いて脱
保護を行った。
精製も実施例１と同様に再結晶法、イオン交換を行いペ
プチド脂質−１４を得た。
〔有用性〕
不発明の化合物は細胞移動抑制剤、細胞接着膜、細胞培
養基体として有用である。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a peptide lipid having a tripeptide unit of Arg-Gly-Asp, which is optimal for forming molecular aggregates such as ribosomes or micelles. [Prior Art] Fibronectin is a protein involved in cell-extracellular matrix adhesion, and is also thought to be involved in platelet aggregation and cancer metastasis. These interactions are mediated by a series of cell surface receptors, and these receptors are linked to arginine-glycine-aspartate (Ar) of fibronectin, a macromolecule with a molecular weight of approximately 250,000.
g-Gly-Asp or RGD) sequence, and has been reported to be important for interaction with the receptor (Nature (N
ature), Vol. 309, p. 30, 1984). Since then, research using oligos or polypeptides having the Arg-Gly-Asp sequence has been progressing. For example, a method of inhibiting platelet aggregation using various linear and cyclic oligopeptides having an Arg-Gly-Asp sequence (Proceedings of the Society of Polymer Science and Technology (PolymerPre
prints, Japan), Volume 38, Page 3149,
1989, JP-A-2-174797), Arg-G
Method of using a peptide having a ly-Asp sequence as a cell migration inhibitor (Japanese Patent Application Laid-Open No. 2-4716), Arg-G
Method of using PMMA membrane with immobilized ly-Asp as a cell adhesion membrane (Proceedings of the Society of Polymer Science and Technology (Polymer P
(Reprints, Japan), Vol. 37, p. 705, 1988). Furthermore, a method of covalently bonding a peptide having Arg-Gly-Asp as an essential constituent unit to a polymer and using it as an animal cell culture substrate or a biocomposite artificial organ substrate (Japanese Patent Application Laid-open Nos. 1-309682 and 1-305960); Arg-Gly-Asp-
A method of using a polypeptide having a Ser sequence as a platelet protective agent for extracorporeal blood has been disclosed (Japanese Patent Application Laid-Open No. 1986-1999).
No. 6217). In addition, a method of suppressing cancer metastasis using an oligopeptide having an Arg-Gly-Asp sequence or a polypeptide having a repeating structure thereof is known (International Journal of Biological Sciences).
Macromolecules (Int.J.Biol.Macr)
omol. ), vol. 11, p. 23, 1989, same magazine.
Volume 11, page 226, 1989, Japan Journal of Cancer Research (Jpn.J.Can
cerRes. ) Vol. 60, p. 722, 1989)
. On the other hand, many methods using molecular aggregates such as ribosomes and micelles as drug carriers have been investigated (e.g., Ribosomes, pp. 245-271, Nankodo, 198
8 years, Cancer Research (Cancer Res.
) Volume 43, page 5328, 1983, Journal of Controlled. Release (J.Control
ed Release) p. 269, 1990). However, Arg-
There are no known examples using a peptide lipid having a Gly-Asp sequence. [Problems to be Solved by the Invention] The purpose of the present invention is to provide a peptide-lipid derivative having a tripeptide unit of Arg-Gly-Asp, which is optimal for forming molecular aggregates such as ribosomes or micelles, and a method for synthesizing the same. It is to provide. [Means for Solving the Problems] The compound of the present invention is a synthetic peptide lipid represented by the following general formula [I] or a salt thereof. R1-([X]-Arg-Gly-Asp-[Y])n
-Z-R2...[I] In the formula, Arg, Gly, and Asp represent arginine, glycine, and aspartic acid residues, respectively. [X] and [Y] represent an amino acid residue that is present or absent, or a peptide residue consisting of two or three amino acid residues. If it exists, [X] [Y
] is Ser, Gly, Val, Asn, Pro, Cy
Preferred are amino acid residues selected from s and Thr, or peptide residues composed of a combination of these amino acid residues. In particular, [Y] is preferably Ser. Furthermore, it is particularly preferable that both [X] and [Y] are absent. Furthermore, [X] is Gly, [Y] is Ser
-Pro is also particularly preferred. Ser, Val,
Asn, Pro, Cys, and Thr represent serine, valine, asparagine, proline, cysteine, and threonine residues, respectively. n represents an integer of 1 to 5, particularly preferably 1 to 3. Z represents -O- or -NH-. In the present invention, the amino acid may be L-, D-, or racemic, but L-amino acids are preferred. R1 is a linear or branched acyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group. Preferably it has 12 to 18 carbon atoms. For example, preferred examples include myristoyl group, palmitoyl group, stearoyl group, 3,7,11,15-tetramethylhexadecanoyl group, and 3,7,11-trimethyldodecanoyl group. R2 is a straight chain or branched alkyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group. Preferably it has 12 to 18 carbon atoms. For example, myristyl group, palmityl group, stearyl group, phytyl group 3,7,11,1
Preferred examples include 5-tetramethylhexadecyl group and 3,7,11-trimethyldodecyl group. Examples of preferred salts include trifluoroacetate, hydrochloride,
Examples include acetate, sulfate, and lactate. Preferred specific examples of the present invention are shown below along with physical property values, but the present invention is not limited thereto. Peptide lipid-1 C13H27CO-Arg-Gly-Asp-O-C1
4H29FAB-MS (Pos.) (M+Na)+77
5(M+H)+753FAB-MS(Neg.)(M+
Na)-775(MH)-751 amino acid analysis: Ar
g 0.96, Gly 0.97, Asp 0.96,
Peptide lipid-2 C15H31CO-Arg-Gly-Asp-Ser-
O-C16H33FAB-MS (Pos.) (M+Na
)+918(M+H)+896FAB-MS(Neg.
