JPH041751B2 - - Google Patents
Info
- Publication number
- JPH041751B2 JPH041751B2 JP60032253A JP3225385A JPH041751B2 JP H041751 B2 JPH041751 B2 JP H041751B2 JP 60032253 A JP60032253 A JP 60032253A JP 3225385 A JP3225385 A JP 3225385A JP H041751 B2 JPH041751 B2 JP H041751B2
- Authority
- JP
- Japan
- Prior art keywords
- halichondrin
- methyl alcohol
- solvent
- fraction
- extract
- 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.)
- Expired - Lifetime
Links
- ZBLLGPUWGCOJNG-UHFFFAOYSA-N Halichondrin B Natural products CC1CC2(CC(C)C3OC4(CC5OC6C(CC5O4)OC7CC8OC9CCC%10OC(CC(C(C9)C8=C)C%11%12CC%13OC%14C(OC%15CCC(CC(=O)OC7C6C)OC%15C%14O%11)C%13O%12)CC%10=C)CC3O2)OC%16OC(CC1%16)C(O)CC(O)CO ZBLLGPUWGCOJNG-UHFFFAOYSA-N 0.000 claims description 18
- FXNFULJVOQMBCW-VZBLNRDYSA-N halichondrin b Chemical compound O([C@@H]1[C@@H](C)[C@@H]2O[C@@H]3C[C@@]4(O[C@H]5[C@@H](C)C[C@@]6(C[C@@H]([C@@H]7O[C@@H](C[C@@H]7O6)[C@@H](O)C[C@@H](O)CO)C)O[C@H]5C4)O[C@@H]3C[C@@H]2O[C@H]1C[C@@H]1C(=C)[C@H](C)C[C@@H](O1)CC[C@H]1C(=C)C[C@@H](O1)CC1)C(=O)C[C@H](O2)CC[C@H]3[C@H]2[C@H](O2)[C@@H]4O[C@@H]5C[C@@]21O[C@@H]5[C@@H]4O3 FXNFULJVOQMBCW-VZBLNRDYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 239000002904 solvent Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 238000011765 DBA/2 mouse Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 241000243142 Porifera Species 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 208000001382 Experimental Melanoma Diseases 0.000 description 2
- 241000353756 Halichondria okadai Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 210000001099 axilla Anatomy 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 210000003200 peritoneal cavity Anatomy 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 240000007049 Juglans regia Species 0.000 description 1
- 235000009496 Juglans regia Nutrition 0.000 description 1
- 208000008342 Leukemia P388 Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005238 degreasing Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- VEFJHAYOIAAXEU-UHFFFAOYSA-N okadaic acid Natural products CC(CC(O)C1OC2CCC3(CCC(O3)C=CC(C)C4CC(=CC5(OC(CC(C)(O)C(=O)O)CCC5O)O4)C)OC2C(O)C1C)C6OC7(CCCCO7)CCC6C VEFJHAYOIAAXEU-UHFFFAOYSA-N 0.000 description 1
- QNDVLZJODHBUFM-WFXQOWMNSA-N okadaic acid Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-WFXQOWMNSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
Description
産業上の利用分野：
この発明は、抗腫瘍作用を有し医薬として有用
なハリコンドリンＢに関するものである。
問題を解決するための手段：
この発明のハリコンドリンＢは新規物質であり
次のような化学構造式を有する。
（※の絶対配置は不明）
このハリコンドリンＢ（HalichondinB）は例え
ばくろいそかいめん（Halichondria Okadai）
を有機溶媒（例えば、メタノール、エタノール、
ｎ−プロパノール、ｎ−ブタノール等のアルコー
ル、アセトン、ピリジン、酢酸エチルまたはこれ
らの混液）またはこれらの有機溶媒と水との混合
溶媒で抽出し、得られた抽出液から単離、採取す
ることにより得ることができる。
抽出液からハリコンドリンＢを単離するために
は、一般に天然物の単離に用いられる公知の手段
が適用される。すなわち、まず、抽出液を濃縮
し、得られた濃縮液を用いて、２種液相間におけ
る分配の差、種々の吸着剤に対する吸着親和力の
差および適当な溶媒に対する溶解性および析出速
度の差等を利用して、目的とする有効成分ハリコ
ンドリンＢを単離し、精製し、さらに適当な溶媒
を用いて結晶化することによりハリコンドリンＢ
の結晶が得られる。
この様にして得られるハリコンドリンＢの理化
学的性質は次の通りである。
