JP5892508B2 - Antitumor agent and method for producing the same - Google Patents
Antitumor agent and method for producing the same Download PDFInfo
- Publication number
- JP5892508B2 JP5892508B2 JP2011258221A JP2011258221A JP5892508B2 JP 5892508 B2 JP5892508 B2 JP 5892508B2 JP 2011258221 A JP2011258221 A JP 2011258221A JP 2011258221 A JP2011258221 A JP 2011258221A JP 5892508 B2 JP5892508 B2 JP 5892508B2
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- Prior art keywords
- compound
- antitumor agent
- hexane
- ethyl acetate
- cancer
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Images
Description
本発明は、抗腫瘍剤及びその製造方法に関する。特に、本発明は、シソ科植物ヒプティス・ヴェルチシラータ(Hyptis verticillata)由来の抗腫瘍剤及びその製造方法に関する。具体的には、ヒプティス・ヴェルチシラータ由来の化合物及び組成物を有効成分として含有する抗腫瘍剤及びその製造方法に関する。 The present invention relates to an antitumor agent and a method for producing the same. In particular, the present invention relates to an antitumor agent derived from the Labiatae plant Hyptis verticillata and a method for producing the same. Specifically, the present invention relates to an antitumor agent comprising a compound and composition derived from Hiptis / Verticillata as an active ingredient and a method for producing the same.
シソ科植物であるヒプティス・ヴェルチシラータは熱帯アメリカ原産で、南北アメリカの熱帯から亜熱帯地方に生息している。メキシコでは、一般に「hierba maltina」と呼ばれているこの植物の葉は、経口的に頭痛、胃痛及び消化器疾患等の薬として用いられている。また、この植物全体を煮詰めたものは、虫刺され、リウマチ及び皮膚感染症等の塗り薬として用いられており、さらに、駆虫剤や下剤としても広く用いられている。 Hyptis Vertisirata, a Labiatae plant, is native to tropical America and lives in the tropical and subtropical regions of the Americas. In Mexico, the leaves of this plant, commonly called “hierba maltina”, are used orally as drugs for headaches, stomach pains and digestive disorders. Moreover, what boiled down this whole plant is used as a coating agent, such as an insect bite, a rheumatism, and a skin infection, and is also widely used as an anthelmintic and a laxative.
ヒプティス・ヴェルチシラータからは、過去の研究により、多くのリグナン骨格を有する化合物が単離されている(非特許文献1及び2)。非特許文献2には、図1に示すようなリグナン骨格を有する化合物が記載されている。
From Hiptis vertisirata, compounds having many lignan skeletons have been isolated by past studies (Non-patent
成人T細胞白血病(Adult T−cell Leukemia:以下、ATLという)は、細胞性免疫担当細胞であるT細胞がHTLV−1というウイルスに侵されてガン化する白血病のことであり、T細胞がガン化したATL細胞の一部は花びらのような形状をした核を有し、「花細胞」と呼ばれている。感染経路としては、母乳、胎盤、産道を介した垂直感染、及び、性交、輸血、臓器移植を介した水平感染等が挙げられる。ATLの発症までの潜伏期間は40〜60年であり、成人期以降に水平感染した人からは、ATLの発症はほとんど見られない。HTLV−1ウイルスのキャリアは日本で120万人、世界では1000万〜2000万人とされており、日本では九州・沖縄地方に多いという特徴をもつ。発症すると、白血球数の増加、リンパ節腫脹、肝臓や脾臓の腫大、皮膚紅斑や皮下腫瘤等の皮膚病変、下痢や腹痛等の消化器症状がしばしばみられる。また病勢の悪化によって血液中のカルシウム値が上昇(高カルシウム血症)すると、全身の倦怠感、意識障害等の症状を引き起こす。さらに免疫能の低下により感染症にかかりやすくなり、真菌、原虫、寄生虫及びウイルス等による日和見感染症を高頻度に合併する。ATL細胞は抗ガン剤が効きにくく、また寛解が得られたとしても、再発率が高い。このため、従来の治療法ではきわめて難治性であるため有効な治療薬の探索が求められている。 