)(M+Na)-918(MH)-894 Amino acid analysis: Arg 0.99, Gly 1.01, Asp 0
．． 95, Ser 0.79 Peptide lipid-3 C8H17CO-Gly-Arg-Gly-Asp-S
er-O-C10H21FAB-MS (Pos.) (M
+Na)+793(M+H)+771FAB-MS(N
eg. )(M+Na)-793(MH)-769 Amino acid analysis: Arg 0.98, Gly 2.17, As
p 0.92, Ser 0.76 Peptide lipid-4 C17H35CO-Cys-Arg-Gly-Asp-
Cys-O-C18H37FAB-MS (Pos.) (
M+Na)+1093(M+H)+1071FAB-M
S(Neg.)(M+Na)-1093(MH)-1
069 amino acid analysis: Arg 0.97, Gly 0.
92, Asp 0.82, Cys 1.71 Peptide lipid-5 C8H17CO-Gly-Arg-Gly-Asp-T
hr-O-C20H41FAB-MS (Pos.) (M
+Na)+947(M+H)+925FAB-MS(N
eg. )(M+Na)-947(MH)-923 Amino acid analysis: Arg 0.93, Gly 1.94, As
p 0.97, Thr 0.74 Peptide lipid-6 C13H27CO-Arg-Gly-Asp-NH-C
14H29FAB-MS (Pos.) (M+Na)+7
74(M+H)+752FAB-MS(Neg.)(M
+Na)-774(MH)-750 amino acid analysis: A
rg 0.99, Gly 0.95, Asp 0.91
, peptide lipid-7 C15H31CO-Arg-Gly-Asp-Ser-
NH-C16H33FAB-MS (Pos.) (M+N
a)+917(M+H)+895FAB-MS(Neg
．． )(M+Na)-917(MH)-893 Amino acid analysis: Arg 0.97, Gly 0.98, Asp
0.88, Ser 0.75 Peptide lipid-8 C17H35CO-Gly-Arg-Gly-Asp-
Thr-NH-C18H37FAB-MS (Pos.)
(M+Na)+1043(M+H)+1022FAB-
MS(Neg.)(M+Na)-1043(MH)-
1020 amino acid analysis: Arg 0.94, Gly 1
．． 84, Asp 0.92, Thr 0.72 Peptide lipid-9 FAB-MS (Pos.) (M+Na)+943 (M+
H)+921FAB-MS(Neg.)(M+Na)-
943(MH)-919 amino acid analysis: Arg 0.
99, Gly 0.95, Asp 0.96, Peptide lipid-10 C17H35CO(Arg-Gly-Asp)2-O-
C18H37FAB-MS (Pos.) (M+Na)+
1215(M+H)+1193FAB-MS(Neg.
)(M+Na)-1215(MH)-1191 Amino acid analysis: Arg 1.99, Gly 1.94, Asp
1.92, peptide lipid-11 C13H27CO-(Arg-Gly-Asp-Ser
) 2-NH-C14H29FAB-MS (Pos.) (
M+Na)+1276(M+H)+1254FAB-M
S(Neg.)(M+Na)-1276(MH)-1
252 amino acid analysis: Arg 1.92, Gly 1.
