JP2020002014A - Inhibitory activity and purification method thereof - Google Patents
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Abstract
Description
本発明は、阻害活性物及びその精製方法に関し、詳しくは、真菌株であるアスペルギルス属株（Ａｓｐｅｒｇｉｌｌｕｓ ｕｄａｇａｗａｅ ＩＦＭ５４３０２株）を基にした血小板凝集阻害活性やがん細胞増殖抑制効果を有効に発揮させることができる阻害活性物及びその精製方法に関するものである。 The present invention relates to an inhibitory substance and a method for purifying the same, and more particularly, to effectively exhibit a platelet aggregation inhibitory activity and a cancer cell growth inhibitory effect based on a fungal strain of the genus Aspergillus (Aspergillus udagawae IFM54302). And a purification method thereof.
従来、血小板凝集阻害活性やがん細胞増殖抑制効果を発揮させるための阻害活性物や阻害活性方法が種々提案されている。 Conventionally, various inhibitory substances and inhibitory activity methods for exhibiting platelet aggregation inhibitory activity and cancer cell growth inhibitory effect have been proposed.
特許文献１には、本発明に関連する技術として、所定の植物の抽出物から特定の化合物を得てこれを対象物に添加し、ＵＶを照射しＤＮＡ活性を阻害するように構成したＤＮＡ活性阻害方法が提案されている。 Patent Literature 1 discloses a technique related to the present invention, in which a specific compound is obtained from an extract of a predetermined plant, added to a target, and irradiated with UV to inhibit DNA activity. Inhibition methods have been proposed.
しかし、上述した特許文献１の技術を含め、真菌株であるアスペルギルス属株を利用した阻害活性物は開発されていないのが現状である。 However, at present, no inhibitory activity utilizing a fungal strain of the genus Aspergillus has been developed, including the technology of Patent Document 1 described above.
本発明は、従来における上記事情に鑑み開発されたものであり、真菌株であるアスペルギルス属株（Ａｓｐｅｒｇｉｌｌｕｓ ｕｄａｇａｗａｅ ＩＦＭ５４３０２株）を利用し、血小板凝集阻害活性やがん細胞増殖抑制効果を有効に発揮させることができる阻害活性物及びその生成方法を提供するものである。 The present invention has been developed in view of the above circumstances, and utilizes a fungal strain of the genus Aspergillus (Aspergillus udagagawae IFM54302) to effectively exhibit platelet aggregation inhibitory activity and cancer cell growth inhibitory effect. And a method for producing the same.
本発明は、真菌株であるアスペルギルス属株（Ａｓｐｅｒｇｉｌｌｕｓ ｕｄａｇａｗａｅ ＩＦＭ５４３０２株）を精製し、化１の絶対立体化学構造式で特定されるＡＵ−１ａ（１Ｒ，２Ｓ）−メチル ２，８−ジヒドロキシ−６−（ヒドロキシメチル）−９−オキソ−２，９―ジヒドロ−１Ｈ−キサンテン−１−カルボキシレートと、化２の絶対立体化学構造式で特定されるＡＵ−１ｂ（１Ｓ，２Ｒ）−メチル ２，８−ジヒドロキシ−６−（ヒドロキシメチル）−９−オキソ−２，９―ジヒドロ−１Ｈ−キサンテン−１−カルボキシレートと、前記ＡＵ−１ａ、ＡＵ−１ｂのラセミ体であるＡＵ−１ａｂと、を得て、前記ＡＵ−１ａ、ＡＵ−１ｂ、ＡＵ−１ａｂを生体の阻害活性薬として用いることを最も主要な特徴とする。 The present invention purifies a fungal strain of the genus Aspergillus (Aspergillus udagawaway IFM54302), and expresses AU-1a (1R, 2S) -methyl 2,8-dihydroxy-6 specified by the absolute stereochemical formula of Chemical formula 1. -(Hydroxymethyl) -9-oxo-2,9-dihydro-1H-xanthen-1-carboxylate and AU-1b (1S, 2R) -methyl 2, specified by the absolute stereochemical formula 8-Dihydroxy-6- (hydroxymethyl) -9-oxo-2,9-dihydro-1H-xanthene-1-carboxylate and AU-1ab which is a racemate of AU-1a and AU-1b The main feature of the present invention is that the AU-1a, AU-1b, and AU-1ab are used as biologically active inhibitors.
請求項１記載の発明によれば、血小板凝集を抑制する抗血小板薬として有効で、そして、抗がん剤として有効で、更に、チロシンキナーゼの阻害活性薬として有効な阻害活性物を実現し提供することができる。 ADVANTAGE OF THE INVENTION According to the invention of claim 1, an inhibitory active substance which is effective as an antiplatelet drug for suppressing platelet aggregation, effective as an anticancer agent, and further effective as a tyrosine kinase inhibitory active agent is provided and provided. can do.