Adult T-cell leukemia (hereinafter referred to as ATL) is a leukemia in which T cells, which are cells responsible for cellular immunity, are invaded by a virus called HTLV-1 and become cancerous. Some of the converted ATL cells have nuclei shaped like petals and are called “flower cells”. Examples of infection routes include vertical infection via breast milk, placenta and birth canal, and horizontal infection via sexual intercourse, blood transfusion and organ transplantation. The incubation period until the onset of ATL is 40 to 60 years, and the onset of ATL is hardly seen from those who have been horizontally infected after adulthood. The carrier of HTLV-1 virus is 1.2 million in Japan and 10 to 20 million in the world. In Japan, there are many carriers in the Kyushu and Okinawa regions. Onset of symptoms often leads to increased white blood cell count, lymphadenopathy, enlargement of the liver and spleen, skin lesions such as erythema and subcutaneous masses, and gastrointestinal symptoms such as diarrhea and abdominal pain. In addition, when the calcium level in the blood rises (hypercalcemia) due to the worsening of the disease state, it causes symptoms such as general malaise and impaired consciousness. Furthermore, it becomes easy to get an infectious disease due to a decrease in immunity, and opportunistic infectious diseases caused by fungi, protozoa, parasites and viruses are frequently combined. ATL cells are less effective for anticancer drugs and have a high recurrence rate even if remission is obtained. For this reason, since the conventional treatment method is extremely refractory, a search for an effective therapeutic agent is required.
非特許文献3には、リグナン類に属する化合物であるエトポシド(etoposide)(VP−16):
また特許文献1には、キク科植物ベニバナボロギクからの抽出物がATL細胞に対して抗腫瘍活性を有することが記載されている。
しかしながら、シソ科植物ヒプティス・ヴェルチシラータ由来の化合物又は抽出物がATL細胞に対して抗腫瘍活性を有することはこれまで報告されていない。 However, it has not been reported so far that a compound or extract derived from the Labiatae plant Hyptis verticillata has antitumor activity against ATL cells.
本発明は、極めて効果の高い抗腫瘍剤、特に難治性のATLをはじめとする多種の白血病、リンパ腫及び固形癌に対して極めて高い効果を有する抗腫瘍剤並びにその製造方法を提供することを目的とする。 An object of the present invention is to provide an antitumor agent having a very high effect, particularly an antitumor agent having a very high effect on various leukemias, lymphomas and solid cancers including refractory ATL, and a method for producing the same. And
本発明者は、シソ科植物ヒプティス・ヴェルチシラータ由来の化合物及び組成物が高い抗腫瘍活性を有することを見出した。 The inventor has found that compounds and compositions derived from the Labiatae plant Hyptis verticillata have high antitumor activity.
本発明は以下の発明を包含する。
(1)一般式(I):
(1) General formula (I):
[式中、
R1は、ヒドロキシル基、メトキシ基、メチレンジオキシ基及びリン酸基から選ばれる少なくとも1個の基により置換されているフェニル基であり;
R2は、水素原子、ヒドロキシル基、メトキシ基、アセチル基、アニリノ基、及び、以下:
R3は、水素原子、ヒドロキシル基、メトキシ基及びアセチル基から選択され;
R4は、水素原子、ヒドロキシル基、メトキシ基及びアセチル基から選択される]
で示される化合物(ただし、式(D):
(2)R3が、ヒドロキシル基、メトキシ基及びアセチル基から選択される、上記(1)に記載の化合物。
(3)式(A):
(4)上記(3)に記載の化合物を含有するヒプティス・ヴェルチシラータ(Hyptis verticillata)由来の組成物。
(5)前記組成物が式(B):
式(C):
式(D):
式(E):
(6)前記組成物がヒプティス・ヴェルチシラータの抽出物又はその処理物である、上記(4)又は(5)に記載の組成物。
(7)ヒプティス・ヴェルチシラータのメタノール抽出物をエーテルと水で分配して得られたエーテル層を85〜95%メタノール水溶液とヘキサンで分配した場合の前記メタノール水溶液抽出物を、シリカゲルカラムクロマトグラフィーにより処理して得られる組成物。
(8)シリカゲルカラムクロマトグラフィーの移動相として酢酸エチル/ヘキサン−酢酸エチルを用いた場合の60%酢酸エチル/ヘキサン溶出画分である、上記(7)に記載の組成物。