95, Asp 1.79, Ser 1.53 Peptide lipid-12 C15H31CO-(Arg-Gly-Asp)3-O
-C16H33FAB-MS (Pos.) (M+Na)
+1487(M+H)+1465FAB-MS(Neg
．． )(M+Na)-1487(MH)-1463 Amino acid analysis: Arg 3.03, Gly 2.81, As
p 3.01, peptide lipid-13 C9H19CO-Arg-Gly-Asp-Ser-P
ro-NH-C10H21FAB-MS (Pos.) (
M+H)+825FAB-MS(Neg.)(M+H)
-823 Peptide Lipid-14 FAB-MS (Pos.) (M+H)+1022FAB
-MS(Neg.)(M+H)-1020 The compound of the present invention can be synthesized, for example, by the following four-step process. ■ Condensation of a protected amino acid with R2-Z-H (R2 is a corresponding alkyl group, Z represents -O- or -NH-) ■ Sequential stretching of a protected amino acid ■ Condensation with R1-W (R1 is This represents a corresponding acyl group. W represents a hydroxyl group or a halogen atom.) (1) Deprotection and purification Each step of the process will be explained in detail below. ■In the case of the compound represented by the general formula [I], the protected form of the amino acid represented by Y or, if Y does not exist, the protected form of Asp and the corresponding R2-Z-H are condensed to form an ester or amide. . Regarding condensation, DCC method, DCC-additive
General methods such as the method and CDI method are adopted. ■There are known methods for sequentially elongating protected amino acids, such as "Basics and Experiments of Peptide Synthesis" edited by Izumiya et al.
Maruzen) and “PRINCIPLES” by Bodanszky.
OF PEPTIDE SYNTHESIS“THE
PRACTICE OF PEPTIDE SYNTH
SIS” (Springer Verlag, New Y
All of the methods described in (ork) are effective. At the stage of condensation reaction, DCC method, DCC-additi
Any of the ve method, azide method, CDI method, mixed acid anhydride method, and activated ester method may be employed, but the DCC-HOBt method using 1-hydroxybenzotriazole (HOBt) and DCC in combination is preferred. ■ Corresponding R1-OH and ([X]-Arg-Gly-A
The methods for condensing with sp-[Y])n-Z-R2 include DCC method, DCC-additive method, CDI method,
Either one may be adopted. Further, amidation may be performed by changing R1-OH to an acid chloride such as R1-Cl. Regarding peptide lipids with many amino acid residues, R1
-, R2-Z- It is preferable to perform sequential peptide elongation from both ends and perform fragment condensation. This condensation method follows method (2) above. ■The conditions used to deprotect a protecting group are highly dependent on the type of protecting group used. Commonly used deprotection methods include hydrolysis, trifluoroacetic acid, anhydrous hydrogen fluoride, trifluoromethanesulfonic acid-thioanisole mixed system, trifluoroacetic acid-thioanisole mixed system, etc., but depending on the type of protecting group. Even more diverse methods are possible. Below, peptide lipid-2 and peptide lipid-6 of the present invention
and peptide lipid-10, but the synthesis method of the present invention is not limited thereto. In addition, the peptide lipids (1) - (12) shown as preferred specific examples of the compounds of the present invention are R1 corresponding to the corresponding Boc-amino acids in which the amino acid side chain is protected with benzyl ether, benzyl thioether or benzyl ester.
-OH and the corresponding R2-OH or R2-NH2
can be synthesized in the same manner as in the synthesis example shown below. Example 1 Synthesis of Peptide Lipid-2 5.9 g of Boc-serine benzyl ether, 4.8 g of hexadecyl alcohol (Catechol 60, Kao product), 4.6 g of dicyclohexylcarbodiimide, and 0.24 g of dimethylaminopyridine were dissolved in dichloromethane. 10
The mixture was stirred at ℃ overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel chromatography (eluent: chloroform) to obtain Boc-Ser(Bzl)-OC16.
10.3 g of H33 was obtained. Next, Boc-Ser(Bzl)-OC16H33 1
0.3g of dichloromethane and trifluoroacetic acid mixture (
20ml/20ml) and stirred for 30 minutes. After the solvent was distilled off under reduced pressure, it was dissolved in chloroform, treated with a saturated aqueous sodium bicarbonate solution, and the organic layer was dried with sulfur salt.The chloroform was distilled off under reduced pressure to obtain Ser(Bzl).
