CS271083B1 - Method of formyl-l-peptides winning - Google Patents

Method of formyl-l-peptides winning Download PDF

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CS271083B1
CS271083B1 CS862351A CS235186A CS271083B1 CS 271083 B1 CS271083 B1 CS 271083B1 CS 862351 A CS862351 A CS 862351A CS 235186 A CS235186 A CS 235186A CS 271083 B1 CS271083 B1 CS 271083B1
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formyl
phe
ala
general formula
peptides
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CS862351A
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Czech (cs)
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CS235186A1 (en
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Valentin M Stepanov
Ljudmila A Ljublinskaja
Svetlana J Bojcova
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Valentin M Stepanov
Ljudmila A Ljublinskaja
Svetlana J Bojcova
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Abstract

This solution concerns substituted peptides, particularly N-formyl-L-peptides of the general formula: I : R - A - B - X, where R - formyl, A - Asp, Met, Ala-Ala, Phe; B - Phe, Leu; X -methyl - HN-C6H4 - n - NO2 which can be used in experimental biochemistry and medicine. "I" synthesis is carried out by condensation of N-formyl-substituted carboxylate composition (KK) of the general formula: R-A-OH with amine composition of the general formula: H-B-X, where R, A, B and X are introduced above, substituted in a carboxylate group. The process is done in the presence of (2.10<5>) up to (1.10<4>) mmol of metalloproteinase Bac. thermoproteolyticus per 1 mmol KK at pH 6.5 up to 8.0, at a temperature of 15 to 37 degrees Celsius in aqueous or water N,N-dimethylformamide atmosphere under a molar ratio at the amine composition and KK equal 1:1 to 2.

Description

i 271 083 OMfCAIlHE H30GPETEIIHÍI K ADTOPCKOMy CBHflETEJIIiCTBy 3aHBKa= No. 3855631 3aíiBjieno: 15.02.85 MKH4s CI2P 21/02

Abtopu: n.M.CTerienoB. JI. A. JIweJiHiiCKaíi h C. E. GoRiiobíi

3a«BHTeJii.: Bcccoio3iiuh nay*ino-HccjieaciBaTejibcKHH HHCTH-ryT reiieTHKH h ceJieKUHH npoMMuiJieiiiibixMHKpOOpralIHSMOB

HajBaHHe H3O<-.[’HTI?HHSI: CnOCOG nanyiEIIHSI Ν-ΦΠΡΜΗΛ-Ε-ΠΕΠΤΗΛΟΒ Μ3οβρβτκΗΗβ otiiochtcsi κ ycoBepuieHCTBoBaimoMy cnocoey nojiy*ieiiH$i Ν-φορμηλ-L -ποπτηλοβoeuieft «opMyjiu

Eor - Λ-Β-Χ ΓΛβ Eor - ΦΟρΜΗΛΙ A - Asp. Met. Ala-Ala. Phe; D - Phe. Leu. X - MeTHJi. - IIN - NO2 . KOTopue MoryT iiaňTH npHMeiieiiHe b 3KcnepHMeiiTajn.noň shoxhmhh η μθληκηκο.

Uej|ž> ιοοβρΕΤβιΐΗϋ - noBuuieHHe euxoaa h pacuiHpeiiHe accopTHMeiiTa Ν-φορμηλ-L - πβτΗΛΟΒ.roMoreHHOCTt kohciiiux coeziHiieiiHfí npoDepnioT c noMouibn tohkocjioKiioH xpoMaTaorpa«HH 11a n-nacTHHKax "CHJiyeoji" <'ICCP) a cncTeMax: 1 - 11 - eyTaiioji - πηρηληη - Boaa - yxcycHan KHcjioTa. 15 = 10:12:3; 2-neTaHOji - xjiopo«opM. 3 = 7. yrjiu BpauteHHX onpeaejixuT Ha cneKTponoasipHMeTpe “llllger'' (AurjiHX).

AmhhokhcjiotiiuR aiiajiHa BunoJiiisiioT na aMHtioKHCJioTiioM aHaJiH3aTope Diirrum D-500 (CIUA) nocjierHApojiHsa nenTHBa b TeneiiHe 24 "lacoa o 3anasuinoíí axnyjfe c 5.7 11. IICI πρη 110°C. B cHHTeae HcnojiboyioT MeTaJiJiciiipOTeHiiaay Bac. thermoproteolytlcus φηρμη “Ierva" (ΦΡΓ) -

TepMOJIH3Hll. H3O<speneiiHe HjuuocTPHpyeTCa cjieaynuiHMH HPHMepaMH.npHMep 1. Π -ΗΗΤΡΟβΗΗΛΗΛ - N -♦OPMHJI-L-MeTHOHHJI-L-J«eňUHHa<l ).

Cxecb 0.354 r. (2 mmojib) Ν-φορμηλ- L -ΜβτΗΟΗΗΗβ H 0,502 r (2 MMOJib) π -HHTpoaiiHJiHaa L-JieňuHiia pacTBOpsusT b 1.5 mji AHMeTHjieopMaMHAa (ΑΜΦΑ). npx nepeMeuiHBaHHH MeajieHHO npHeaejisnoTp5,0 mji 5.10-2M pacTBopa xJiopHCToro KajibUHSi. λοβθλθιιηογο λο pH 7.1 0.1 li. NaOH, h 3aTeM πρηnepeHeuiHBaiiHH aoaaBJínnT 5 μγ (l.SS.lO-^MHoab) TepMojiHOHiia. PeaKUHOHHyu cMecb nepeMeuiHoaioT 6 <iπρη 20°C h ocTaeJisiiOT na no*ib B xojiOAHJibHHKe. OunaBiUHň ecaaox οτΦΗ-nbTpOBwnaioT προμμβλιοτ 0.5H.llCl (2 x 0.5 mji). eoaoň <2 x 0.5 mji). 0.5 H.NalIC03<2 x 0.5 mji). βολοΑ <2 x 0.5 mji) h cyuiaTb BaxyyMe. nojiy'ia»T 0,784 r (95.5¾) coeaHHeiiHsi 1 c TOMiiepaTypoií nJiaBJíeiiHsi 164°C. Rí0.77 (1), 0.54 (2); í eó i£e “+5.5° <c 0.5; ΛΜΦΛ). AmhhokhcjiotiiuH aitaJiHa: Met 0.89 (1): Leu 1,1’. (1).

