CS259571B1 - Method of bisindole alkaloid insulation - Google Patents
Method of bisindole alkaloid insulation Download PDFInfo
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- CS259571B1 CS259571B1 CS868926A CS892686A CS259571B1 CS 259571 B1 CS259571 B1 CS 259571B1 CS 868926 A CS868926 A CS 868926A CS 892686 A CS892686 A CS 892686A CS 259571 B1 CS259571 B1 CS 259571B1
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- CS
- Czechoslovakia
- Prior art keywords
- alkaloid
- vincarubin
- mixture
- benzene
- concentrated
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 8
- TYGUTURXHKSOBP-UHFFFAOYSA-N 10-bromo-5,12-dihydroindolo[2,3-g]carbazole-2,3-diol Chemical compound C1=C(Br)C=C2NC3=C(C4=C(C=C(C(=C4)O)O)N4)C4=CC=C3C2=C1 TYGUTURXHKSOBP-UHFFFAOYSA-N 0.000 title claims description 4
- 238000009413 insulation Methods 0.000 title 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 12
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 8
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229930013930 alkaloid Natural products 0.000 claims abstract description 6
- 241000863486 Vinca minor Species 0.000 claims abstract description 5
- 238000000605 extraction Methods 0.000 claims abstract description 5
- 238000000926 separation method Methods 0.000 claims abstract description 5
- 229960002726 vincamine Drugs 0.000 claims abstract description 5
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000872 buffer Substances 0.000 claims abstract description 4
- 150000003797 alkaloid derivatives Chemical class 0.000 claims abstract 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000000284 extract Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- -1 benzene-butanol-formic acid Chemical compound 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- 238000004587 chromatography analysis Methods 0.000 claims 2
- 239000007853 buffer solution Substances 0.000 claims 1
- JZZXXDXQBKJBQD-UHFFFAOYSA-N butan-1-ol;formic acid Chemical compound OC=O.CCCCO JZZXXDXQBKJBQD-UHFFFAOYSA-N 0.000 claims 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 abstract description 3
- 235000019253 formic acid Nutrition 0.000 abstract description 2
- 230000001093 anti-cancer Effects 0.000 abstract 1
- 238000003556 assay Methods 0.000 abstract 1
- 238000011097 chromatography purification Methods 0.000 abstract 1
- 208000032839 leukemia Diseases 0.000 abstract 1
- 239000002904 solvent Substances 0.000 abstract 1
- CLSRDWBICGYSOB-VAPIAZESSA-N vincarubine Chemical class C1CC(C2C(=O)OC)C(=C\C)/CN3CCC42C2=CC(=O)C(C5=C(OC)C=C6N(C)C=7C8(C6=C5)CCN5CCCC(C85)(CC=7C(=O)OC)CC)=CC2=NC431 CLSRDWBICGYSOB-VAPIAZESSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LDZLXQFDGRCELX-UHFFFAOYSA-N 4-phenylbutan-1-ol Chemical compound OCCCCC1=CC=CC=C1 LDZLXQFDGRCELX-UHFFFAOYSA-N 0.000 description 1
- 240000001829 Catharanthus roseus Species 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- XRMUNMNHHCNRSL-UHFFFAOYSA-N benzene;ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O.C1=CC=CC=C1 XRMUNMNHHCNRSL-UHFFFAOYSA-N 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
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- Medicines Containing Plant Substances (AREA)
Abstract
Očelom riešenia je izolácia nového bisíndolového alkaloidu vinkarubínu zo zmesi alltaloidov produkovaných rastlinou Vinca minor L. po oddělení vinkamínu. Uvedený účel sa dosiahne extrakciou zmesi alkaloidov nízkopolárnym rozpúšťadlom, protiprúdnou extrakciou zvyšku v systéme benzén— —butanol—kyselina mravčia—tlmivý roztok o pH 3,5 a chromatografickým přečištěním surového vinkarubínu na oxide hlinitom. Pri testoch na buňky leukémie P-388 vinkarubín preukázal potenciálně protinádorové účinky a preto bude mať použitie vo farmaceutlckom priemysle.The solution is to isolate the new bisindole vincarubine alkaloid from the mixture alltaloids produced by Vinca minor L. after vincamine separation. stated the purpose is achieved by extraction of the alkaloid mixture low polarity solvent, countercurrent extraction of the residue in the benzene system - —Butanol — formic acid — buffer pH 3.5 and chromatographic purification of crude vincarubin on alumina. In P-388 leukemia cell assays, vincarubin potentially anticancer effects and therefore will be of use in pharmaceuticals industry.