-OC16H33 9.3g was obtained. Boc-aspartic acid-β-benzyl ester 7.1
g, Ser(Bzl)-OC16H33 9.3g, 1
4.9 g of dicyclohexylcarbodiimide was added to 60 ml of a mixed solution of 3.7 g of -hydroxybenzotriazole in dichloromethane and dimethylformamide, and the mixture was stirred all day and night. The reaction solution was filtered, the filtrate was distilled off under reduced pressure, and then dissolved in chloroform. After washing the organic layer with a saturated aqueous sodium bicarbonate solution and drying it over salt water, chloroform was distilled off under reduced pressure.
The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate = 6/4) to obtain Boc-Asp.
(OBzl)-Ser(Bzl)-OC16H33 1
4.2g was obtained. Then Boc-Asp(OBzl)-Ser(Bzl)
-Dissolve 14.2 g of OC16H33 in dichloromethane and trifluoroacetic acid mixture (20 ml/20 ml) and
Stirred for 0 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform and treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried over sulfur salt.The chloroform was distilled off under reduced pressure to obtain Asp(OBzl).
-Ser(Bzl)-OC16H33 13.5g was obtained. Asp(OBzl)-Ser(Bzl)-OC16H3
3 Dissolve 13.5g in dichloromethane 50ml,
8.7 g of oc-glycine anhydride was added and stirred overnight.
The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried with Boc-Gly. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent dichloromethane/ethyl acetate = 6/4) to obtain Boc-Gly. -Asp(OBzl)-Ser(Bzl
)-OC16H33 11.8g was obtained. Next, Boc-Gly-Asp(OBzl)-Ser(
Bzl)-OC16H3311.8g was dissolved in a dichloromethane/trifluoroacetic acid mixture (20ml/20ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform and treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with sulfur salt. The chloroform was distilled off under reduced pressure to give Gly-Asp(O
Bzl)-Ser(Bzl)-OC16H33 10.
2g was obtained. Boc-Arg(Z)2 8.4g, 1-hydroxybenzotriazole 2.4g, Gly-Asp(OBzl
)-Ser(Bzl)-OC16H33 10.2g dichloromethane, dimethylformamide mixture 60ml
20 ml of a dichloromethane solution containing 3.2 g of dicyclohexylcarbodiimide was added to the mixture, and the mixture was stirred all day and night. The reaction solution was filtered, the filtrate was distilled off under reduced pressure, and then dissolved in chloroform. After washing the organic layer with a saturated aqueous solution of sodium hydrogen carbonate and drying with sulfur salt, chloroform was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent dichloromethane/ethyl acetate = 6/4), and then purified with ethyl acetate. Recrystallized Boc-Arg(Z)2-Gly-As
p(OBzl)-Ser(Bzl)-OC16H336
．． 6g was obtained. Boc-Arg(Z)2-Gly-Asp(OBzl)
-Ser(Bzl)-OC16H332.0g Dichloromethane, trifluoroacetic acid mixture (20ml/20ml
) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform and treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with sulfur salt.The chloroform was distilled off under reduced pressure to obtain Arg(Z)2-G.
ly-Asp(OBzl)-Ser(Bzl)-OC1
1.5 g of 6H33 was obtained. After dissolving 0.56 g of palmitic acid and 0.23 g of dicyclohexylcarbodiimide in 50 ml of dichloromethane and stirring at room temperature for 1 hour, Arg(Z)2-Gly-A
sp(OBzl)-Ser(Bzl)OC16H33
30 ml of a dichloromethane solution containing 1.1 g was added, and the mixture was stirred all day and night. The reaction solution was filtered, the filtrate was washed with a saturated aqueous sodium bicarbonate solution and dried over salt water, and then dichloromethane was distilled off under reduced pressure. The residue was purified by silica gel chromatography (
Eluent chloroform/ethyl acetate = 5/5), then recrystallized from chloroform and ethyl acetate to obtain C15H31CO
-Arg(Z)2-Gly-Asp(OBzl)-Se
1.3 g of r(Bzl)-OC16H33 was obtained. C15H31Co-Arg(Z)2-Gly-Asp(
OBzl)-Ser(Bzl)-OC16H33 50
0 mg was dissolved in 70 ml of acetic acid, 150 mg of platinum dioxide was added, and hydrolysis was performed at 50°C. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from acetic acid and ethyl acetate to give C15H31C
O-Arg-Gly-Asp-Ser-OC16H33
260 mg was obtained. Example 2 Synthesis of Peptide Lipid-6 Boc-aspartic acid-β-benzyl ester 6.5
g, 1-tetradecylamine 4.3g, 1-hydroxybenzotriazole 3.1g, dicyclohexylcarbodiimide 4.6g, dimethylaminopyridine 0.24g
was dissolved in dichloromethane and stirred at 10°C overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel chromatography (eluent: chloroform).
c-Asp(OBzl)-NH-C14H29 9.7
I got g. Next, Boc-Asp(OBzl)-NH-C14H2
9.7 g was dissolved in dichloromethane and trifluoroacetic acid mixture (20 ml/20 ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform, treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with salt water.