IlpHMepu 2-4 ocytuecTBJísiioT aiiajiorHHHo npHMepy 1 c τβΜ οτ-ιτημμηθμ hto HCxoaHasi meči. coaepwHT 0.63 MMOJib Ν-φορμηλ- L -MeTHOHHHa h 0.63 mmojib n—HHTpoaHHJiHaa L-JieňuHna b 0.6 mjiΑΜΦΑ h 2.0 mji 0.1 M UHTpaTiioro eyeepa. a τθρμιμιη3ηη eepyT b KOJiH»iecTBe 2.5 μγ<0.63.10~'4MMOJib) h cxecb BuaepiMHBaiDT 2 xaca πρη 20°C. ΠρΗΜβρω 5-9 ocyiuecTBJíHMT anajiortriHO npHMepy 1 c τθμ οτληηηθμ. hto Hcxoanan peaKUHomiasi CMecb coaepxiHT 0,63 mmojib Ν-φορμηλ- L-MeTHoiiHiia h 0,63 mmojib n-iiHTpoatiHJiHaa L-jieHunna b 2.0 mji 0.05M eopaTiioro ey-tepa, a TepMOjiH3Hii eepyT a KOJiHMecTee 2.5 μγ (O.ĎB.lO—^MMOJib) h peaKUHOHHyn cMecb BuaepwHBaioT 2 ’iaca npw 20°C. 271 003 2 B npHMepax 2-9 H3y>iawT 3aBHcxMocTi> buxoab uejieeoro npoayKTa ot pH peaKUHamioň cpew.nojiy'ieiiiiue peayjibTaTU npHBeAexu b TaejiHiie 1.

TafiJiHua 1 (lpXMep pil CPCAM Buxoa.% 1 2 3 2 5.6 1.97 3 6.0 8.8 4 6.5 17.2 5 7.0 77.0 6 7.3 79.8 7 7.5 84.4 8 8.0 70.3 9 8.4 60.4 ΠρΗΜβρ 10. n-IlHTpoaiiHJiHa - N - «opmhji - L - ajiaiiHJi - L - ajiaiiHA - L - «eXHJiaAaiiHHa (11).

Cmoci, 0.180 r <1 mmojib) N -ΦορΜΗΛ- L-ajiaHHJi- L-ajiaHHJia x 0.290 r <1 μμολ)n-HHTpoaiiHJiHaa N -«eiiHJiaJiaiiuna pacTBOpsnoT o 0.4 mji ΛΜΦΑ, npx nepeMeiuHBaxHx MeAJieiixonpHeaBJínioT 0.6 mji 1.10“3M pacTeopa CaCIa. aoBeAexxoro no pH 6.9 0,1 H.NaOH, x oaTeM npxnepeMeuiHoaiiHH AoaaBJíflUT 40 mkji 1 mM pacTBOpa TepMOJiH3Hiia (4.10~5mmojii<) b 1.10-3M pacTBopcCaCl2 c p|{ 6,9. PeaxuHOHxy» cMeci. BUAepwxBaioT npx nepeMeuiHBaHxx 24 Maca. ot»hai>tpobubu»t

BunaBUixR ocaaoK. npOMMBanT ero. ksk onxcano b npxMepe. x cyuiaT b BaxyyMe. nojiyxaiOT 0,35 r <85£) cocAHiieiixn 11 c TeMnepaTypoH nJiaBJíeHXX 201°C. Rt 0.94 (1). 0.88(2); C Z/ ]^θ - -7.5° <c 0.5 ΑΜΦΑ). ňMHHOKxcJioTHuň axajixs: Ala 1.99 (2): Phe 1.01 (1). npxMepu 11-12 eicyuiecTBJííiioT aiiaJiorxMiio npxMepy 10 c τβΜ OTJiHMHeM, ‘ΐτο τβΡΜθΛΧ3Η„XCnOJU.3y»T B KOJIXMeCTBe 1.10”B X 2.10-B MMOJII, ΟΟΟΤΒβΤΟΤΒβΗΧΟ.

DpxMepu 13-14 ocyuiecTBJííiioT anajiorx'ixo npxMepy 10 c tbm οταημηθμ, mto peaKUHOHHax cMectcoAepwxT 0,6 mji 1.10-3M pacTBOpa CaCl2 x TepMOJixaxx eepyT b KojixMecTBe 6.10-s x 10.10-5 mmojii,cooTBeTCTBemio. B -npHMepax 11-14 H3y»ia»T aaBHCHMOCTi, βμχοαο uejieeoro npoayxTa ot KOJixnecTBa TepMOjiX3Hiia.nojiyMeuxue peoyjtBTaTu npHBeAexu b TaejiHue 2.

Taejixua 2 ΠρΗΜβρ KOJIHMOCTBO TepMOJTHBHIia . MMOJIB Buxoa.% 1 2 3 11 1.10~B 40 12 2.10-® 64 13 6.10-S 85 14 1.ío-4 95 ΠρΗΜβρυ 15-19 ocyuiecTBJíxuT anajiorx*ino npHMepy 10 c τβΜ οτλημηθμ. mto peaKUxoHiiyn CMeci,BMJtepwxBauT npx pa3JiMMHMX TeMnepaTypax b xHTepeaJie ot 6 ao 45°C. B πρχΜθτβχ 15-19 xayiaioT3aBHCHMOCTi> BuxoAa nejiesoro npoAyKTa ot TeMnepaTypu peaKUHOHHoR cMecx. nojiyMeHHNe peayjibTaaTunpHBeAexu b Taejixne 3. 271 083