請求項２記載の発明によれば、前記ＡＵ−１ａ、ＡＵ−１ｂをそれぞれ血小板凝集を抑制する抗血小板薬として有効に機能させることができる阻害活性物を実現し提供することができる。 According to the second aspect of the present invention, it is possible to realize and provide an inhibitory active substance that can effectively function the AU-1a and AU-1b as antiplatelet drugs that suppress platelet aggregation.
請求項３記載の発明によれば、前記ＡＵ−１ａ、ＡＵ−１ｂのラセミ体であるＡＵ−１ａｂを血小板凝集を抑制する抗血小板薬として有効に機能させることができる阻害活性物を実現し提供することができる。 According to the third aspect of the present invention, an inhibitory substance capable of effectively functioning AU-1ab, which is a racemate of AU-1a and AU-1b, as an antiplatelet drug for inhibiting platelet aggregation is provided and provided. can do.
請求項４記載の発明によれば、前記ＡＵ−１ａ、ＡＵ−１ｂ及び前記ＡＵ−１ａｂを抗がん剤として有効に機能させることができる阻害活性物を実現し提供することができる。 According to the invention described in claim 4, an inhibitory active substance capable of effectively functioning the AU-1a, AU-1b and AU-1ab as an anticancer agent can be realized and provided.
請求項５記載の発明によれば、前記ＡＵ−１ｂを、チロシンキナーゼの阻害活性薬として有効に機能させることができる阻害活性物を実現し提供することができる。 According to the invention as set forth in claim 5, it is possible to realize and provide an inhibitory substance capable of effectively functioning the AU-1b as a tyrosine kinase inhibitory agent.
請求項６記載の発明によれば、既述した効果を奏する阻害活性物であるＡＵ−１ａｂ、ＡＵ−１ａ及びＡＵ−ｌｂを、主に各種クロマトグラフィー処理により効率よく精製することができる阻害活性物の精製方法を実現し提供することができる。 According to the invention described in claim 6, the inhibitory activity capable of efficiently purifying AU-1ab, AU-1a and AU-lb, which are the inhibitory active substances having the above-mentioned effects, mainly by various chromatographic treatments. A method for purifying a product can be realized and provided.
請求項７記載の発明によれば、請求項６記載の発明と同様に、既述した効果を奏する阻害活性物であるＡＵ−１ａｂ、ＡＵ−１ａ及びＡＵ−ｌｂを、主に各種クロマトグラフィー処理により効率よく精製することができる阻害活性物の精製方法を実現し提供することができる。 According to the invention of claim 7, similarly to the invention of claim 6, AU-1ab, AU-1a and AU-lb which are the inhibitory active substances having the above-mentioned effects are mainly subjected to various chromatographic treatments. Thus, a method for purifying an inhibitory substance that can be purified more efficiently can be realized and provided.
本発明は、真菌株であるアスペルギルス属株（Ａｓｐｅｒｇｉｌｌｕｓ ｕｄａｇａｗａｅ ＩＦＭ５４３０２株）を利用し、血小板凝集阻害活性やがん細胞増殖抑制効果を有効に発揮させることができる阻害活性物を実現し提供するという目的を、真菌株であるアスペルギルス属株（Ａｓｐｅｒｇｉｌｌｕｓ ｕｄａｇａｗａｅ ＩＦＭ５４３０２株）を精製し、化１の絶対立体化学構造式で特定されるＡＵ−１ａ（１Ｒ，２Ｓ）−メチル ２，８−ジヒドロキシ−６−（ヒドロキシメチル）−９−オキソ−２，９―ジヒドロ−１Ｈ−キサンテン−１−カルボキシレートと、化２の絶対立体化学構造式で特定されるＡＵ−１ｂ（１Ｓ，２Ｒ）−メチル ２，８−ジヒドロキシ−６−（ヒドロキシメチル）−９−オキソ−２，９―ジヒドロ−１Ｈ−キサンテン−１−カルボキシレートと、前記ＡＵ−１ａ、ＡＵ−１ｂのラセミ体であるＡＵ−１ａｂと、を得て、前記ＡＵ−１ａ、ＡＵ−１ｂ、ＡＵ−１ａｂを、血小板凝集抑制、がん細胞増殖抑制、更にはチロシンキナーゼ阻害活性を発揮する阻害活性薬として用いる構成により実現した。 An object of the present invention is to use an Aspergillus genus Aspergillus strain (Aspergillus udagawae IFM54302 strain) to realize and provide an inhibitory substance capable of effectively exhibiting platelet aggregation inhibitory activity and cancer cell growth inhibitory effect. Was purified from a fungal strain of the genus Aspergillus (Aspergillus udagawaway IFM54302), and AU-1a (1R, 2S) -methyl 2,8-dihydroxy-6- ( (Hydroxymethyl) -9-oxo-2,9-dihydro-1H-xanthen-1-carboxylate and AU-1b (1S, 2R) -methyl 2,8-specified by the absolute stereochemical structural formula Dihydroxy-6- (hydroxymethyl) -9-oxo-2,9-dihydro-1H Xanthene-1-carboxylate and AU-1a, AU-1ab, which is a racemic form of AU-1b, are obtained, and AU-1a, AU-1b, AU-1ab are used to inhibit platelet aggregation, cancer This was achieved by a configuration used as an inhibitory agent that exerts cell growth suppression and tyrosine kinase inhibitory activity.