)-NH-C14H29 9.3g was obtained. 9.3 g of Asp(OBzl)-NH-C14H29 was dissolved in 40 ml of dichloromethane, 10.0 g of Boc-glycine anhydride was added, and the mixture was stirred all day and night. After washing the reaction solution with a saturated aqueous solution of sodium hydrogen carbonate and drying the dichloromethane under reduced pressure, the residue was purified by silica gel chromatography (eluent dichloromethane/ethyl acetate = 6/4) to obtain Boc-Gly- Asp(OBzl)
-NH-C14H29 9.1g was obtained. Next, Boc-Gly-Asp(OBzl)-NH-C
9.1 g of 14H29 was dissolved in a mixture of dichloromethane and trifluoroacetic acid (20 ml/20 ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform and treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with sulfur salt. The chloroform was distilled off under reduced pressure to give Gly-Asp(O
8.8 g of Bzl)-NH-C14H29 was obtained. Boc-Arg(Z)2 9.5g, 1-hydroxybenzotriazole 2.8g, Gly-Asp(OBzl
)-NH-C14H 298.8 g of dichloromethane and 60 ml of dimethylformamide mixture to 20 ml of dichloromethane solution of 3.7 g of dicyclohexylcarbodiimide
was added and stirred overnight. The reaction solution was filtered, the filtrate was distilled off under reduced pressure, and then dissolved in chloroform. After washing the organic layer with a saturated aqueous solution of sodium hydrogen carbonate and drying with sulfur salt, chloroform was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent dichloromethane/ethyl acetate = 7/3), and then purified with ethyl acetate. Recrystallized Boc-Arg(Z)2-Gly-As
12.4 g of p(OBzl)-NH-C14H29 was obtained. Boc-Arg(Z)2-Gly-Asp(OBzl)
-NH-C14H29 2.0g was dissolved in dichloromethane and trifluoroacetic acid mixture (20ml/20ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform and treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with sulfur salt.The chloroform was distilled off under reduced pressure to obtain Arg(Z)2-G.
ly-Asp(OBzl)-NH-C14H29 1.
8g was obtained. 0.45 g of myristic acid and 0.23 g of dicyclohexylcarbodiimide were dissolved in 50 ml of dichloromethane, and after stirring at room temperature for 1 hour, Arg(Z)2-Gly-As
A solution of 1.4 g of p(OBzl)-NH-C14H29 in 30 ml of dichloromethane was added, and the mixture was stirred all day and night. The reaction solution was filtered, the filtrate was washed with a saturated aqueous sodium bicarbonate solution and dried over salt water, and then dichloromethane was distilled off under reduced pressure. The residue was purified by silica gel chromatography (
After eluent dichloromethane/ethyl acetate = 6/4),
Recrystallize from chloroform and ethyl acetate to obtain C13H27CO
-Arg(Z)2-Gly-Asp(OBzl)-NH
-C14H29 1.7g was obtained. C13H27CO-Arg(Z)2-Gly-Asp(
OBzl)-NH-C14H29500mg to acetic acid 70
ml, and 150 mg of platinum dioxide was added thereto, followed by hydrogenolysis at 50°C. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from acetic acid and ethyl acetate to give C13H27CO-Arg-Gly-Asp-NH-
220 mg of C14H29 was obtained. Example 3 Synthesis of peptide lipid-10 (Asp(OBzl)-Arg(Z)2-Gly-As
Synthesis of p(OBzl)-O-C18H37) Boc-aspartic acid-β-benzyl ester 6.5
g, octadecyl alcohol 5.4 g, dicyclohexylcarbodiimide 4.6 g, dimethylaminopyridine 0
．． 24g was dissolved in dichloromethane and stirred at 10°C all day and night. Filter the reaction solution, concentrate the filtrate under reduced pressure, and purify with silica gel chromatography (eluent: chloroform).
Boc-Asp(OBzl)-O-C18H37
10.3g was obtained. Next, Boc-Asp(OBzl)-O-C18H37
10.3 g was dissolved in a dichloromethane/trifluoroacetic acid mixture (20 ml/20 ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform, treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with salt water.