(9)シリカゲルカラムクロマトグラフィーの移動相として酢酸エチル/ヘキサン−酢酸エチルを用いた場合の40%〜50%酢酸エチル/ヘキサン溶出画分である、上記(7)に記載の組成物。
(10)上記(1)〜(3)のいずれかに記載の化合物、又は上記(4)〜(9)のいずれかに記載の組成物を有効成分として含有する抗腫瘍剤。
(11)成人T細胞白血病治療剤である、上記(10)に記載の抗腫瘍剤。
(12)薬剤耐性を有する患者に投与するための、上記(10)又は(11)に記載の抗腫瘍剤。
(13)医薬品である、上記(10)〜(12)いずれかに記載の抗腫瘍剤。
(14)食品に添加するための、上記(10)〜(12)のいずれかに記載の抗腫瘍剤。
(15)ヒプティス・ヴェルチシラータを抽出し、得られた抽出物を精製することを特徴とする、式(A):
R 1 is a phenyl group substituted by at least one group selected from a hydroxyl group, a methoxy group, a methylenedioxy group and a phosphate group;
R 2 represents a hydrogen atom, a hydroxyl group, a methoxy group, an acetyl group, an anilino group, and the following:
R 3 is selected from a hydrogen atom, a hydroxyl group, a methoxy group and an acetyl group;
R 4 is selected from a hydrogen atom, a hydroxyl group, a methoxy group and an acetyl group]
(Wherein the formula (D):
(2) The compound according to (1) above, wherein R 3 is selected from a hydroxyl group, a methoxy group, and an acetyl group.
(3) Formula (A):
(4) A composition derived from Hiptis verticillata containing the compound according to (3) above.
(5) The composition has formula (B):
Formula (C):
Formula (D):
(6) The composition according to (4) or (5) above, wherein the composition is an extract of Hyptis vertisirata or a processed product thereof.
(7) When the ether layer obtained by partitioning the methanol extract of Hyptis vertisirata with ether and water was partitioned with 85-95% aqueous methanol and hexane, the aqueous methanol extract was subjected to silica gel column chromatography. A composition obtained by treatment with
(8) The composition as described in (7) above, which is a fraction eluted with 60% ethyl acetate / hexane when ethyl acetate / hexane-ethyl acetate is used as the mobile phase of silica gel column chromatography.
(9) The composition according to (7) above, which is a fraction eluted with 40% to 50% ethyl acetate / hexane when ethyl acetate / hexane-ethyl acetate is used as a mobile phase of silica gel column chromatography.
(10) An antitumor agent comprising the compound according to any one of (1) to (3) or the composition according to any one of (4) to (9) as an active ingredient.
(11) The antitumor agent according to (10) above, which is a therapeutic agent for adult T cell leukemia.
(12) The antitumor agent according to (10) or (11) above, which is administered to a patient having drug resistance.
(13) The antitumor agent according to any one of (10) to (12), which is a pharmaceutical product.
(14) The antitumor agent according to any one of (10) to (12), which is added to food.
(15) Extracting Hyptis vertisilata and purifying the obtained extract, the formula (A):
本発明によれば、極めて効果の高い抗腫瘍剤、特に難治性のATLをはじめとする多種の白血病、リンパ腫及び固形癌に対して極めて高い効果を有する抗腫瘍剤並びにその製造方法を提供することができる。 According to the present invention, an antitumor agent having a very high effect, particularly an antitumor agent having a very high effect on various leukemias, lymphomas and solid cancers including refractory ATL, and a method for producing the same are provided. Can do.