以下、図面を参照して、本発明の実施例に係る阻害活性物及びその精製方法について詳細に説明する。 Hereinafter, the inhibitory activity and the purification method thereof according to the examples of the present invention will be described in detail with reference to the drawings.
まず、本実施例に係る阻害活性物について図１乃至図６を参照して詳細に説明する。 First, the inhibitory substance according to this example will be described in detail with reference to FIGS.
本実施例に係る阻害活性物は、真菌株であるアスペルギルス属株（Ａｓｐｅｒｇｉｌｌｕｓ ｕｄａｇａｗａｅ ＩＦＭ５４３０２株）を精製して、下記の化１の絶対立体化学構造式で特定されるＡＵ−１ａ（１Ｒ，２Ｓ）−メチル ２，８−ジヒドロキシ−６−（ヒドロキシメチル）−９−オキソ−２，９―ジヒドロ−１Ｈ−キサンテン−１−カルボキシレートと、下記の化２の絶対立体化学構造式で特定される前記ＡＵ−１ａの立体異性体であるＡＵ−１ｂ（１Ｓ，２Ｒ）−メチル ２，８−ジヒドロキシ−６−（ヒドロキシメチル）−９−オキソ−２，９―ジヒドロ−１Ｈ−キサンテン−１−カルボキシレートと、前記ＡＵ−１ａ、ＡＵ−１ｂのラセミ体であるＡＵ−１ａｂと、を得て、前記ＡＵ−１ａ、ＡＵ−１ｂ、ＡＵ−１ａｂを生体の阻害活性薬として用いるものである。 The inhibitory active substance according to the present example is obtained by purifying a fungal strain of the genus Aspergillus (Aspergillus udagawaway IFM54302), and specifying AU-1a (1R, 2S) identified by the following absolute stereochemical structural formula. -Methyl 2,8-dihydroxy-6- (hydroxymethyl) -9-oxo-2,9-dihydro-1H-xanthen-1-carboxylate, and the above-mentioned compound represented by the following absolute stereochemical structural formula AU-1b (1S, 2R) -methyl 2,8-dihydroxy-6- (hydroxymethyl) -9-oxo-2,9-dihydro-1H-xanthene-1-carboxylate, which is a stereoisomer of AU-1a And AU-1ab, which is a racemate of AU-1a and AU-1b, to produce the AU-1a, AU-1b, and AU-1ab. It is intended to be used as inhibitory active agent.
図１は本実施例に係る阻害活性物におけるＡＵ−１ｂ及びＡＵ−ｌａｂと、Ｓｙｄｏｗｉｎｉｎ Ｂのコラーゲンに関する血小板凝集に及ぼす影響についての濃度と凝集能との関係を示すものであり、また、図２は本実施例に係る阻害活性物におけるＡＵ−１ｂのコラーゲンに関する血小板凝集に及ぼす影響についての濃度と凝集能との関係を示すものである。 FIG. 1 shows the relationship between the concentration of AU-1b and AU-lab in the inhibitory active substance according to the present example and the effect of Sydowinin B on platelet aggregation with respect to collagen, and the aggregation ability. Shows the relationship between the concentration and the aggregating ability of the inhibitory active substance according to the present example regarding the effect of AU-1b on platelet aggregation with respect to collagen.
図１から明らかなように、ＡＵ−１ｂ及びＡＵ−ｌａｂはＳｙｄｏｗｉｎｉｎ Ｂに比べ特に低濃度（０以上１０未満）の範囲でコラーゲンに関する血小板凝集能が少なく、優れた阻害活性を発揮することが分かる。 As is clear from FIG. 1, AU-1b and AU-lab have a lower platelet aggregation ability with respect to collagen than Sydowinin B, particularly in a low concentration (0 to less than 10) range, and exhibit excellent inhibitory activity. .