(1) 分子量
1110（FDマススペクトル、M+＋Na1133、第１
図参照）
(2) 分子式
C60H36O19
(3) 融点
164〜166℃
(4) 赤外吸収スペクトル
第２図参照
νCHC/3 naxcm-1、3360，2960，2900，2480，1735，
1595，1450，1430，1395，1370，1330，
1285，1260，1225，1180，1145，1128，
1100，1080，1069，1010，990，970，
(5) H1核磁気共鳴スペクトル
400MHz、CD3OD中で測定、TMS内部基準。
第３図参照、
(6) C13核磁気共鳴スペクトル
100MHz、CD3OD中で測定、TMS内部基準。
第４図参照。δCD 3 OP TMSppm、
172.752，153.264，153.152，114.774，
111.235，105.675，104.746，98.387，83.812，
82.418，81.245，80.733，79.076，78.016，
77.942，77.869，77.341，77.252，76.299，
76.073，75.829，75.342，75.029，74.871，
73.753，73.309，73.119，72.987，71.634，
69.565，67.141，65.671，45.523，44.911，
41.171，39.704，37.908，37.783，37.493，
37.447，37.154，36.242，35.753，33.006，
31.823，31.278，31.050，30.836，29.381，
27.111，18.390，18.317，18.115，15.816
上記理化学的性質及び別途研究の結果、ハリコ
ンドリンＢの化学構造式は次の通り決定された。
発明の効果：
この発明のハリコンドリンＢは抗腫作用を有
し、医薬として有用である。
次にハリコンドリンＢの抗腫瘍作用を試験例に
より説明する。
〔抗腫瘍活性試験〕
＜マウス白血病Ｐ−388＞
DBA／２マウスの腹部で継代されているｐ−
388リンパ球性白血病細胞を継代６日目に腹腔よ
り採取し、106個／0.2ml Hanks液に調整して
CDF1（DBA／２〓×Balb／ｃ♀）系マウスの腹
部に接種した（１群10匹）。
薬剤（ハリコンドリンＢ）は、下記第１表に示
す濃度となる様に0.5％C.M.C.生理食塩水に懸濁
し、腫瘍移植から24時間経過後第１表の投与スケ
ジユールに従つて腹腔内へ投与し、延命効果を調
べた。
結果は第１表に示す通りであり、ハリコンドリ
ンＢの優れた抗腫瘍活性を確認することができ
る。
Industrial Application Field: This invention relates to halichondrin B, which has antitumor activity and is useful as a medicine. Means for solving the problem: Halichondrin B of the present invention is a new substance and has the following chemical structural formula. (The absolute placement of * is unknown) This Halichondrin B (HalichondinB) is, for example, Halichondria Okadai.
with an organic solvent (e.g. methanol, ethanol,
By extracting with alcohol such as n-propanol, n-butanol, acetone, pyridine, ethyl acetate, or a mixture thereof) or a mixed solvent of these organic solvents and water, and isolating and collecting from the obtained extract. Obtainable. In order to isolate halichondrin B from the extract, known means generally used for isolation of natural products are applied. That is, first, the extract is concentrated, and the resulting concentrated liquid is used to determine the difference in distribution between the two liquid phases, the difference in adsorption affinity to various adsorbents, and the difference in solubility and precipitation rate in appropriate solvents. The target active ingredient halichondrin B is isolated and purified using a solvent, etc., and further crystallized using an appropriate solvent to obtain halichondrin B.
crystals are obtained. The physicochemical properties of halichondrin B thus obtained are as follows. (1) Molecular weight 1110 (FD mass spectrum, M + +Na1133, 1st
(See figure) (2) Molecular formula C 60 H 36 O 19 (3) Melting point 164-166℃ (4) Infrared absorption spectrum See figure 2 ν CHC/3 nax cm -1 , 3360, 2960, 2900, 2480, 1735 ，
1595, 1450, 1430, 1395, 1370, 1330,
1285, 1260, 1225, 1180, 1145, 1128,
1100, 1080, 1069, 1010, 990, 970, (5) H 1 nuclear magnetic resonance spectrum 400MHz, measured in CD 3 OD, TMS internal reference.