本発明の化合物は、一般式(I):
R1は、ヒドロキシル基、メトキシ基、メチレンジオキシ基及びリン酸基から選ばれる少なくとも1個の基により置換されているフェニル基であり;
R2は、水素原子、ヒドロキシル基、メトキシ基、アセチル基、アニリノ基、及び、以下:
R3は、水素原子、ヒドロキシル基、メトキシ基及びアセチル基から選択され;
R4は、水素原子、ヒドロキシル基、メトキシ基及びアセチル基から選択される]
で示される構造を有する(ただし、式(D):
R 1 is a phenyl group substituted by at least one group selected from a hydroxyl group, a methoxy group, a methylenedioxy group and a phosphate group;
R 2 represents a hydrogen atom, a hydroxyl group, a methoxy group, an acetyl group, an anilino group, and the following:
R 3 is selected from a hydrogen atom, a hydroxyl group, a methoxy group and an acetyl group;
R 4 is selected from a hydrogen atom, a hydroxyl group, a methoxy group and an acetyl group]
(Wherein the formula (D):
本発明の式(I)の化合物は、1位における絶対配置はR体及びS体のいずれであってもよく、またラセミ体であってもよい。好ましい絶対配置はR体である。また、式(I)の化合物は、2〜3位に二重結合があるという点でエトポシドと異なる。さらに、式(I)の化合物は、5位の置換基、ラクトン環の向きが上記エトポシドと異なる。 In the compound of the formula (I) of the present invention, the absolute configuration at the 1-position may be either R-form or S-form, or a racemate. The preferred absolute configuration is the R form. Also, the compound of formula (I) differs from etoposide in that there is a double bond in the 2-3 position. Furthermore, the compound of formula (I) is different from the above etoposide in the direction of the substituent at the 5-position and the lactone ring.
R1は、好ましくは、以下:
R2は、水素原子、ヒドロキシル基又はメトキシ基であることが好ましい。
R3は、水素原子、メトキシ基又はヒドロキシル基であることが好ましく、メトキシ基又はヒドロキシル基であることが特に好ましい。
R4は、水素原子であることが好ましい。
R 2 is preferably a hydrogen atom, a hydroxyl group or a methoxy group.
R 3 is preferably a hydrogen atom, a methoxy group or a hydroxyl group, particularly preferably a methoxy group or a hydroxyl group.
R 4 is preferably a hydrogen atom.
本発明の式(I)の化合物は、極めて効果の高い抗腫瘍活性を有し、特に難治性のATLをはじめとする多種の白血病、リンパ腫及び固形癌に対して極めて高い効果を有する。 The compound of the formula (I) of the present invention has a highly effective antitumor activity, and particularly has a very high effect on various leukemias, lymphomas and solid cancers including refractory ATL.
本発明の組成物は、式(I)の化合物を有効成分として含有する。 The composition of the present invention contains a compound of formula (I) as an active ingredient.
本発明の化合物は、特に好ましくは、式(A):
本発明の組成物は、シソ科イガニガクサ属のヒプティス・ヴェルチシラータに由来する。用いるヒプティス・ヴェルチシラータの部分は、特に限定されず、全ての植物体を使用できるが、葉及び茎等を用いることが好ましい。 The composition of the present invention is derived from Hyptis verticillata belonging to the family Lamiaceae. The part of Hiptis vertisirata to be used is not particularly limited, and all plants can be used, but it is preferable to use leaves and stems.
本発明の組成物は化合物(A)を含有することが好ましい。
本発明の組成物は化合物(B)−(E)から選ばれる少なくとも1種を含有することが好ましい。
It is preferable that the composition of this invention contains a compound (A).
The composition of the present invention preferably contains at least one selected from the compounds (B)-(E).
本発明の組成物は、化合物(A)と化合物(B)−(E)から選ばれる少なくとも1種を含有することが好ましい。 It is preferable that the composition of this invention contains at least 1 sort (s) chosen from a compound (A) and a compound (B)-(E).
本発明の組成物は、ヒプティス・ヴェルチシラータの抽出物(以下、抽出物という)又はその処理物(以下、処理物という)であることが好ましい。処理物とは、抽出物に分離、精製、単離等の各種処理の少なくとも1つを施したものである。 The composition of the present invention is preferably an extract of Hyptis verticillata (hereinafter referred to as an extract) or a processed product thereof (hereinafter referred to as a processed product). The treated product is obtained by subjecting the extract to at least one of various treatments such as separation, purification, and isolation.