Description
253571
Vynález sa týká spůsobu izolácie bisindo-lového alkaloidu vinkarubínu, vzorca I, zo zmesi alkaloidov produkovaných rastlinouVinca minor L., po oddělení vinkamínu.
Zo zmesi alkaloidov produkovaných rast-linou Vinca minor L. sa v priemyselnommeradle izoluje vinkamín, zavedený do le-kárskej praxe ako málo toxické cerebrova-zodilatans a hypotenzívum. Vinkarubín,prvý bisindolový alkaloid izolovaný z uve-denej rastliny představuje novů, doteraz ne-opísanú látku, vyznačujúcu sa potenciálny-mi protinádorovými účinkami. Pri hodnote-ní účinku vinkarubínu na buňky leukémieP-388 sa ukázala vačšia aktivita tejto látky'(tab. 1) ako vinblastínu, bisindolového al-kaloidu izolovaného z rastliny Catharanthusroseus, ktorý sa používá v klinickej ipraxi.
Pri sposobu izolácie vinkarubínu pódiavynálezu sa postupuje tak, že zmes alkaloi-dov izolovaných z rastliny Vinca minor L.po oddělení vinkamínu sa extrahuje nízko-polárnym rozpúšťadlom, napr. dietyléteromalebo dichlórmetánom. extrakt sa zahustí,zvvšok sa podrobí protiprúdnej extrakcii vsystéme benzén-butanol-kyselina mravčia--tlmivý roztok o pH 3,5 (25:5: 1 : 31 ], po-dle! obsahujúci vinkarubín sa zahustí a pře-čistí stlpcovou chromatografiou na oxidehlinitom v sústave pozostávajúcej z aroma-tického uhTovodíka a alkoholu s počtomuhlíkov Cl alebo Cz, napr. v sústave ben-zén-metanol (9:1), alebo toluén-etanol(9:1).
Bližšie podrobnosti spůsobu izolácie po-dlá vynálezu sú zřejmé z příkladu převede-ním. Příklad 1
Suchá droga (300 kg) z rastliny Vindaminor L. sa zmiešala s 10 %-ným vodnýmhydroxidom amonným (240 1), po 24 h sasuspenzia extrahovala 5-krát po 500 1 ben- zenu. Benzénový extrakt sa zahustil, zvyšoksa trituroval 6-krát po 15 1 0,5 °/o-nej kyse-liny chlorovodíkovej. V spojených kyslýchextraktoch sa prídavkom hydroxidu amon-ného upravilo pH na hodnotu 8,5, extraho-valo sa 5-krát po 10 1 chloroformu. Chloro-formový extrakt sa zahustil a zvyšok sa dě-lil stlpcovou chromatografiou na oxide hli-nitom (12 kg) elúciou dietyléterom (160 I)a metanolom (10 1). Zo zahuštěného étero-vého eluátu sa kryštalizáciou získalo 50 g( + )-vinkamínu. Příklad 2
Zmes látok (1 kg), ktorá zostala po od-dělení ( + )-vinkamínu sa triturovala 5-krátpo 6 1 dietyléteru (alebo dichlórmetánu),extrakt sa zahustil (zvyšok 75 g) a podrobilsa protiprúdnej extrakcii v systéme benzén--butanol-kyselina mravčia-tlmivý roztok opH 3,5 (Mc Ilvainov timivý roztok) (25:5:: 1: 31), podiel obsahujúci vinkarubín (pre-jav.ujúci sa červenou farbou) sa oddělil azahustil. Získalo sa 7,7 g surového vinkaru-bínu, ktorý sa přečistil stlpcovou chroma-tografiou na oxide hlinitom (300 g) v sústa-ve benzén-metanol (9:1) alebo toluén-etnol(9:1).