また、図２から明らかなように、ＡＵ−１ａも低濃度の範囲でコラーゲンに関する血小板凝集能が少なく、優れた阻害活性を発揮することが分かる。 In addition, as is clear from FIG. 2, AU-1a also has a low platelet aggregation ability with respect to collagen in a low concentration range, and exhibits excellent inhibitory activity.
図３は、本実施例に係る阻害活性物におけるＡＵ−１ａｂ、ＡＵ−１ａ、ＡＵ−ｌｂと、Ｓｙｄｏｗｉｎｉｎ Ｂのコラーゲンに関する５０％阻害活性値（ＩＣ５０）を示すものであり、ＡＵ−１ａｂのＩＣ５０＝２．５、ＡＵ−１ａのＩＣ５０＝２、ＡＵ−１ｂのＩＣ５０＝４．５、Ｓｙｄｏｗｉｎｉｎ ＢのＩＣ５０＝６．８である。 FIG. 3 shows AU-1ab, AU-1a, AU-lb and 50% inhibitory activity value (IC 50 ) of Sydowinin B collagen in the inhibitory active substance according to the present example. IC 50 = 2.5, IC 50 = 4.5 of IC 50 = 2, AU-1b of AU-1a, an IC 50 = 6.8 of Sydowinin B.
図４は、本実施例に係る阻害活性物におけるＡＵ−１ａｂ、ＡＵ−ｌｂと、Ｓｙｄｏｗｉｎｉｎ Ｂ及びＥｎｇｙｏｄｏｎｔｉｕｍｏｎｅ Ｈの各種のがん細胞増殖抑制効果を示すものであり、本実施例に係るＡＵ−１ａｂ、ＡＵ−ｌｂの各種のがん細胞増殖に関する５０％阻害活性値（ＩＣ５０）は、Ｓｙｄｏｗｉｎｉｎ Ｂ及びＥｎｇｙｏｄｏｎｔｉｕｍｏｎｅ ＨのＩＣ５０に比べてはるかに小さく、各種のがん細胞増殖抑制に関して優れた阻害活性を発揮することが分かる。 FIG. 4 shows the inhibitory effects of AU-1ab, AU-lb, and Sydowinin B and Engyodoniumone H on various types of cancer cell growth in the inhibitory active substances according to the present example, and AU-1ab according to the present example. , 50% inhibitory activity value (IC 50 ) of AU-lb with respect to various cancer cell proliferation is much smaller than IC 50 of Sydowinin B and Engidontonium H, and excellent inhibitory activity with respect to various cancer cell proliferation inhibition. It turns out that it exerts.
すなわち、本実施例に係るＡＵ−１ａｂ、ＡＵ−ｌｂは、肺がん、胃がん、大腸がん、卵巣がん、脳腫瘍、乳がん、胃がん、前立腺がん、メラノーマ等の治療薬として極めて有益である。
そして、本実施例に係るＡＵ−１ａについても同様な効果が予想される。
That is, AU-1ab and AU-lb according to this example are extremely useful as therapeutic agents for lung cancer, stomach cancer, colon cancer, ovarian cancer, brain tumor, breast cancer, stomach cancer, prostate cancer, melanoma, and the like.
A similar effect is expected for the AU-1a according to the present embodiment.
図５は、本実施例に係る阻害活性物におけるＡＵ−１ａｂ、ＡＵ−１ｂと、Ｓｙｄｏｗｉｎｉｎ Ｂのがん細胞増殖抑制効果に関する５０％阻害活性値ＩＣ５０の逆数プロットを示すものである。 Figure 5 shows AU-1ab in inhibiting actives according to the present embodiment, the AU-1b, the reciprocal plot of 50% on cancer cytostatic effect inhibition activity value IC 50 of Sydowinin B.
次に、慢性骨髄性白血病というのは、遺伝子の転座により起きており、その転座により新しい遺伝子（フィラデルフィア遺伝子と称される）ができるため、それにより新しいキナーゼの一種である「ｂｃｒ−ａｂｌチロシンキナーゼ」という酵素が合成される。 Next, chronic myelogenous leukemia is caused by a translocation of a gene, and the translocation creates a new gene (referred to as a Philadelphia gene). An enzyme called abl tyrosine kinase is synthesized.
図６は、ｂｃｒ−ａｂｌチロシンキナーゼとＡＵ−１ｂ分子の分子解析ソフトを用いた分子ドッキングの結合像（立体構造）を示すものであり、ＡＵ−１ｂ分子はｂｃｒ−ａｂｌチロシンキナーゼの酵素を阻害活性するとされており、阻害活性物として機能するものである。 FIG. 6 shows a binding image (stereostructure) of molecular docking of bcr-abl tyrosine kinase and AU-1b molecule using molecular analysis software. The AU-1b molecule inhibits the enzyme of bcr-abl tyrosine kinase. It is said to be active and functions as an inhibitory activity.