抽出溶媒としては、水;脂肪族炭化水素類、例えばヘキサン;アルコール類、例えばメタノール、エタノール、プロパノール、ブタノール;エステル類、例えば酢酸エチル等の酢酸エステル;エーテル類、例えばエチルエーテル、ジオキサン;ケトン類、例えばアセトン等が挙げられる。抽出物を一旦溶媒除去して乾燥物として用いる場合には、前述した任意の溶媒を単独で又は混合して用いることができる。一方、抽出物を溶媒に溶解した状態で用いる場合には、人体に対して有害な作用を示さない溶媒を用いる必要があり、この場合には、水、エタノール又はこれらの混合物を用いることが好ましい。抽出に際して、ヒプティス・ヴェルチシラータは、そのまま用いることができ、また乾燥後に破砕又は粉砕して溶媒との接触を高めることもできる。 As an extraction solvent, water; aliphatic hydrocarbons such as hexane; alcohols such as methanol, ethanol, propanol and butanol; esters such as acetate such as ethyl acetate; ethers such as ethyl ether and dioxane; ketones For example, acetone etc. are mentioned. When the extract is once solvent-removed and used as a dried product, any of the above-described solvents can be used alone or in combination. On the other hand, when the extract is used in a state dissolved in a solvent, it is necessary to use a solvent that does not have a harmful effect on the human body. In this case, it is preferable to use water, ethanol, or a mixture thereof. . In the extraction, Hiptis vertissirata can be used as it is, or can be crushed or pulverized after drying to enhance contact with the solvent.
本発明の抽出物は、ヒプティス・ヴェルチシラータ1kg当たり、好ましくは5〜30L、特に好ましくは10〜15Lの抽出溶媒で抽出することができる。抽出温度は、好ましくは室温ないし加圧下での沸点の範囲内であり、抽出時間は、抽出温度等により異なるが、好ましくは24〜60時間であり、特に好ましくは36〜48時間である。 The extract of the present invention can be extracted with an extraction solvent of preferably 5 to 30 L, particularly preferably 10 to 15 L, per 1 kg of Hyptis verticillata. The extraction temperature is preferably within the range of room temperature to the boiling point under pressure, and the extraction time varies depending on the extraction temperature and the like, but is preferably 24 to 60 hours, particularly preferably 36 to 48 hours.
このようにして得られた抽出液は、必要に応じて、布、ステンレスフィルター、濾紙、濾過滅菌用フィルター等で濾過して不溶物、不純物等を除去してもよい。また、濾過後の抽出液に、スプレードライ処理、フリーズドライ処理、超臨界処理等の処理を施してもよい。 The extract thus obtained may be filtered with a cloth, a stainless steel filter, a filter paper, a filter sterilization filter or the like as necessary to remove insoluble matters, impurities, and the like. Moreover, you may give processes, such as a spray-dry process, a freeze-dry process, a supercritical process, to the extract after filtration.
このようにして得られた抽出物又はその処理物を、シリカゲルカラムクロマトグラフィー、高速液体クロマトグラフィー(HPLC)、吸着・逆相分配クロマトグラフィー、イオン交換クロマトグラフィー、ゲル濾過クロマトグラフィー、透析等の各種精製手段により処理し、さらに活性を高めた処理物としてもよい。 The extract thus obtained or its treated product is subjected to various types such as silica gel column chromatography, high performance liquid chromatography (HPLC), adsorption / reverse phase partition chromatography, ion exchange chromatography, gel filtration chromatography, dialysis and the like. It is good also as a processed material which processed by the refinement | purification means and raised activity further.
本発明の抽出物としては、例えば、ヒプティス・ヴェルチシラータのメタノール抽出物、これをエーテルと水で分配して得られたエーテル層を85〜95%、好ましくは90%メタノール水溶液とヘキサンで分配した場合のメタノール水溶液抽出物等が挙げられる。 As the extract of the present invention, for example, a methanol extract of Hiptis veltisillata, and an ether layer obtained by partitioning it with ether and water is distributed with 85 to 95%, preferably 90% methanol aqueous solution and hexane. And an aqueous methanol solution extract.