See Figure 3. (6) C 13 nuclear magnetic resonance spectrum, measured in CD 3 OD at 100 MHz, TMS internal reference.
See Figure 4. δ CD 3 OP TMS ppm, 172.752, 153.264, 153.152, 114.774,
111.235, 105.675, 104.746, 98.387, 83.812,
82.418, 81.245, 80.733, 79.076, 78.016,
77.942, 77.869, 77.341, 77.252, 76.299,
76.073, 75.829, 75.342, 75.029, 74.871,
73.753, 73.309, 73.119, 72.987, 71.634,
69.565, 67.141, 65.671, 45.523, 44.911,
41.171, 39.704, 37.908, 37.783, 37.493,
37.447, 37.154, 36.242, 35.753, 33.006,
31.823, 31.278, 31.050, 30.836, 29.381,
27.111, 18.390, 18.317, 18.115, 15.816 As a result of the above physical and chemical properties and separate research, the chemical structural formula of halichondrin B was determined as follows. Effects of the Invention: Halichondrin B of the present invention has antitumor activity and is useful as a medicine. Next, the antitumor effect of halichondrin B will be explained using test examples. [Anti-tumor activity test] <Mouse leukemia P-388> p- that is passaged in the abdomen of DBA/2 mice
388 lymphocytic leukemia cells were collected from the peritoneal cavity on the 6th day of passage and adjusted to 10 6 cells/0.2 ml Hanks' solution.
It was inoculated into the abdomen of CDF 1 (DBA/2〓×Balb/c♀) mice (10 mice per group). The drug (halichondrin B) was suspended in 0.5% CMC physiological saline at a concentration shown in Table 1 below, and administered intraperitoneally 24 hours after tumor implantation according to the administration schedule in Table 1. , investigated the life-prolonging effect. The results are shown in Table 1, and the excellent antitumor activity of halichondrin B can be confirmed.
【表】【table】
【表】
＜マウスＢ−16メラノーマ＞
C57BL／６マウスの腋窩皮下で継代されてい
るＢ−16メラノーマ細胞を、継代14日目に腋窩皮
下より採取し、ホモゲナイズ後50mg（w.w.）／
0.2ml Hanks液に調整し、BDF1（DBA／２〓×
C57BL／６♀）系マウスの腹腔に接種した（１
群10匹）。
薬剤（ハリコンドリンＢ）は、下記第２表の濃
度となる様に0.5％C.M.C.生理食塩水に懸濁し、
腫瘍移植から24時間経過後９日間に亘り、連日１
日おき及び３日おきに腹腔内へ投与し、また２日
おきに静脈内投与した。
結果は第２表に示す通りであり、この実験にお
いてもハリコンドリンＢの優れた抗腫瘍活性を確
認することができる。[Table] <Mouse B-16 melanoma> B-16 melanoma cells passaged subcutaneously in the axilla of C57BL/6 mice were collected subcutaneously in the axilla on the 14th day of passage, and after homogenization, 50 mg (ww)/
Adjust to 0.2ml Hanks solution and add BDF 1 (DBA/2〓×
C57BL/6♀) mice were inoculated into the peritoneal cavity (1
group of 10). The drug (halichondrin B) was suspended in 0.5% CMC saline to the concentration shown in Table 2 below.
1 day every day for 9 days 24 hours after tumor transplantation
It was administered intraperitoneally every day and every third day, and intravenously every two days. The results are shown in Table 2, and the excellent antitumor activity of halichondrin B can be confirmed in this experiment as well.