)-O-C18H37 8.2g was obtained. 8.2 g of Asp(OBzl)-O-C18H37 was dissolved in 40 ml of dichloromethane, 12.0 g of Boc-glycine anhydride was added, and the mixture was stirred all day and night. After washing the reaction solution with a saturated aqueous sodium hydrogen carbonate solution and drying it with salt water, dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent dichloromethane/ethyl acetate=
6/4) and Boc-Gly-Asp(OBzl)-O
-C18H37 10.7g was obtained. Next, Boc-Gly-Asp(OBzl)-O-C1
10.7 g of 8H37 was dissolved in a dichloromethane/trifluoroacetic acid mixture (20 ml/20 ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform and treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with sulfur salt. The chloroform was distilled off under reduced pressure to give Gly-Asp(O
9.1 g of Bzl)-O-C18H37 was obtained. Boc-Arg(Z)2 9.1g, 1-hydroxybenzotriazole 2.5g, Gly-Asp(OBzl
)-O-C18H37 A solution of 3.4 g of dicyclohexylcarbodiimide in 20 ml of dichloromethane in 60 ml of a mixture of 8.8 g of dichloromethane and dimethylformamide.
was added and stirred overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and then dissolved in chloroform. After washing the organic layer with a saturated aqueous solution of sodium hydrogen carbonate and drying with sulfur salt, chloroform was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent dichloromethane/ethyl acetate = 7/3), and then purified with ethyl acetate. Recrystallize to form Boc-Arg(Z)2-Gly-A
13.7 g of sp(OBzl)-O-C18H37 was obtained. Boc-Arg(Z)2-Gly-Asp(OBzl)
13.7 g of -O-C18H37 was dissolved in a dichloromethane/trifluoroacetic acid mixture (20 ml/20 ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform, treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with sulfur salt.The chloroform was distilled off under reduced pressure to obtain Arg(Z)2-
Gly-Asp(OBzl)-O-C18H3712.
4g was obtained. Boc-aspartic acid-β-benzyl ester 4.2
g, Arg(Z)2-Gly-Asp(OBzl)-O
After dissolving 12.4 g of -C18H3 and 2.9 g of 1-hydroxybenzotriazole in 50 ml of dichloromethane, 3.9 g of dicyclohexylcarbodiimide was added and stirred all day and night. The reaction solution was filtered, the filtrate was washed with a saturated aqueous sodium bicarbonate solution and dried over salt water, and then dichloromethane was distilled off under reduced pressure. The residue was purified by silica gel chromatography (
Eluent chloroform/ethyl acetate = 6/4) and Boc
-Asp-(OBzl)-Arg(Z)2-Gly-A
713.9 g of sp(OBzl)-O-C18H3 was obtained. Boc-Asp(OBzl)-Arg(Z)2-Gly
-Asp(OBzl)-O-C18H3713.9g was mixed with dichloromethane and trifluoroacetic acid mixture (20ml/
20 ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform, treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with salt water.
)-Arg(Z)2-Gly-Asp(OBzl)-O
12.2g of -C18H37 was obtained. (Synthesis of C17H35-CO-Arg(Z)2-Gly-) N-hydroxysuccinimide 2.5.6 g of stearic acid and 4.2 g of dicyclohexylcarbodiimide were dissolved in 100 ml of dichloromethane and stirred at room temperature.
3 g was added and stirred all day and night. The reaction solution was filtered, and the filtrate was washed with water and dried over salt water, and then dichloromethane was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent hexane/ethyl acetate 8/2). continue,
Fractional crystallization was performed in an ethyl acetate/hexane system to remove the condensing agent transfer product to obtain 2.7 g of stearic acid-N-hydroxysuccinimide ester. 2.7 g of stearic acid-N-hydroxysuccinimide ester, 3.5 g of Arg(Z)2-Gly, and 0.2 g of dimethylaminopyridine were dissolved in dichloromethane and stirred overnight. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution and an aqueous citric acid solution, and then dried over sulfate. The residue was recrystallized from dichloromethane/ethyl acetate system to obtain C17H.