本発明の処理物としては、例えば、上記抽出物をシリカゲルカラムクロマトグラフィー(例えば移動相として酢酸エチル/ヘキサン−酢酸エチル、塩化メチレン/メタノール/水及びメタノールを順次用いる)を用いて分取した溶出画分、好ましくは60%酢酸エチル/ヘキサン溶出画分が挙げられる。 As the treated product of the present invention, for example, elution obtained by fractionating the above extract using silica gel column chromatography (for example, using ethyl acetate / hexane-ethyl acetate, methylene chloride / methanol / water and methanol sequentially as the mobile phase) Fraction, preferably 60% ethyl acetate / hexane elution fraction.
本発明の処理物としては、上記溶出画分をさらに、例えばHPLC(例えばCosmosil 5C18−MS−II、φ4.6×250mm、φ10×250mm、例えば移動相として51%メタノール/水、50%メタノール/水を用いる)を用いて分取した溶出画分が挙げられる。 As the treated product of the present invention, the elution fraction is further purified by, for example, HPLC (for example, Cosmosil 5C18-MS-II, φ4.6 × 250 mm, φ10 × 250 mm, for example, 51% methanol / water, 50% methanol / water as a mobile phase). Elution fractions collected using water).
本発明の処理物としては、上記60%酢酸エチル/ヘキサン溶出画分をさらに、例えばHPLC(例えばCosmosil 5C18−AR、φ10×250mm、例えば移動相として50%メタノール/水を用いる)を用いて分取した溶出画分が挙げられる。本発明の化合物(A)及び(C)は、これらの溶出画分から得られる。本発明の化合物(B)、(D)及び(E)は、これらの溶出画分を例えばHPLC(例えばCosmosil 5C18−MS−II、φ4.6×250mm、φ10×250mm、例えば移動相として30%アセトニトリル/水、43%メタノール/水)を用いて精製した場合に得られる。 As the treated product of the present invention, the fraction eluted with 60% ethyl acetate / hexane is further separated using, for example, HPLC (for example, Cosmosil 5C18-AR, φ10 × 250 mm, for example, using 50% methanol / water as a mobile phase). The collected elution fraction is mentioned. Compounds (A) and (C) of the present invention are obtained from these elution fractions. The compounds (B), (D) and (E) of the present invention can be obtained by, for example, HPLC (for example, Cosmosil 5C18-MS-II, φ4.6 × 250 mm, φ10 × 250 mm, for example, 30% as a mobile phase). (Acetonitrile / water, 43% methanol / water).
本発明の式(I)の化合物又は化合物(B)〜(E)は、合成により製造してもよい。本発明の化合物は、リグナン類の合成法についての総説Eur. J. Org. Chem., 2007, 3815-3828の記載に基づき合成することができる。 The compound of formula (I) or the compounds (B) to (E) of the present invention may be produced by synthesis. The compounds of the present invention can be synthesized based on the description of the review method for synthesizing lignans Eur. J. Org. Chem., 2007, 3815-3828.
本発明の組成物は、本発明の式(I)の化合物を、組成物全量を100質量部として、好ましくは0.01〜0.02質量部、特に好ましくは0.015〜0.017質量部含有する。 The composition of the present invention is preferably 0.01 to 0.02 parts by mass, particularly preferably 0.015 to 0.017 parts by mass, based on 100 parts by mass of the total amount of the compound of formula (I) of the present invention. Contains.
本発明の組成物は、そのまま本発明の抗腫瘍剤の有効成分として使用することができる。本発明の抗腫瘍剤は医薬品であってもよく、食品に添加されてもよい。 The composition of the present invention can be used as it is as an active ingredient of the antitumor agent of the present invention. The antitumor agent of the present invention may be a pharmaceutical product or may be added to food.