TaejiHua 3 ΠρκΜθρ TeMnepaTypa peaKUHomioH CMecH.°C Biixoa. % 1 2 3 15 6 62 16 15 85 17 22 93 18 37 80 19 45 51 npHMepu 20-23 ocyutecTBJímoT atiajiorHMHo npHMepy 16. B npHMepax 20-23 H3yMa»T aaeHCHKOCTi. Buxofla uejieBoro npoayKTa οτ BpeMeHH peaKUHH. nojiy»ieHHue pe3yjibTaTM npHBeaenu b TaejiHiie 4. Taejiuua 4 ΠρΗΜβρ ΒρβΜΠ peaKUHH. m Buxoa.% 1 2 3 20 3 54 21 6 64 22 48 85 23 72 90 npHMepu 24-26 ocytuecTBJísnoT aiiajioriemo npHMepy 10 c Ten οηίΗΜΗβΜ, mto cHeci. hcxoaiimx ΚΟΜΠΟΗβΗΤΟΒ paCTBOpSIlOT B 0.2 MJI UM® Λ H 0,3KOJiwiecTBe 20 mkji 1 mM pacTBOpa <2.1Q-B>.ueJieBoro npoayKTa ot MOJisipuoro coaTiiouieiiHiinajiyHemiue peoyjibTaTU npHBeaeiiu b TaeJiHiie 5. mji bojím npM pil 6,7 TepMOJiH3HH aoeatuiíiioT nB npHMepax 24-26 H3y»iaioT aaBHCHHOCTi, euxoaaaMHHOKOHnoiieiiTa h KopeoKCHJibiioro KOMnoiieiiTa.

Taajiuua 5 KOJIHHeCTBO , MMOJIb ΠρΗΜβρ - BUXOfl.*

KapiSOKCHJIb- aMHHOKOH- ΗΟΓΟ ΚΟΜΠΟ- ΠΟΗβΗΤβ ΗβΗΤβ 1 2 3 4 24 • 0.8 1.0 96 25 1.0 2.0 22 26 1.0 0.8 70 ΠρΗΜβρ 27. n-IlHTpoaiiHJiHa Ν-φορμηλ L-aJiamui- L -aJiaHHJi- L -JieftUHHa <III>. CMecb 0,188 r <1 mmojib) Ν-φορμηλ L-ajiaHHJi- L -ajiailHHa H 0,21111 r <1 MMOJib) n-iiHTpoaiiHJixaa L-jieňuHHa pacTBopfWT b 1 mji ΑΜΦΑ. Μβ/υιβΗΗΟ πρη πβρβΜβηΐΗΒβΗΗΗ aoeaBJíxioT 5 mji 5.10-2M pacTBopa

CaCl2. πρη nepeMeuiHBaHHH aoeaBJíniDT 5 μγ <1.33 x 10-4 mmojib) TepMOJiH3HHa. PeaKUHOHnye CMeci

BuaepMtHBaioT 6 Macoe πρη 22° C h noMeutanT Ha komb b xojioaHJibiiHK. BunaBuiHň ocaaoK οτΦΗΛί,τροΒΜΒβιοτ, npoMUBauT. xax onHcano b npHMepe 1. cyuiaT b BaKyyMe. 271 083 4 ílojiyMaioT 0.305 r (72,5¾) coejiHiienHH III c TeMnepaTypofi njiaBJíeiiHíi 176°C. Rf 0.71(2): t e>(y 1^® - -21° (c 0.5: ΑΜΦΑ). AmhiiokhcjiothuB anajiM3= Ala 1.93 (2), Leu 1.08 (1). Πρημθρ 28. n-IlHTpoaiiHJtHa N-*opmhji- L - ®eiiHJiajiaHHji-jiefiUHiia (IV). CMecb 19 ΜΓ (0.1 MMOJib) Ν-φορμηλ-L - «eiiHJiajiaHHiia M 25 μγ (0.1 mmojib) n-HHTpoaiiajinaaL-jteBuHiia pacTBopsuoT b 0.15 mji ΚΜΦΛ, Meajieiiiio πρη nepeMeiunaaiiHH npH<saBJi$uoT 0.2 mji βολμ (pil6.8). 3βΤβΜ npHOaBJIXlOT 0,7 ΜΓ (2 X 10" SMMOJlb) TePMOJIH3HHa H BUaepWHBalOT ΠΡΗ KOMllaTHOBTeMnepaType 24 Maca. OunasuiuB ocaaoK pacTBopsuoT b 5 mji sTHJianeTaTa m npoMUBanT 0.5 h jihmcihiiohkhcjiotu (1 x 1 mji), 0,5 H.NaIIC03 (1 x 1 mji). cyuiaT nají cyjib*aTOM ιιβτρκίΐ h ynapHBanT bBaxyyMe. nojiyMa»T 27 μγ (66¾) οοθληηθιιηπ iy c TennepaTypoB njiatuienHíi 181°C, Rt 0.81 (1). 0.91(2): [ eó· - -16° (c 0.5: ΑΜΦΑ). AmhhokhcjiotiimB aiiajiH3'· Leu 1,0 (1): Phe 1.0 (1). Πρημθρ 29.

MeTHJiOBuB 3ΦΗΡ Μ -φορμη-τι- L -acnapTHJi- L - *eiiHJiaJiaHHiia (Y). K 2.1 r (10 mmojib) xjioprnapaTa μθτη.ποβογο 3®npa N- ®eHHJiajiaHmia npHeaBJínioT 0.66 r (4.1MMOJib) N -φορμηλ- L -acnaparHHOBoň khcjiotu b 2.0 mji bojím. Ilocjie pacTBOpeHHsi hcxojihuxκοΜΠΟΗβιιτοβ pH peaKUHOHHoB CMecH ΛΟΒΟΛίΐτ ao 6.6-6.8 npHaaBJíeiiHeM 6 h. NaOH. 3btgmoepaeaTUBaMT 20 μγ (5,3 x 10-4 mmojib) TepMOJiH3Hiia h nepeMewHBanT 24 Maca πρη 25°C. OcajioxpacTBOpaiOT o 25 mji IM yxcyciioB khcjiotu h oepaeaTUBaMT 30 mji SP-ce®aaexca. CMOJiyOT®HjibTpoBUBaioT, npoMUBaNT 1 M yxcyciioB khcjiotu. Πθπτηα 3KCTparnpyi0T cMecbn oTHJiaueTaT - bojib(9=1) (8x8 mji). OebeaHHeHHuB bkctpskt ynapneauT b BaxyyMe. Macjio KpHCTajuiHoyeTcsi na xowoaeΠΟΛ 3ΦΗΡΟΜ. noJiyMaioT 0.42 r (35¾) coeAHiieiiHsi V: £ oč* y® · -24.5° (c 0,5: H2O): £ l18 - -15° (c 1,0: AcOH). AmhiiokhcjiothuB aiiajiH3: Aspl.03 (I), Phe 0.97 (1). Πρημθρ 30.