また、ＡＵ−１ａ分子も同様に、阻害活性物として機能すると予想される。 AU-1a molecule is also expected to function as an inhibitor.
以上説明した本実施例に係る阻害活性物であるＡＵ−１ａ、ＡＵ−１ｂは、血小板凝集を抑制する抗血小板薬として、また、前記ＡＵ−１ａ、ＡＵ−１ｂのラセミ体であるＡＵ−１ａｂも、血小板凝集を抑制する抗血小板薬として有用に用いることができる。 AU-1a and AU-1b which are the inhibitory active substances according to the present example described above are used as antiplatelet drugs for suppressing platelet aggregation, and AU-1ab which is a racemate of AU-1a and AU-1b. Can also be usefully used as an antiplatelet drug that suppresses platelet aggregation.
また、前記ＡＵ−１ａ、ＡＵ−１ｂ及び前記ＡＵ−１ａｂは、抗がん剤として、更に前記ＡＵ−１ｂは、チロシンキナーゼの阻害活性薬として有用に用いることができる。 Further, AU-1a, AU-1b and AU-1ab can be usefully used as anticancer agents, and AU-1b can be usefully used as a tyrosine kinase inhibitory active agent.
次に、本実施例に係る阻害活性物の精製方法について説明する。 Next, a method for purifying an inhibitory activity according to the present example will be described.
（精製方法Ａ）
真菌株であるアスペルギルス属株（Ａｓｐｅｒｇｉｌｌｕｓ ｕｄａｇａｗａｅ ＩＦＭ５４３０２株）を米培地で、２５℃で２１日間培養した。
(Purification method A)
A fungal strain Aspergillus sp. (Aspergillus udagawaway IFM54302 strain) was cultured in a rice medium at 25 ° C. for 21 days.
そして、ＣＨＣｌ３−ＭｅＯＨ（１：１）で抽出後に溶媒を留去し、水とＥｔＯＡｃで液々分配を行って水可溶部を除き、有機層を濃縮してＥｔＯＡｃエキスを得た。 Then, CHCl 3 -MeOH: the solvent was distilled off after extraction with (1 1), with water and EtOAc performing liquid-liquid distribution remove water-soluble portion, was obtained EtOAc extract was concentrated and the organic layer.
更に、ＭｅＣＮとｈｅｘａｎｅを加えて、液々分配を行って低極性化合物を多く含むｈｅｘａｎｅ可溶部分及び不溶物を除いた。 Further, MeCN and hexane were added, and liquid-liquid distribution was performed to remove hexane-soluble portions and insolubles containing a large amount of low-polarity compounds.
ＭｅＣＮ可溶部を濃縮して得たエキスについて、エキスの２０倍量のシリカゲルを用いたカラムクロマトグラフィーに付し、ＣＨＣｌ３−ＥｔＯＨ（１００：１、５０：１、２０：１、１０：１、５：１、１：１、０：１）の混合比を変化させ、順次フラクションを溶出した。 The extract obtained by concentrating the soluble portion of MeCN was subjected to column chromatography using 20 times the amount of silica gel of the extract, and CHCl 3 -EtOH (100: 1, 50: 1, 20: 1, 10: 1). 5: 1, 1: 1 and 0: 1), and fractions were eluted sequentially.
ＣＨＣｌ３−ＥｔＯＨ＝２０：１で溶出したフラクションを濃縮後、再度シリカゲルを用いたカラムクロマトグラフィーに付し、ＣＨＣｌ３−ＥｔＯＨ＝３０：１を移動相に用いて精製した。 The fraction eluted with CHCl 3 -EtOH = 20: 1 was concentrated and then again subjected to column chromatography using silica gel to purify using CHCl 3 -EtOH = 30: 1 as a mobile phase.
得られた粗精製物は、固定相にシリカゲルを用いた中圧クロマトグラフィーでＣｙｃｌｏｈｅｘａｎｅ−ＣＨＣｌ３−ＥｔＯＨ＝５：５：１にて更に精製した。 The resulting crude product was further purified by medium pressure chromatography using silica gel as the stationary phase with Cyclohexane-CHCl 3 -EtOH = 5: 5: 1.
ここで得られる粗製生物からＡｃｅｔｏｎｅ又はＭｅＯＨを用いて再結晶化を行うことにより、ＡＵ−１ａ／１ｂのラセミ体であるＡＵ−１ａｂが得られる。 The crude product obtained here is recrystallized using acetone or MeOH to obtain AU-1ab which is a racemic AU-1a / 1b.