本発明において、「腫瘍」には固形腫瘍及び造血器腫瘍が含まれる。ここで、固形腫瘍は、例えば、脳腫瘍、頭頸部癌、食道癌、甲状腺癌、小細胞肺癌、非小細胞肺癌、乳癌、胃癌、胆のう・胆管癌、肝癌、膵癌、結腸癌、直腸癌、卵巣癌、絨毛上皮癌、子宮体癌、子宮頸癌、腎盂・尿管癌、膀胱癌、前立腺癌、陰茎癌、睾丸癌、胎児性癌、ウイルス腫瘍、皮膚癌、悪性黒色腫、神経芽細胞腫、骨肉腫、ユーイング腫、軟部肉腫等であり、好ましくは非小細胞肺癌、結腸癌である。一方、造血器腫瘍は、例えば、急性骨髄性白血病(AML)、急性リンパ性白血病(ALL)、急性前骨髄球性白血病(APL)、慢性骨髄性白血病(CML)、慢性リンパ性白血病(CLL)、有毛細胞白血病(HCL)、成人T細胞白血病(ATL)等の白血病、ホジキン病、非ホジキンリンパ腫(例えばB細胞リンパ腫、T細胞リンパ腫等)等のリンパ腫、多発性骨髄腫等であり、好ましくは急性骨髄性白血病(AML)、急性リンパ性白血病(ALL)、急性前骨髄球性白血病(APL)、成人T細胞白血病(ATL)であり、特に好ましくは成人T細胞白血病(ATL)である。 In the present invention, “tumor” includes solid tumor and hematopoietic tumor. Here, the solid tumor is, for example, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, gallbladder / bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovary Cancer, choriocarcinoma, endometrial cancer, cervical cancer, renal pelvis / ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, viral tumor, skin cancer, malignant melanoma, neuroblastoma Osteosarcoma, Ewing's tumor, soft tissue sarcoma, etc., preferably non-small cell lung cancer and colon cancer. On the other hand, hematopoietic tumors include, for example, acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), chronic myelogenous leukemia (CML), and chronic lymphocytic leukemia (CLL). Leukemia such as hair cell leukemia (HCL) and adult T cell leukemia (ATL), Hodgkin disease, lymphoma such as non-Hodgkin lymphoma (eg B cell lymphoma, T cell lymphoma, etc.), multiple myeloma, etc. Are acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), and adult T cell leukemia (ATL), particularly preferably adult T cell leukemia (ATL).
さらに、本発明の抗腫瘍剤は、薬剤耐性を有する腫瘍細胞に対しても抗腫瘍活性を有する。上記薬剤耐性に関与する遺伝子としては、MRP−1、P−糖蛋白質遺伝子、BCRP等が挙げられる。このように、本発明の抗腫瘍剤は、従来の抗癌剤に対して耐性を獲得した癌患者に対しても治療効果が期待できる。 Furthermore, the antitumor agent of the present invention also has antitumor activity against tumor cells having drug resistance. Examples of the gene involved in drug resistance include MRP-1, P-glycoprotein gene, BCRP and the like. Thus, the antitumor agent of the present invention can be expected to have a therapeutic effect on cancer patients who have acquired resistance to conventional anticancer agents.
本発明の抗腫瘍剤は、公知の食品用担体又は医薬用担体と組合せて製剤化することができる。投与形態としては、特に制限はなく、必要に応じ適宜選択されるが、一般には錠剤、カプセル剤、顆粒剤、細粒剤、散剤、液剤、シロップ剤、懸濁剤、乳剤、エリキシル剤等の経口剤として使用される。また、本発明の抗腫瘍剤は、注射剤、点滴剤、坐剤、吸入剤、経皮吸収剤、経粘膜吸収剤、貼付剤、軟膏剤等の非経口剤として使用してもよい。また、本発明の抗腫瘍剤は、食品、チューインガム、飲料等に添加して、いわゆる特定保健用食品(例えば、癌予防食品)等とすることもできる。 The antitumor agent of the present invention can be formulated in combination with a known food carrier or pharmaceutical carrier. The dosage form is not particularly limited and is appropriately selected as necessary. In general, tablets, capsules, granules, fine granules, powders, solutions, syrups, suspensions, emulsions, elixirs, etc. Used as an oral agent. In addition, the antitumor agent of the present invention may be used as a parenteral agent such as an injection, infusion, suppository, inhalation, transdermal absorption agent, transmucosal absorption agent, patch, ointment and the like. In addition, the antitumor agent of the present invention can be added to foods, chewing gums, beverages and the like to make so-called foods for specific health (for example, cancer preventive foods).