MeTHJiOBuB 3ΦΗΡ N--»opmhji- L - acnapTHJi- L -®eiiHJiaJiaiiHiia (Y). ÍIojiyuaioT anajiorHMHo npHMepy 29, hcxoah H3 2 mmojib xjioprHpaTa μθτηλοβογο οφηρβ L-®eiiHjiaJiaHHiia η I mojib Ν-φορμηλ- L -acnaparHiioeoH khcjiotu. Ajih BuaeJieHHH uejieeoro npoayxTa xpeaKUHOHiioB cmbch npHeaBJínnT 4.5 mji yxcyciioB khcjiotu. a 3aTew 40 mji oTHJiaueTaTa. BunaewHHocaaoK οτΦΜϋΒτροΒΗΒβητ. opraiiHMecxyio ®aay προμμββμτ bojioB (7 x 2 mji). cyuiaT iiaa σν4ΐΒΦΒΤθΜιιβτρΗΗ h ynapHBanT b BUKyyMe. nojiyianT 0.14r (43¾) coeaHHeHHsi Y.

KaK bhjuio H3 npHBeaeiuiux πρημθροβ. onucuBaeMuB cnocoe noasojisieT nojiyuaTb οπτημθοκηMHCTUe N -®OPMHJ|- L -nenTHJlU B ΜΪΙΓΚΗΧ yejlOBHHX 603 SaUlHTU 6OKOBUX eyilKUHOHaJlblIUX rpyrinHPOBOK. 5 271 0B3

•ΟΡΜΥΛΛ H30BPETEIIHB

Cnocoe nojiyneHHa Ν-φορμηλ - L -πθητηλοβ oemeň »opHyjiu

For -Λ-Β-Χ.

ΓΑβ For - 'KIPMHJG n - Asp, Met.Ala-Ala. Phe: B - Phe,Leu.

BKJi»'ia»uiHň KOHíejicaiiHio N-*opMHJi3amniueiiHoro KapeoxciuibHoro κοΜΠοκβΗΤβ c aMHHOKOMnoHetrroM.BaiuHiueHHMM KapeoKCHJibHoR rpynne. OTjiH'ia»iuHflcq τβΜ. ίτο, c uejibn noBumenHfl βμχοαβ 11pacuiHpeHH$i accopTMMeHTa ueJieeux npoAyKToa, a KanecTBe K -®opMHJi3auiHmeiiHoro KapeoKCHAbtioroκοΜΠΟΗβιιτβ KcnojibayioT coeanneniie oemeň ΦορΜν-πΜ

For -Λ-ΟΗ.

rae For h A ΗΜβητ 3naMeiiHH. yKa3aiiuue Buuie, a a xanecTBe aMHHOKOMnonenTa - coeíHHeiiHe oemeňBOpMyJlU

H-B-X rae B η X ΗΜβητ 3HaneHH$i. ytcaaaHHMe euiue. h KOHAencauHn προβοαατ b npHcyTCTBHH 2.10-5 -1.10-·4MMOJib MeTaAAonpoTeHi<a3u Bac. bhermoprobeolytlcus na 1 mmojib KapeoKCHJibnoro κοΜποιιβιιτβ πρη pH6,5-8,0. TexnepaType 15-37°C a boaiioB hjih ΒΟΑΗΟ-ΑΗΜβΤΗΑΦΟΡΜβΜΗΑΗοΑ cpeae πρη mojisiphomCOOTHOUieHHH aMHlIO- H KapeoKCHJibHoro ΚΟΜΠΟΙΙΘΙΙΤΟΒ 1=1 - 1:2. HCTOHHHKH ΗΗΦΟρΜβΙΙΗΗ. ΠΡΗΗΛΤΜβ BO BHHMalIHe ΠΡΗ 3ΚΟΠβρΤΗ3β= DE. B. 2256055. 271 083

P E · Ε Ρ Λ T CI1OCOB ΠΟΠΥΊΕΙΙΗΗ N-SOPMyJI- L - ΙΙΕΙ1ΤΗΛΠΒ H3o<speTenHe KacaeTcq 3aMeuteiinux πβπτηλοβ, b "ibcthocth Μ-φορμηλ- L - πθπτηλοβ oemeH«opMyjiu 1: R - A - B - X, rae R - φορμοιι. A-Asp. Met. Ala-Ala. Phe; B-Phe.Leu; X - mbthji . -HN- CeíU-n-NOz, κοτορΝβ μογυτ Ha Rtu πρημθιιθιιμθ b 3KcnepHMeiiTajibHoň 6Moxhhhh h MeanitHiie.(loBuuienHe auxoaa h pacuiHpeHHe accopTHHeHTa 1 aocTHraeTcn hobumh hcxoahmmh npoayKTaMH honpeaejieiuiMMH ycjioBHííMH npoBeaeiiHsi peaKUHH. CHiiTea 1 seayT KOHaeHcauHeň N-*opMHJi3amHmennoraKapňOKcmii.iioro KOMnaiieiiTa <KK) orsmeR «opMyjiu: R-A-OII c aMHHQKOMnoiienTOM oeuieři <i>opMyjiU: II-B-X,r«e R.A.B η X yKaaanu Buuie, 3aiuHmeniiuM na KapeoKCHJibiioti rpynne. Ilponecc aeayT b npHCyrcTBHH(2.10"s )-<l. 10~4) mmojib MeTajiJionpOTeHna3U Bac. thermoproteolytlcus na 1 MMOJib KK iiph pH6.5-8.0, TewnepaType 15-37°C b BonHoň hjih βοληο-λημβτηιιφορμβμηληοΗ cpeae πρη mojixpiiomcooTHOUieiiHH aMHHOKOMnoneHTa h KK. paBHOH 1:1-2. Cnocoe oeecneMHBaeT noJiyueHHe οπτηίθοκηMHCTUX 1 B ΜΒΓΚΗΧ yCJlOBHBX ββ3 3aUIHTU 6HKOBUX ®yHKAUHOHajlbHUX Tpynn C BUCOKHM ΒΗΧΟΛΟΜ (ao96*). 1