【表】【table】
クロイソ海綿（Halichondria Okadai）（湿重
200Kg）を40Kgずつ５バツチに分割し、次の抽出
を行なつた。
上記海綿40Kg（湿重）をメチルアルコール40
中に投入し、ウオリンブレンダーで粉砕する。１
夜放置後過し、残渣を40のメチルアルコール
で２度抽出した後液を合し、次いでメチルアル
コールを減圧留去する。残留エキスに水を加えて
３に調整し、該水性エキスを２のｎ−ブタノ
ールで３回抽出した後、溶媒を減圧下に留去す
る。得られた濃縮エキスを70容量％水性メチルア
ルコールに懸濁させ、脱脂の目的でｎ−ヘキサン
２で３回抽出する。脱脂後の70％水性メチルア
ルコール層よりメチルアルコールを減圧留去し、
水を加えて３に調整した後酢酸エチル２で３
回抽出する。酢酸エチル層を合して減圧濃縮して
濃緑色のペースト状物を得る。上記の処理を前記
５バツチについて夫々行ない、クロイソ海綿200
Kgから酢酸エチルエキスを合計で54ｇを得た。
この酢酸エチルエキス54ｇを、予めメチルアル
コールでパツクしたポリスチレンゲルカラム
（100ml、Hitachi3019）に通し、メチルアルコー
ル２で溶出する。該メチルアルコール分画の初
期に、既に構造の確認されているオカダ酸が溶出
する。メチルアルコール溶出を終えた後、溶出液
をメチルアルコール−10％（容量）クロロホルム
混合液に変え、この混合液２で溶出する。次い
でこの溶出液をメチルアルコール−20容量％クロ
ロホルム混合液に変えて３溶出すると、この分
画に活性物質が溶出してくる。この溶出液から溶
媒を留去すると、緑褐色の粉末830mgが得られる。
この活性分画830mgをメチルアルコールに溶解
し、予めメチルアルコールで処理したセフアデツ
クスＬ−20充填カラム（３×70cm、フアルマシア
社製）に通し、メチルアルコールで溶出する。溶
出液を５mlずつフラクシヨンレクターで分取し、
各フラクシヨンを薄層クロマトグラフイー（以下
TLCという）（メルク社製のKieselgel溶剤Ａ＝
CHCl3／CH3OH：9/1、溶剤Ｂ＝水飽和酢酸エ
チル／CH3OH：9/1、10％硫酸処理後加熱発色）
で検出し、上記と同じシリカゲルプレートを使用
し、溶剤Ａと溶剤Ｂを用いて夫々Rf0.6及び
Rf0.57付近にスポツトを与える分画を採取し、溶
媒を留去することにより57mgの活性分画を得る。
この活性分画57mgを再度上記と同様のカラム
（１×50cm）に通し、TLCで検出しつつ同一の条
件で略単一のスポツトを与える分画を集め、溶媒
を留去して15mgの活性フラクシヨンを得る。
次に、メルク社製のLichrosorb（RP−18.5μm、
８×500mm）を充填した高速液体クロマトグラフ
イー用カラムを80％メチルアルコールで平衡化し
ておき、メチルアルコールに溶解した上記活性フ
ラクシヨン14mgを通し、前記と同じTLCで検出
しながら常法に従つて目的物質を分取した後、該
分画から溶媒を留去することにより針状結晶のハ
リコンドリンＢ（3.1mg）を得た。
Halichondria Okadai (wet weight)
200Kg) was divided into 5 batches of 40Kg each, and the following extraction was performed. 40kg (wet weight) of the above sponge and 40kg of methyl alcohol
Pour it in and crush it with a walnut blender. 1
After standing overnight, the mixture was filtered, the residue was extracted twice with 40% methyl alcohol, the liquids were combined, and then the methyl alcohol was distilled off under reduced pressure. The remaining extract was adjusted to 3 by adding water, and the aqueous extract was extracted three times with n-butanol in 2, and then the solvent was distilled off under reduced pressure. The concentrated extract obtained is suspended in 70% by volume aqueous methyl alcohol and extracted three times with 2 portions of n-hexane for the purpose of defatting. Methyl alcohol was distilled off under reduced pressure from the 70% aqueous methyl alcohol layer after degreasing.
Add water to adjust to 3, then add 2 ethyl acetate to 3
Extract times. The ethyl acetate layers were combined and concentrated under reduced pressure to obtain a dark green paste. The above treatment was applied to each of the 5 batches, and 200 pieces of Croiso sponge were prepared.