5.8 g of 35CO-Arg(Z)2-Gly was obtained. (C17H35CO-(Arg-Gly-Asp)2-
Synthesis of O-C18H37) C17H35CO obtained above
-Arg(Z)2-Gly0.75gAsp(OBzl
)-Arg(Z)2-Gly-Asp(OBzl)-O
-C18H371.16g, synchhexylcarbodiimide 2.1g, 1-hydroxybenzotriazole 1
．． 53 g of dimethylaminopyridine and 0.3 g of dimethylaminopyridine were dissolved in 100 ml of dichloromethane-DMF mixture and stirred overnight. The reaction solution was distilled off under reduced pressure, dichloromethane was added to the residue, and the organic layer was dissolved in a saturated aqueous sodium bicarbonate solution and a citric acid aqueous solution. Washed with salt and dried. Dichloromethane was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent chloroform/ethyl acetate - 4/6), then recrystallized from dichloromethane-ethyl acetate system to obtain C17H35CO-(Arg(Z)2- Gly-Asp
(OBzl)) 0.85 g of 2-O'-C18H37 was obtained. C17H35CO-(Arg(Z)2-Gly-ASP
(OBzl)) 370.5g of 2-O-C18H was dissolved in acetic acid 4
0 ml, add 200 mg of 5% palladium on carbon and 200 mg of platinum dioxide, and perform hydrolysis (65°C) to obtain C17H35CO-(Arg-Gly-Asp)2-
0.08g of O-C18H37 was obtained. Example 4 Synthesis of Peptide Lipid-14 50 g of farnesol was dissolved in 350 ml of ethanol, 500 mg of platinum dioxide was added, and hydrolysis was carried out for 12 hours. The reaction solution was filtered using Celite, and the filtrate was concentrated under reduced pressure to quantitatively obtain 3,7,11-trimethyldodecyl alcohol. 10 g of 3,7,11-trimethyldodecyl alcohol was dissolved in acetone, and Jones reagent (Org.Syntheses) was added under stirring at room temperature.
Col. Volume 4, page 310) was added dropwise. Ethyl acetate was added to the reaction solution, and the organic layer was washed with saturated brine, dried over borax, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent hexane/ethyl acetate 9/1),
, 8.6 g of 7,11-trimethyldodecanoic acid was obtained. DCC condensation was performed in the same manner as in Example 1 using 21.5 g of Boc-Pro, 20.6 g of dicyclohexylcarbodiimide (DCC), 22.8 g of 3,7,11-trimethyldodecyl alcohol, and 10.1 g of triethylamine. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Dissolve the residue in 50 ml of dichloromethane and add 50 ml of trifluoroacetic acid.
ml was added and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure. Subsequently, in the same manner as in Example 1, DCC-additive
Boc-Ser (Bzl) by e method, symmetric acid anhydride method
, Boc-Asp(OBzl), Boc-glycine anhydride, Boc-Arg(Z)2, Boc-glycine anhydride and condensation with 3,7,11-trimethyldodecanoic acid, 5% -Deprotection was performed using palladium on carbon. Purification was carried out in the same manner as in Example 1 by recrystallization and ion exchange to obtain peptide lipid-14. [Utility] The uninvented compound is useful as a cell migration inhibitor, a cell adhesion membrane, and a cell culture substrate.
Claims (4)
ド 脂質またはその塩。 Ｒ１−（〔Ｘ〕−Ａｒｇ−Ｇｌｙ−Ａｓｐ−〔Ｙ〕）ｎ
−Ｚ−Ｒ２…〔Ｉ〕式中、Ａｒｇ、Ｇｌｙ、Ａｓｐはそ
れぞれアルギニン、グリシン、アスパラギン酸残基を示
す。 〔Ｘ〕、〔Ｙ〕は、存在するかあるいは存在しないアミ
ノ酸残基または、二つあるいは三つのアミノ酸残基から
なるペプチド残基を示す。 ｎは１〜５の整数を示す。Ｚは−Ｏ−または−ＮＨ−を
示す。 Ｒ１は炭素数８〜２４の直鎖または分岐のアシル基であ
り、置換基、不飽和基を有していてもよい。Ｒ２は炭素
数８〜２４の直鎖または分岐のアルキル基であり、置換
基、不飽和基を有していてもよい。Claims 1: A synthetic peptide lipid represented by the following general formula [I] or a salt thereof. R1-([X]-Arg-Gly-Asp-[Y])n
-Z-R2...[I] In the formula, Arg, Gly, and Asp represent arginine, glycine, and aspartic acid residues, respectively. [X] and [Y] represent an amino acid residue that is present or absent, or a peptide residue consisting of two or three amino acid residues. n represents an integer of 1 to 5. Z represents -O- or -NH-. R1 is a linear or branched acyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group. R2 is a straight chain or branched alkyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group.