i 271 083 OMfCAIlHE H30GPETEIIHÍI K ADTOPCKOMY CBHflETEJIIiCTBy 3aHBKa = No. 3855631 3aíiBjieno: 15.02.85 MKH4s CI2P 21/02

Abtopu: nMCTerienoB. HER. A. JI

3a «BHTeJii .: Bcccoio3iiuh nay * ino-HccjieaciBaTejibcKHH HHCTH-ryT reiieTHKH h ceJieKUHH npoMMuiJieiiiibixMHKpOOpralIHSMOB

HajBaHHe H3O <-.

Eor - Λ-Β ΓΛβ Eor - ΜΗΛΙρΜΗΛΙ A - Asp. Met. Ala-Ala. Phe; D - Phe. Leu. X - MeTHJi. - IIN - NO2. KOTopue MoryT iiaňTH npHMeiieiiHe b 3KcnepHMeiiTay.no shoxhmhh η μθληκηκο.

Uej | z> ιοοβρΕΤβιΐΗϋ - noBuuieHHe euxoaa h pacuiHpeiiHe accopTHMeiiTa Ν-φορμηλ L - πβτΗΛΟΒ.roMoreHHOCTt kohciiiux coeziHiieiiHfí npoDepnioT c noMouibn tohkocjioKiioH xpoMaTaorpa «HH 11a-n nacTHHKax" CHJiyeoji "<'ICCP) and cncTeMax: 1-11 - eyTaiioji - πηρηληη - Boaa - yxcycHan KHcjioTa. 15 = 10: 12: 3; 2-neTaHOji - xjiopo «opM. 3 = 7. Yrjiu BpauteHHX onpeaejixuT Ha cneKTponoasipHMeTpe "llllger"'(AurjiHX).

AmhhokhcjiotiiuR aiiajiHa BunoJiiisiioT to aMHtioKHCJioTiioM aHaJiH3aTope Diirrum D-500 (CIUA) nocjierHApojiHsa nenTHBa b TeneiiHe 24 "by LACO 3anasuinoíí axnyjfe C5-7 11th IIci πρη 110 ° C. B cHHTeae HcnojiboyioT MeTaJiJiciiipOTeHiiaay Bac. Thermoproteolytlcus φηρμη" Ierva "(ΦΡΓ) -

TepMOJIH3Hll. H3O <speneiiHe HjuuocTPHpyeTCa cjieaynuiHMH HPHMepaMH.npHMep 1. Π -ΗΗΤΡΟβΗΗΛΗΛ-N-♦ OPMHJI-L-MeTHOHHI-LJ eeHUHa <1).

Cxecb 0.354 r. (2 mmojib) Ν-φορμηλ- L-βτΗΟΗΗΗβ H 0.502 r (2 MMOJib) π -HHTpoaiiHJiHaa L-uňuHi pacTBOpsusT b 1.5 mji AHMeTHjieopMaMHAa (ΑΜΦΑ). npx nepeMeuiHBaHHH MeajieHHO npHeaejisnoTp5.0 mji 5.10-2M pacTBopa xJiopHCToro KajibUHSi. λοβθλθιιοοο λο pH 7.1 0.1 li. NaOH, h 3aTeMeHeHeHeHaHHaAnAnS 5 μg (1. PeaKUHOHHyu cMecb nepeMeuiHoaioT 6 <iπρη 20 ° C h ocTaeJisiiOT to no * ib B xojiOAHJibHHKe. OunaBiUHň ecaaox οτΦΗ-nbTpOBwnaioT προμμβλιοτ 0.5H.llCl (2 x 0.5 mji). eoaoň <2 x 0.5 mji). 0.5 H.NalICO3 <2 x 0.5 mji). βολοΑ <2 x 0.5 mji) h cyuiaTb BaxyyMe. The pH is 0.784 r (95.5 µl) coHHeiiH 2 O 1 TOMiPeLiTiTiOnBiHiHeiHiIi 164 ° C. R i 0.77 (1), 0.54 (2); e e i e e “+ 5.5 ° <c 0.5; ΛΜΦΛ). AmhhokhcjiotiiuH aitaJiHa: Met 0.89 (1): Leu 1.1 '. (1).

IlpHMepu 2-4 ocytuecTBJísiioT aiiajiorHHHo npHMepy 1 c τβΜ οτ-ιτημμηθμ hto HCxoaHasi swords. coaepwHT 0.63 MMOJib Ν-φορμηλ- L-MeTHOHHHa h 0.63 mmojib n — HHTpoaHHJiHaa L-JieňuHna b 0.6 mjiΑΜΦΑ h 2.0 mji 0.1 M UHTpaTiioro eyeepa. and 33 33 η3 ec b ec »ececec μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ μ x x x x x x x x x x x x x x x x x x x x x x ΠρΗΜβρω 5-9 ocyiuecTBJíHMT anajiortriHO npHMepy 1 c τθμ οτληηηθμ. hto Hcxoanan peaKUHomia CMecb coaepxiHT 0.63 mmojib Ν-φορμηλ- L-MeTHoiiHiia h 0.63 mmojib n-iiHTpoatiHJiHaa L-jieHunna b 2.0 mji 0.05M eopaTiioro ey-tepa, and TepMOjiH3Hii eepyT and KOJiHMecTee 2.5 μγ (O.ĎB.lO - [M] i [iota] h peaKUHOHHyn cMecb BuaepwHBaioT 2 [iota] npw 20 [deg.] C. 271 003 2 B npHMepax 2-9 H3y> iawT 3aBHcxMocTi> buxoab uejieeoro npoayKTa ot pH peaKUHamioN cpew.nojiy'ieiiiiu peayjibTaTu npHBeAexu b TaejiHiie 1.