A total of 54 g of ethyl acetate extract was obtained from Kg. 54 g of this ethyl acetate extract was passed through a polystyrene gel column (100 ml, Hitachi 3019) packed in advance with methyl alcohol, and eluted with 2 methyl alcohol. At the beginning of the methyl alcohol fraction, okadaic acid, whose structure has already been confirmed, is eluted. After completing the methyl alcohol elution, the eluate is changed to a mixture of methyl alcohol and 10% (volume) chloroform, and this mixture 2 is used for elution. Next, this eluate is changed to a mixture of methyl alcohol and 20% by volume chloroform for three elutions, and the active substance is eluted in this fraction. When the solvent is distilled off from this eluate, 830 mg of greenish brown powder is obtained. 830 mg of this active fraction was dissolved in methyl alcohol, passed through a Sephadex L-20 packed column (3 x 70 cm, manufactured by Pharmacia) that had been previously treated with methyl alcohol, and eluted with methyl alcohol. Collect 5 ml of the eluate using a fractionator,
Each fraction was analyzed by thin layer chromatography (see below).
TLC) (Merck Kieselgel Solvent A =
CHCl 3 /CH 3 OH: 9/1, solvent B = water-saturated ethyl acetate / CH 3 OH: 9/1, color developed by heating after treatment with 10% sulfuric acid)
Using the same silica gel plate as above, Rf0.6 and Rf0.6 were detected using solvent A and solvent B, respectively.
A fraction giving a spot around Rf0.57 is collected and the solvent is distilled off to obtain 57 mg of active fraction. 57 mg of this active fraction was passed through the same column (1 x 50 cm) as above again, and the fractions that gave almost a single spot under the same conditions were collected while being detected by TLC, and the solvent was distilled off to obtain 15 mg of active fraction. Get the fraction. Next, Merck's Lichrosorb (RP-18.5μm,
A column for high performance liquid chromatography packed with 8 x 500 mm) was equilibrated with 80% methyl alcohol, and 14 mg of the above active fraction dissolved in methyl alcohol was passed through it, and detected using the same TLC as above, according to a conventional method. After the target substance was fractionated, the solvent was distilled off from the fraction to obtain halichondrin B (3.1 mg) in the form of needle-shaped crystals.
第１〜４図はハリコンドリンＢの理化学的性状
を示すもので、第１図はマススペクトル、第２図
は赤外線吸収スペクトル、第３，４図はH1核及
びC13核の核磁気共鳴スペクトルである。
Figures 1 to 4 show the physical and chemical properties of halichondrin B. Figure 1 is the mass spectrum, Figure 2 is the infrared absorption spectrum, and Figures 3 and 4 are the nuclear magnetic resonance of H1 and C13 nuclei. It is a spectrum.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60032253A JPS61191687A (en) | 1985-02-20 | 1985-02-20 | Halichondrin b |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60032253A JPS61191687A (en) | 1985-02-20 | 1985-02-20 | Halichondrin b |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61191687A JPS61191687A (en) | 1986-08-26 |
| JPH041751B2 true JPH041751B2 (en) | 1992-01-14 |
Family
ID=12353849
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60032253A Granted JPS61191687A (en) | 1985-02-20 | 1985-02-20 | Halichondrin b |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61191687A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5358949A (en) * | 1986-03-05 | 1994-10-25 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives and salts thereof and anti-arrhythmic agents containing the carbostyril derivatives |
| US5426194A (en) * | 1993-01-19 | 1995-06-20 | Arizona Board Of Regents, A Body Corporate Acting On Behalf Of Arizona State University | Isolation and structure of Halistatin 1 |
| US11498892B2 (en) | 2017-07-06 | 2022-11-15 | President And Fellows Of Harvard College | Fe/Cu-mediated ketone synthesis |
| IL271660B (en) | 2017-07-06 | 2022-09-01 | Harvard College | Synthesis of halichondrins |
| CN111566113B (en) | 2017-11-15 | 2024-01-09 | 哈佛大学的校长及成员们 | Macrocyclic compounds and uses thereof |
-
1985
- 1985-02-20 JP JP60032253A patent/JPS61191687A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61191687A (en) | 1986-08-26 |
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