Zahuštěním frakcie obsahujúcej vinkaru-bín sa získala čistá látka, C43H50N4O6 (718,9), t. t. 170 °C (rozklad),
Amax (log ε, mz.mél"1), nm: 273 (3,21), 340 (3,29), 480 (2,40), IC (KBr): 1 730, 1 680, 1 605 cnr1, [a]D23 —550 + 10° (c 0,1 etanol),
Rf = 0,5 (silikagel, sústava benzén-octan etylnatý-etanol 20 : 29 :1).
253571
The present invention relates to a process for the isolation of a bisindole alkaloid of the vincarubin of formula I from a mixture of alkaloids produced by Vinca minor L., after separation of the vincamine.
From the mixture of alkaloids produced by Vinca minor L., vincamine, which has been introduced into the practice of medicine as a low-toxicity cerebrospinal fluid and hypotensive, is isolated in the industrial plant. Vincarubin, the first bisindole alkaloid isolated from the plant, is a novel, not yet described substance, characterized by potential antitumor effects. In evaluating the effect of vincarubin on leukemiaP-388 cells, the greater activity of this substance (Table 1) was shown as vinblastine, a bisindole al-caloid isolated from a Catharanthusroseus plant used in clinical ipraxi.
In the process of isolating the vincarubin according to the invention, the mixture of alkaloids isolated from the Vinca minor L. plant after the separation of the vincamine is extracted with a low polar solvent such as diethyl ether or dichloromethane. the extract is concentrated, subjected to countercurrent extraction in benzene-butanol-formic acid - pH 3.5 buffer (25: 5: 1: 31), the vincarubin-containing solution being concentrated and purified by column chromatography on oxide aluminum in a system consisting of an aromatic hydrocarbon and an alcohol having carbon numbers of C1 or C2, for example benzene-methanol (9: 1) or toluene-ethanol (9: 1).
Further details of the method of isolation of the invention are apparent from the example of conversion. Example 1
The dry drug (300 kg) from Vindaminor L. was mixed with 10% aqueous ammonium hydroxide (240 L), after 24 h the sasuspension was extracted 5 times after 500 l benzene. The benzene extract was concentrated, the residue triturated 6 times with 15 1 of 0.5 ° / hydrochloric acid. The combined acidic extracts were adjusted to pH 8.5 by the addition of ammonium hydroxide, extracted 5 times with 10 L of chloroform. The chloroform extract was concentrated and the residue was separated by column chromatography on alumina (12 kg) eluting with diethyl ether (160 L) and methanol (10 L). 50 g of (+) - vincamine were obtained from the concentrated ethereal eluate by crystallization. Example 2
The mixture of substances (1 kg) which remained after the separation of (+) - vincamine was triturated with 5-fold in 6 l of diethyl ether (or dichloromethane), the extract was concentrated (residue 75 g) and subjected to countercurrent extraction in the benzene-butanol system formic acid buffer opH 3.5 (Mc Ilvain solution) (25: 5: 1: 31), the vincarubin-containing portion (appearing in red) was separated and concentrated. 7.7 g of crude vincarbine were obtained, which was purified by column chromatography on alumina (300 g) in the form of benzene-methanol (9: 1) or toluene-ethanol (9: 1).
Concentration of the vincarbine-containing fraction gave pure material, C 43 H 50 N 4 O 6 (718.9), mp 170 ° C (decomposition),
Λ max (log ε, mzm -1), nm: 273 (3.21), 340 (3.29), 480 (2.40), IC (KBr): 1,730, 1,680, 1,605 cm -1, [α] D 23 -550 + 10 ° (c 0.1 ethanol),
Rf = 0.5 (silica gel, benzene-ethyl acetate-ethanol 20: 29: 1).
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS868926A CS259571B1 (en) | 1986-12-04 | 1986-12-04 | Method of bisindole alkaloid insulation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS868926A CS259571B1 (en) | 1986-12-04 | 1986-12-04 | Method of bisindole alkaloid insulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS892686A1 CS892686A1 (en) | 1988-03-15 |
| CS259571B1 true CS259571B1 (en) | 1988-10-14 |
Family
ID=5440506
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS868926A CS259571B1 (en) | 1986-12-04 | 1986-12-04 | Method of bisindole alkaloid insulation |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS259571B1 (en) |
-
1986
- 1986-12-04 CS CS868926A patent/CS259571B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS892686A1 (en) | 1988-03-15 |
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