TafiJiHua 1 (lpXMep pil CPCAM Buxoa.% 1 2 3 2 5.6 1.97 3 6.0 8.8 4 6.5 17.2 5 7.0 77.0 6 7.3 79.8 7 7.5 84.4 8 8.0 70.3 9 8.4 60.4 ΠρΗΜβρ 10 n-IlHTpoaiiHJiHa - N - «opmhji - L - ajiiiHJi - L - ajiaiiHA - L - eXHJaAaiiHHa (11).

Cmoci, 0.180 r <1 mmojib) N-ΦορΜΗΛ-L-ajiaHHJ-L-ajiaHHJia x 0.290 r <1 μμολ) n-HHTpoaiiHJiHaa N - «eiiHJiaJiaiiuna pacTBOpsnoT 0.4 mji ΛΜΦΑ, npx nepeMeiuHBaxHx MeAJieiixonpHeaBJínio 0.6 mji 1.10” 3M pacTeopa CaCIa. aBeAexxoro no pH 6.9 0.1NaOH, xaaTeMeMeHeHaAaaBaIlIllUT 40 mkji 1mM pacTBOpa TepMOJiH3Hiia (4.10 ~ 5mmoji <) b 1.10-3M pacTBopcCaCl2 cp | {6.9. PeaxuHOHxy »cMeci. BUAepwxBaioT npx nepeMeuiHBaHxx 24 Mac. ot »hai> tpobub» t

BunaBUixR ocaaoK. npOMMBanT ero. ksk onxcano b npxMepe. x cyuiaT b BaxyyMe. nojiyxaiOT 0.35 r < 85 < tb &gt;&lt; tb &gt; Rt 0.94 (1). 0.88 (2); CZ /] ^ θ - -7.5 ° <c 0.5 ΑΜΦΑ). MMHHOKxcJioTHuň axajixs: Ala 1.99 (2): Phe 1.01 (1). npxMepu 11-12 eicyuiecTBJííiioT aiiaJiorxMiio npxMepy 10 c τβΜ OTJiHMHeM, 'οτο τβΡΜθΛΧ3Η „XCnOJU.3y» TB KOJIXMeCTBe 1.10 ”BX 2.10-B MMOJII, ΟΟΟΤΒβΤΟΤΒβΗΧΟ.

DpxMepu 13-14 ocyuiecTBJííiioT anajiorx'ixo npxMepy 10 c tbm οταημηθμ, mto peaKUHOHHax cMectcoAepwxT 0.6 mji 1.10-3M pacTBOpa CaCl2 x TepMOJixaxx eepyT b KojixMecTBe 6.10-sx 10.10-5 mmojii, cooTBeTCTBemio. B -npHMepax 11-14 H3y »ia» T aaBHCHMOCTi, βμχοαο uejieeoro npoayxTa ot KOJixnecTBa TepMOjiX3Hiia.nojiyMeuxue peoyjtBTaTu npHBeAexu b TaejiHue 2.

Taejixua 2 ΠρΗΜβρ KOJIHMOCTBO TepMOJTHBHIia. MMOJIB Buxoa.% 1 2 3 11 1.10 ~ B 40 12 2.10-® 64 13 6.10-S 85 14 1.io-4 95 ΠρΗΜβρυ 15-19 ocyuiecTBJixuT anajiorx * ino npHMepy 10 c τβΜ οτλημηθμ. mto peaKUxoHiiyn CMeci, BMJtepwxBauT npx pa3JiMMHMX TeMnepaTypax b xHTepeaJie ot 6 o 45 ° C. B πρχΜθτβχ 15-19 xayiaioT3aBHCHMOCTi> BuxoAa nejiesoro npoAyKTa ot TeMnepaTypu peaKUHOHHoR cMecx. nojiyMeHHNe peayjibTaaTunpHBeAexu b Taejixne 3. 271 083

TaejiHua 3 ΠρκΜθρ TeMnepaPeakuHomioH CMecH. ° C Biixoa. % 1 2 3 15 6 62 16 15 85 17 22 93 18 37 80 19 45 51 npHMepu 20-23 ocyutecTBJimoT atiajiorHMHo npHMepy 16. B npHMepax 20-23 H3yMa »T aaeHCHKOCTi. Buxofla uejieBoro npoayKTa οτ BpeMeHH peaKUHH. nojiy »ieHHue pe3yjibTaTM npHBeaen b TaejiHiie 4. Taejiuua 4 ΠρΗΜβρ ΒρβΜΠ peaKUHH. m Buxoa.% 1 2 3 20 3 54 21 6 64 22 48 85 23 72 90 npHMepu 24-26 ocytuecTBJisnoT aiiajioriemo npHMepy 10 c Ten οηίΗΜΗβΜ, mto cHeci. hcxoaiimx ΚΟΜΠΟΗβΗΤΟΒ paCTBOpSIlOT B 0.2 MJI UM® Λ H 0,3KOJiwiecTBe 20 mkji 1mM pacTBOpa <2.1QB> .ueJieBoro npoayKTa rpm MOJisipuoro coaTiiouieiiHiinajiyHemiue peoyjibTaTU npHBeaeiiu b TaeJiHiie fifth vk afraid NPM pH 6.7 TepMOJiH3HH aoeatuiíiioT nB npHMepax 24-26 H3Y » iaioT aaBHCHHOCTi, euxoaaaMHHOKOHnoiieiiTa h KopeoKCHJibiioro KOMnoiieiiTa.