次いで、ＯＤＳ（オクタデシルシリル（Ｏｃｔａ Ｄｅｃｙｌ Ｓｉｌｙｌ） 基）を担体とした逆相のＨＰＬＣでＭｅＣＮ−Ｈ２Ｏ−ＴＦＡ＝３２：６８：０．０３の移動相を使用して、ＡＵ−１ａ及びＡＵ−ｌｂの混合物を得た。 Then, ODS (octadecylsilyl (Octa Decyl Silyl) group) MeCN-H 2 by HPLC on reversed phase to the carrier O-TFA = 32: 68: using 0.03 mobile phase, AU-1a and AU A mixture of -lb was obtained.
ＡＵ−１ａ及びＡＵ−ｌｂの混合物は、移動相にＭｅＯＨを用いた多糖誘導体キラルカラムＨＰＬＣに付すことにより、ＡＵ−ｌａ、ＡＵ−ｌｂを光学分割した。 The mixture of AU-1a and AU-lb was subjected to chiral column HPLC of a polysaccharide derivative using MeOH as a mobile phase, thereby optically resolving AU-la and AU-lb.
更に、Ａｃｅｔｏｎｅ又はＡｃｅｔｏｎｅ−Ｈｅｘａｎｅ混合溶媒により再結晶化を行ってＡＵ−ｌａ、ＡＵ−１ｂを単離した。 Further, AU-la and AU-1b were isolated by recrystallization using Acetone or an Acetone-Hexane mixed solvent.
以上説明した本実施例に係る阻害活性物の精製方法Ａによれば、既述した効果を奏する阻害活性物であるＡＵ−１ａｂ、ＡＵ−１ａ及びＡＵ−ｌｂを主に各種クロマトグラフィー処理により効率よく精製することができる。 According to the purification method A of the inhibitory activity according to the present example described above, the inhibitory activity AU-1ab, AU-1a and AU-lb exhibiting the above-mentioned effects are mainly obtained by various chromatographic treatments. Can be well purified.
（精製方法Ｂ）
真菌株であるアスペルギルス属株（Ａｓｐｅｒｇｉｌｌｕｓ ｕｄａｇａｗａｅ ＩＦＭ５４３０２株）を米培地で、２５℃で２１日間培養した。
(Purification method B)
A fungal strain Aspergillus sp. (Aspergillus udagawaway IFM54302 strain) was cultured in a rice medium at 25 ° C. for 21 days.
次に、ＣＨＣｌ３−ＭｅＯＨ（１：１）で抽出後に溶媒を留去し、水を加えて懸濁させた。 Next, after extraction with CHCl 3 -MeOH (1: 1), the solvent was distilled off, and water was added to suspend the mixture.
そして、懸濁溶液に対して、Ｈｅｘａｎｅ、ＥｔＯＡｃ、ｎ−ＢｕＯＨで順に液々分配を行った。 Then, the suspension was liquid-separated sequentially with Hexane, EtOAc, and n-BuOH.
上記ＥｔＯＡｃ可溶部を濃縮して得たエキスについて、エキスの２０倍量のシリカゲルを用いたカラムクロマトグラフィーに付し、ＣＨＣｌ３−ＥｔＯＨ（１：０、１００：１、５０：１、２０：１、１０：１、５：１、１：１、０：１）の混合比を変化させ、順次フラクションを溶出した。 The extract obtained by concentrating the above-mentioned EtOAc-soluble portion was subjected to column chromatography using 20 times the amount of silica gel of the extract, and CHCl 3 -EtOH (1: 0, 100: 1, 50: 1, 20: (1, 10: 1, 5: 1, 1: 1, 0: 1) were changed and fractions were eluted sequentially.
ＣＨＣｌ３−ＥｔＯＨ＝１０：１で溶出したフラクションを濃縮後、再度シリカゲルを用いたカラムクロマトグラフィーに付し、Ｈｅｘａｎｅ−Ａｃｅｔｏｎｅ＝１：１を移動相に用いて精製した。 The fraction eluted with CHCl 3 -EtOH = 10: 1 was concentrated, subjected to column chromatography again using silica gel, and purified using Hexane-Acetone = 1: 1 as a mobile phase.
次に、既述した場合と同様、得られた粗精製物は、固定相にシリカゲルを用いた中圧クロマトグラフィーにてＣｙｃｌｏｈｅｘａｎｅ−ＣＨＣｌ３−ＥｔＯＨ＝５：５：１にて更に精製した。 Next, in the same manner as described above, the obtained crude product was further purified by medium pressure chromatography using silica gel as a stationary phase at Cyclohexane-CHCl 3 -EtOH = 5: 5: 1.
ここで得られる粗製生物からＡｃｅｔｏｎｅ又はＭｅＯＨを用いて再結晶化を行うことにより、ＡＵ−１ａ／１ｂのラセミ体であるＡＵ−１ａｂが得られる。 By recrystallizing the crude product obtained using acetone or MeOH, AU-1ab which is a racemic AU-1a / 1b is obtained.