または、二つあるいは三つのアミノ酸残基からなるペプ
チド残基を示し、〔Ｘ〕、〔Ｙ〕は、Ｓｅｒ、Ｇｌｙ、
Ｖａｌ、Ａｓｎ、Ｐｒｏ、Ｃｙｓ、Ｔｈｒから選択され
るアミノ酸で残基または、これらのアミノ酸残基の組み
合わせにより構成されるペプチド残基である請求項（１
）記載の合成ペプチド脂質。Ｓｅｒ、Ｖａｌ、Ａｓｎ、
Ｐｒｏ、Ｃｙｓ、Ｔｈｒはそれぞれセリン、バリン、ア
スパラギン、プロリン、システイン、トレオニン残基を
示す。[Claim 2] [X] and [Y] represent existing amino acid residues or peptide residues consisting of two or three amino acid residues, and [X] and [Y] represent Ser, Gly,
Claim (1) is a peptide residue composed of an amino acid residue selected from Val, Asn, Pro, Cys, and Thr or a combination of these amino acid residues.
) Synthetic peptide lipids described in ). Ser, Val, Asn,
Pro, Cys, and Thr represent serine, valine, asparagine, proline, cysteine, and threonine residues, respectively.
載の合成ペプチド脂質。 Ｒ１−（Ａｒｇ−Ｇｌｙ−Ａｓｐ−Ｓｅｒ）ｎ−Ｚ−Ｒ
２…〔ＩＩ〕式中、ｎは１〜５の整数を示し、Ｚは−Ｏ
−または−ＮＨ−を示す。 Ｒ１は炭素数８〜２４の直鎖または分岐のアシル基であ
り、置換基、不飽和基を有していてもよい。Ｒ２は炭素
数８〜２４の直鎖または分岐のアルキル基であり、置換
基、不飽和基を有していてもよい。3. The synthetic peptide lipid according to claim 1, which is represented by the following formula [II]. R1-(Arg-Gly-Asp-Ser)n-Z-R
2... [II] In the formula, n represents an integer of 1 to 5, and Z is -O
- or -NH-. R1 is a linear or branched acyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group. R2 is a straight chain or branched alkyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group.
記載の合成ペプチド脂質。 Ｒ１−（Ａｒｇ−Ｇｌｙ−Ａｓｐ）ｎ−Ｚ−Ｒ２…．〔
ＩＩＩ〕式中、ｎは１〜５の整数を示し、Ｚは−Ｏ−ま
たは−ＮＨ−を示す。 Ｒ１は炭素数８〜２４の直鎖または分岐のアシル基であ
り、置換基、不飽和基を有していてもよい。Ｒ２は炭素
数８〜２４の直鎖または分岐のアルキル基であり、置換
基、不飽和基を有していてもよい。Claim 4: Claim (1) represented by the following formula [III]
The synthetic peptide lipids described. R1-(Arg-Gly-Asp)n-Z-R2.... [
III] In the formula, n represents an integer of 1 to 5, and Z represents -O- or -NH-. R1 is a linear or branched acyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group. R2 is a straight chain or branched alkyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2333336A JPH04221395A (en) | 1990-10-26 | 1990-11-29 | Peptide lipid |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28949490 | 1990-10-26 | ||
| JP2-289494 | 1990-10-26 | ||
| JP2333336A JPH04221395A (en) | 1990-10-26 | 1990-11-29 | Peptide lipid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04221395A true JPH04221395A (en) | 1992-08-11 |
Family
ID=26557619
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2333336A Pending JPH04221395A (en) | 1990-10-26 | 1990-11-29 | Peptide lipid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04221395A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5670483A (en) * | 1992-12-28 | 1997-09-23 | Massachusetts Insititute Of Technology | Stable macroscopic membranes formed by self-assembly of amphiphilic peptides and uses therefor |
| WO2004087106A1 (en) * | 2003-03-31 | 2004-10-14 | Fujirebio Inc. | Method of controlling release speed of subject to be transported from liposome |
| WO2017217855A1 (en) * | 2016-06-17 | 2017-12-21 | Erasmus University Medical Center Rotterdam | Geminoid lipopeptide compounds and their uses |
-
1990
- 1990-11-29 JP JP2333336A patent/JPH04221395A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5670483A (en) * | 1992-12-28 | 1997-09-23 | Massachusetts Insititute Of Technology | Stable macroscopic membranes formed by self-assembly of amphiphilic peptides and uses therefor |
| WO2004087106A1 (en) * | 2003-03-31 | 2004-10-14 | Fujirebio Inc. | Method of controlling release speed of subject to be transported from liposome |
| WO2017217855A1 (en) * | 2016-06-17 | 2017-12-21 | Erasmus University Medical Center Rotterdam | Geminoid lipopeptide compounds and their uses |
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