Taajiuua 5 KOJIHHeCTBO, MMOJIb ΠρΗΜβρ - BUXOfl. *

KapiSOKCHJIb- aMHHOKOH- ΗΟΓΟ ΚΟΜΠΟ- ΠΟΗβΗΤβ ΗβΗΤβ 1 2 3 4 24 • 0.8 1.0 96 25 1.0 2.0 22 26 1.0 0.8 70 ΠρΗΜβρ 27. N-IlHTpoaiiHJiHa Ν-φορμηλ L-aJiamui- L -aJiaHHJi- L -JieftUHHa <III>. CMecb 0.188 r <1 mmojib) Ν-φορμηλ L-aiaHHH-L-iaiaiililHHa H 0.21111 r <1 MMOJib) n-iiHTpoaiiHJixaa L-iyuHHa pacTBopfWT b 1 mji ΑΜΦΑ. /Β / υιβΗΗΟ πρη πβρβΜβηΐΗΒβΗΗΗ aoeaBJíxioT 5 mji 5.10-2M pacTBopa

CaCl2. πρη nepeMeuiHBaHHH andDB 5 μγ <1.33 x 10-4 mmojib) TepMOJiH3HHa. PeaKUHOHnye CMeci

BuaepMtHBaioT 6 Macoe πρη 22 ° C h noMeutanT Ha comb b xojioaHJibiiHK. BunaBuiHò ocaaoK οτΦΗΛί, τροΒΜΒβιοτ, npoMUBauT. xax onHcano b npHMepe 1. cyuiaT b BaKyyMe. 271.083 4MiOlMiTiOr 0,305r (72.5µ) coHiHiHiCl 3 TeMnepaTypofiNiLiHiHi 176 ° C. Rf 0.71 (2): te> (y 1 ^ ® - -21 ° (c 0.5: ΑΜΦΑ). AmhiiokhcjiothuB anajiM3 = Ala 1.93 (2), Leu 1.08 (1). N-IlHTpoaiiHJtHa N- * opmhji- L - ®eiiHJiajiaHHji-jiefiUHiia (IV) CMecb 19 ΜΓ (0.1 MMOJib) Ν-φορμηλ-L - «eiiHJiajiaHHiia M 25 μγ (0.1 mmojib) n 0.15 mji ia, Meajieiiiio πρη nepeMeiunaaiiHH npH <saBJi $ uoT 0.2 mji βολμ (pil6.8) 3βΤβΜ npHOaBJIXlOT 0.7 ΜΓ (2X10 "SMMOJlb) TePMOJIH3HHa H BUaepWHBalOT ΠΡΗ KOMllaTHOBTeMnepaType 24 Maca OunasuiuB ocaaoK U 27 u u u u u 27 27 27 27 27 27 27 27 27 27 u u 181 181 181 181 181 181 181 181 181 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 : [eó · - -16 ° (c 0.5: ΑΜΦΑ). AmhhokhcjiotiimB aiiajiH3 '· Leu 1.0 (1): Phe 1.0 (1) Πρημθρ 29.

MeTHJiOBuB 3ΦΗΡΦΗΡ -φορμη-τι- L -acnapTHJi- L - * eiiHJiaJiaHHiia (Y). To 2.1 r (10 mmojib) xjioprnapaTa θτη.ποβογο 3®npa N- ®eHHJiajiaHmia npHeaBJínioT 0.66 r (4.1MMOJib) N -φορμηλ- L -acnaparHHOBoň khcjiotu b 2.0 I'm more afraid. Ilocjie pacTBOpeHHsi hcxojihuxκοΜΠΟΗβιιτοβ pH peaKUHOHHoB CMecH ΛΟΒΟΛίΐτ o 6.6-6.8 npHaaBJieHeM 6h. NaOH. 3btgmoepaeaTUBaMT 20 μγ (5.3 x 10-4 mmojib) TepMOJiH3Hiia h nepeMewHBanT 24 Maca πρη 25 ° C. OcajioxpacTBOpaiOT by 25 mJ IM yxcyciioB khcjiotu h oepaeaTUBaMT 30 mji SP-ce®aaexca. CMOJiyOT®HjibTpoBUBaioT, npoMUBaNT 1 M yxcyciioB khcjiotu. Πθπτηα 3KCTparnpyi0T cMecbn oTHJiaueTaT - bojib (9 = 1) (8x8 mji). OebeaHHeHHuB bkctpskt ynapneauT b BaxyyMe. Macjio KpHCTajuiHoyeTcsi on xowoaeΠΟΛ 3ΦΗΡΟΜ. -24.5 ° (c 0.5: H 2 O): 1818 - -15 ° (c 1.0: AcOH). AmhiiokhcjiothuB aiiajiH3: Aspl.03 (I), Phe 0.97 (1). Πρημθρ 30.

MeTHJiOBuB 3ΦΗΡN - »opmhji- L - acnapTHJ - L - ®eiiHJiaJiaiiHiia (Y). I iy iy aj aj aj aj aj p p p p p p mm oj oj opr oj oj oj oj oj mm mm L L L L L L L L L L L L L L L L L L L-----------. Ajih BuaeJieHHH uejieeoro npoayxTa xpeaKUHOHiioB cmbch npHeaBJinn 4.5 mji yxcyciioB khcjiotu. and 3aTew 40 mji oTHJiaueTaTa. BunaewHHocaaoK οτΦΜϋΒτροΒΗΒβητ. opraiiHMecxyio ®aay προμμββμτ bojioB (7x2 mji). cyuiaT iiaa σν4ΐΒΦΒΤθΜιιβτρΗΗ h ynapHBanT b BUKyyMe. nojiyianT 0.14r (43¾) coeaHHeHHsi Y.

KaK bhjuio H3 npHBeaeiuiux πρημθροβ. onucuBaeMuB cnocoe noasojisieT nojiyuaTb οπτημθοκηMHCTUe N -OOPMHJ | - L -nenTHJlU B ΜΪΙΓΚΗΧ yejlOBHH 603 SaUlHTU 6OKOBUX eyilKUHOHaJlblIUX rpyrinHPOBOK. 5,271 0B3

• 30 H30BPETEIIHB

Cnocoe nojiyneHHa Ν-φορμηλ - L -πθητηλοβ oemeň »opHyjiu

For -Λ-Β-Χ.