次いでＯＤＳを担体とした逆相のＨＰＬＣでＭｅＣＮ−Ｈ２Ｏ−ＴＦＡ＝３２：６８：０．０３の移動相を使用して、ＡＵ−１ａ及びＡＵ−ｌｂ混合物を得た。 Then MeCN-H 2 O-TFA = 32 the ODS by HPLC on reversed phase to the carrier: 68: using 0.03 mobile phase to give the AU-1a and AU-lb mixture.
ＡＵ−１ａ及びＡＵ−ｌｂ混合物は、移動相にＭｅＯＨを用いた、多糖誘導体キラルカラムＨＰＬＣに付すことにより、ＡＵ−ｌａ及びＡＵ−ｌｂを光学分割した。 The AU-1a and AU-lb mixture was subjected to chiral column HPLC of a polysaccharide derivative using MeOH as a mobile phase to optically resolve AU-la and AU-lb.
更に、Ａｃｅｔｏｎｅ又はＡｃｅｔｏｎｅ−Ｈｅｘａｎｅ混合溶媒により再結晶化を行ってＡＵ−ｌａ、ＡＵ−１ｂを単離した。 Further, AU-la and AU-1b were isolated by recrystallization using Acetone or an Acetone-Hexane mixed solvent.
以上説明した本実施例に係る阻害活性物の精製方法Ｂによれば、上述した精製方法Ａの場合と同様、既述した効果を奏する阻害活性物であるＡＵ−１ａｂ、ＡＵ−１ａ及びＡＵ−ｌｂを、主に各種クロマトグラフィー処理により効率よく精製することができる。 According to the purification method B of the inhibitory activity according to the present example described above, as in the case of the purification method A described above, AU-1ab, AU-1a, and AU-1 which are the inhibitory activity having the above-described effects. lb can be efficiently purified mainly by various chromatographic treatments.
本発明の阻害活性物は、上述した場合の他、心筋梗塞、血栓症等の循環器病用の阻害活性物として広範に応用可能である。 In addition to the cases described above, the inhibitory activity of the present invention can be widely applied as an inhibitory activity for cardiovascular diseases such as myocardial infarction and thrombosis.
ＡＵ−ｌａ 阻害活性物
ＡＵ−１ｂ 阻害活性物
ＡＵ−ｌａｂ ＡＵ−１ａ／１ｂのラセミ体
AU-la Inhibitory Activity AU-1b Inhibitory Activity AU-lab Racemic AU-1a / 1b
Claims (7)
下記の化１の絶対立体化学構造式で特定されるＡＵ−１ａ（１Ｒ，２Ｓ）−メチル ２，８−ジヒドロキシ−６−（ヒドロキシメチル）−９−オキソ−２，９―ジヒドロ−１Ｈ−キサンテン−１−カルボキシレートと、
下記の化２の絶対立体化学構造式で特定されるＡＵ−１ｂ（１Ｓ，２Ｒ）−メチル ２，８−ジヒドロキシ−６−（ヒドロキシメチル）−９−オキソ−２，９―ジヒドロ−１Ｈ−キサンテン−１−カルボキシレートと、
前記ＡＵ−１ａ、ＡＵ−１ｂのラセミ体であるＡＵ−１ａｂと、
を得て、
前記ＡＵ−１ａ、ＡＵ−１ｂ、ＡＵ−１ａｂを生体の阻害活性薬として用いることを特徴とする阻害活性物。
AU-1a (1R, 2S) -methyl 2,8-dihydroxy-6- (hydroxymethyl) -9-oxo-2,9-dihydro-1H-xanthene specified by the following absolute stereochemical structural formula -1-carboxylate;
AU-1b (1S, 2R) -methyl 2,8-dihydroxy-6- (hydroxymethyl) -9-oxo-2,9-dihydro-1H-xanthene specified by the following absolute stereochemical structural formula -1-carboxylate;
AU-1ab, which is a racemate of AU-1a and AU-1b;
Get
An inhibitory active substance, wherein the AU-1a, AU-1b, or AU-1ab is used as a biological inhibitory agent.