ΒΑβ For - 'KIPMHJG n - Asp, Met.Ala-Ala. Phe: B - Phe, Leu.

BKJi »ia» uiHn KOHíejicaiiHio N- * opMHJi3amniueiiHoro KapeoxciuibHoro κοΜΠοκβΗΤβ c aMHHOKOMnoHetrroM.BaiuHiueHHMM KapeoKCHJibHoR rpynne. OTjiH'ia »iuHflcq τβΜ. ί ο c ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί op ec op op op op op op op op Μ Μ

For -Λ-ΟΗ.

rae For h ΗΜβητ 3naMeiiHH. yKa3aiiuue Buuie, aa xanecTBe aMHHOKOMnonenTa - coeíHHeiiHe oemeňBOpMyJlU

HBX rae B η X ΗΜβητ 3HaneHH $ i. ytcaaaHHMe euiue. h KOHAencauHn προβοαατ b npHcyTCTBHH 2.10-5 -1.10- · 4MMOJib MeTaAAonpoTeHi <a3u Bac. bhermoprobeolytlcus per 1 mmojib KapeoKCHJibnoro κοΜποιιβιιτβ πρη pH6,5-8,0. TexnepaType 15-37 ° C and boaiioB hjih ΒΟΑΗΟ-ΑΗΜβΤΗΑΦΟΡΜβΜΗΑΗοΑ cpeae πρη mojisiphomCOOTHOUieHHH aMHlIO- H KapeoKCHJibHoro ΚΟΜΠΟΙΙΘΙΙΤΟΒ 1 = 1 - 1: 2. HCTOHHHKH ΗΗΦΟρΜβΙΙΗΗ. ΠΡΗΗΛΤΜβ BO BHHMalIHe ΠΡΗ 3ΚΟΠβρΤΗ3β = DE. B. 2256055. 271,083

· CI Λ 3 3-3 3 3 3 3 3 3 3 3 3 3 3 3 3 My My My My My My My My My My My My My My My My My My My My My My My My My My. A-Asp Met Al-Ala Phe B-Phe.Leu X-mbthji -HN- CeiU-n-NOz, κοτορΝβ μογυτ Ha Rtu πρημθιιθιιμθ b 3KcnepHMeiiTajibHoň 6Moxhhhh h MeanitHiie. hobumh hcxoahmmh npoayKTaMH honpeaejieiuiMMH ycjioBHííMH npoBeaeiiHsi peaKUHH. CHiiTea 1 seayT KOHaeHcauHeň N * opMHJi3amHmennoraKapňOKcmii.iioro KOMnaiieiiTa <KK) orsmeR «opMyjiu: RA-OH c aMHHQKOMnoiienTOM oeuieři <i> opMyjiU: BX-II, R« X η e RAB yKaaanu Buuie, 3nUHmeniiuM at KapoKCHJibiioti rpynne Ilponecc aeayT b npHCyrcTBHH (2.10 "s) - <1. 10 ~ 4) mmojib MeTajiJionpOTeHna3U Bac. thermoproteolytlcus per MMOJib KK iiph pH6.5-8.0, TewnepaType 15-37 ° C b BonHoň hjih βοληο-λημβτηιιφορμβμηληοΗ cpeae πρη mojixpiiomcooTHOUieiiHH aMHHOKOMnoneHTa h KK. paBHOH 1: 1-2. Cnocoe oeecneMHBaeT noJiyueHHe οπτηίθοκηMHCTUX 1 B ΜΒΓΚΗΧ yCJlOBHBX ββ3 3aUIHTU 6HKOBUX ®yHKAUHOHajlbHUX Tpynn C BUCOKHM ΒΗΧΟΛΟΜ (ao96 *). 1

Claims (1)

7 271 083 PŘEDMĚT VYNALEZU Způsob získávání N - formy 1 • - L - peptldů obecného vzorce For - A - B - X . kde For le formyl ; A - Asp. Met, Ala - Ala. Phe : B - Phe. Leu X - methyl. - HH -- NOa zahrnulící kondenzaci H - formy 1substituované karboxylové složky s amlnosložkou substituovanou v karboxylové skupině, v y z n a č u 1 í c í se tím, že za účelem zvýžení výtěžku a rozSíření sortimentu výsledných produktů se lako N - formysubstltuovanákarhoxylová složka využívá sloučenina obecného vzorce For - A - OH . kde For a A malí výge uvedené významy a lako aminová složka le sloučenina obecnéhovzorce Η - B - X . kde B a X malí významy, uvedené výge a kondenzace se provádí v přítomnosti2.10-B až 1.10“é mmol metaloprotelnázy Bac. thermoproteolytlcus na 1 mmol karboxylovésložky při pH 6.5 až 8.0 , při teplotě 15 až 37 °C ve vodním nebo vodně N.N - dlmethyl formámldovém prostředí při molárním poměru amlno - a karboxylových složek1 1 až 1 : 2.OBJECT OF THE INVENTION A method for obtaining the N - form 1 - L - peptides of general formula For - A - B - X. wherein For le formyl; A - Asp. Met, Ala-Ala. Phe: B - Phe. Leu X-methyl. - HH-NOa comprising the condensation of the H-form of the 1-substituted carboxyl component with the carboxyl-substituted amino moiety, characterized in that in order to increase the yield and spread the resulting product range, the N-formysubstituted-carboxylic acid component is used by a compound of the formula For - A - OH. where For and A are small, the meanings and la are the component of the general formula Η - B - X. where B and X are small, said gelling and condensation are carried out in the presence of 2.10-B to 1.10 µmol of Bacalloproteinase Bac. thermoproteolytic acid per 1 mmol of carboxyl component at pH 6.5 to 8.0, at 15 to 37 ° C in aqueous or aqueous N, N -dimethylformamide medium at a molar ratio of amine to carboxyl components of 1 to 1: 2.
CS862351A 1986-04-03 1986-04-03 Method of formyl-l-peptides winning CS271083B1 (en)

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