溶媒を留去した生成物から水可溶部を除去しエキスを得て、低極性化合物を含む可溶部及び不溶部の除去、濃縮を行って濃縮エキスを得る工程と、
濃縮エキスに対するシリカゲルを用いたクロマトグラフィー処理により前記濃縮エキスのフラクションを抽出する工程と、
前記フラクションの濃縮、シリカゲルを用いた再度のクロマトグラフィー処理により粗生成物を得る工程と、
前記粗生成物に対するシリカゲルを用いた中圧クロマトグラフィー処理及び処理後の粗生成物の再結晶化処理によりＡＵ−１ａ、ＡＵ−１ｂのラセミ体であるＡＵ−１ａｂを得る工程と、
前記ラセミ体であるＡＵ−１ａｂに対する逆相の高速液体クロマトグラフィー処理によりＡＵ−１ａ、ＡＵ−１ｂの混合物を得る工程と、
ＡＵ−１ａ、ＡＵ−１ｂの混合物に対する多糖誘導体キラルカラム高速液体クロマトグラフィー処理によりＡＵ−１ａ、ＡＵ−１ｂを光学分割する工程と、
光学分割したＡＵ−１ａ、ＡＵ−１ｂの再結晶化によりこれらを単離する工程と、
を有することを特徴とする阻害活性物の精製方法。 A step of culturing a fungus strain of the genus Aspergillus (Aspergillus udagawaway IFM54302), and distilling off the solvent after extraction with the solvent;
Removing the water-soluble portion from the product obtained by distilling off the solvent to obtain an extract, removing the soluble portion and the insoluble portion containing the low-polarity compound, and performing a concentration to obtain a concentrated extract,
Extracting a fraction of the concentrated extract by chromatography on the concentrated extract using silica gel,
Concentrating the fraction, a step of obtaining a crude product by re-chromatography using silica gel,
A step of obtaining AU-1ab which is a racemate of AU-1a and AU-1b by medium pressure chromatography using silica gel on the crude product and recrystallization treatment of the crude product after the treatment;
A step of obtaining a mixture of AU-1a and AU-1b by reverse-phase high-performance liquid chromatography of the racemic AU-1ab;
Optically resolving AU-1a, AU-1b by a polysaccharide derivative chiral column high-performance liquid chromatography treatment on a mixture of AU-1a, AU-1b;
Isolating the optically resolved AU-1a and AU-1b by recrystallization,
A method for purifying an inhibitory activity, comprising:
溶媒を留去した生成物に対して水を加えて懸濁させ、懸濁溶液の液々分配を行って可溶部を濃縮して得たエキスについて、シリカゲルを用いたカラムクロマトグラフィー処理によりフラクションを溶出する工程と、
溶出したフラクションを濃縮後、再度シリカゲルを用いたカラムクロマトグラフィー処理により粗生成物を精製する工程と、
前記粗生成物に対するシリカゲルを用いた中圧クロマトグラフィー処理及び処理後の粗生成物の再結晶化処理によりＡＵ−１ａ、ＡＵ−１ｂのラセミ体であるＡＵ−１ａｂを得る工程と、
前記ラセミ体であるＡＵ−１ａｂに対する逆相の高速液体クロマトグラフィー処理によりＡＵ−１ａ、ＡＵ−１ｂの混合物を得る工程と、
ＡＵ−１ａ、ＡＵ−１ｂの混合物に対する多糖誘導体キラルカラム高速液体クロマトグラフィー処理によりＡＵ−１ａ、ＡＵ−１ｂを光学分割する工程と、
光学分割したＡＵ−１ａ、ＡＵ−１ｂの再結晶化によりこれらを単離する工程と、
を有することを特徴とする阻害活性物の精製方法。 A step of culturing a fungus strain of the genus Aspergillus (Aspergillus udagawaway IFM54302), and distilling off the solvent after extraction with the solvent;
The product obtained by distilling off the solvent is suspended by adding water, and the extract obtained by distributing the suspension solution and concentrating the soluble portion is fractionated by column chromatography using silica gel. Eluting
After concentrating the eluted fractions, a step of purifying the crude product again by column chromatography using silica gel,
A step of obtaining AU-1ab which is a racemate of AU-1a and AU-1b by medium pressure chromatography using silica gel on the crude product and recrystallization treatment of the crude product after the treatment;
A step of obtaining a mixture of AU-1a and AU-1b by reverse-phase high-performance liquid chromatography of the racemic AU-1ab;
Optically resolving AU-1a, AU-1b by a polysaccharide derivative chiral column high-performance liquid chromatography treatment on a mixture of AU-1a, AU-1b;
Isolating the optically resolved AU-1a and AU-1b by recrystallization,
A method for purifying an inhibitory activity, comprising:
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| JP2018119859A Pending JP2020002014A (en) | 2018-06-25 | 2018-06-25 | Inhibitory activity and purification method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115466241A (en) * | 2021-06-11 | 2022-12-13 | 中国科学院微生物研究所 | Compounds with anti-helicobacter pylori activity and applications |
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| CN115466241A (en) * | 2021-06-11 | 2022-12-13 | 中国科学院微生物研究所 | Compounds with anti-helicobacter pylori activity and applications |
| CN115466241B (en) * | 2021-06-11 | 2024-05-17 | 中国科学院微生物研究所 | Compounds with anti-Helicobacter pylori activity and their applications |
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