本発明の抗腫瘍剤の投与量は、患者の年令、体重、疾患の程度、投与経路により異なるが、経口投与では、本発明の式(I)の化合物の乾燥粉末として、通常1日1〜10mgであり、投与回数は、通常、経口投与では1日1〜3回である。 The dose of the antitumor agent of the present invention varies depending on the age, weight, degree of disease, and route of administration of the patient, but for oral administration, it is usually 1 day as a dry powder of the compound of formula (I) of the present invention. The dose is usually 1 to 3 times a day for oral administration.
経口剤は、例えばデンプン、乳糖、白糖、マンニット、カルボキシメチルセルロース、コーンスターチ、無機塩類等の賦形剤を用いて常法に従って製造される。 Oral preparations are produced according to a conventional method using excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts.
この種の製剤には、適宜前記賦形剤の他に、結合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進剤、矯味剤、着色剤、香料等を使用することができる。 In this type of preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a corrigent, a colorant, a fragrance and the like can be appropriately used in addition to the above-mentioned excipients.
結合剤の具体例としては、結晶セルロース、結晶セルロース・カルメロースナトリウム、メチルセルロース、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、カルメロースナトリウム、エチルセルロース、カルボキシメチルエチルセルロース、ヒドロキシエチルセルロース、コムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン、デキストリン、アルファー化デンプン、部分アルファー化デンプン、ヒドロキシプロピルスターチ、プルラン、ポリビニルピロリドン、アミノアルキルメタクリレートコポリマーE、アミノアルキルメタクリレートコポリマーRS、メタクリル酸コポリマーL、メタクリル酸コポリマー、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコール、アラビアゴム、アラビアゴム末、寒天、ゼラチン、白色セラック、トラガント、精製白糖、マクロゴールが挙げられる。 Specific examples of the binder include crystalline cellulose, crystalline cellulose / carmellose sodium, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carmellose sodium , Ethylcellulose, carboxymethylethylcellulose, hydroxyethylcellulose, wheat starch, rice starch, corn starch, potato starch, dextrin, pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, pullulan, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer E, aminoalkyl METAKU Rate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer, polyvinyl acetal diethylamino acetate, polyvinyl alcohol, gum arabic, gum arabic powder, agar, gelatin, white shellac, tragacanth, purified sucrose, macrogol.
崩壊剤の具体例としては、結晶セルロース、メチルセルロース、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、カルメロースナトリウム、クロスカルメロースナトリウム、コムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン、部分アルファー化デンプン、ヒドロキシプロピルスターチ、カルボキシメチルスターチナトリウム、トラガントが挙げられる。 Specific examples of disintegrants include crystalline cellulose, methylcellulose, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, wheat starch, rice starch, corn starch, potato starch, and partially pregelatinized. Starch, hydroxypropyl starch, sodium carboxymethyl starch, tragacanth can be mentioned.
界面活性剤の具体例としては、大豆レシチン、ショ糖脂肪酸エステル、ステアリン酸ポリオキシル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンポリオキシプロピレングリコール、セスキオレイン酸ソルビタン、トリオレイン酸ソルビタン、モノステアリン酸ソルビタン、モノパルミチン酸ソルビタン、モノラウリン酸ソルビタン、ポリソルベート、モノステアリン酸グリセリン、ラウリル硫酸ナトリウム、ラウロマクロゴールが挙げられる。 Specific examples of surfactants include soybean lecithin, sucrose fatty acid ester, polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate Sorbitan monopalmitate, sorbitan monolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate, lauromacrogol.
滑沢剤の具体例としては、コムギデンプン、コメデンプン、トウモロコシデンプン、ステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウム、含水二酸化ケイ素、軽質無水ケイ酸、合成ケイ酸アルミニウム、乾燥水酸化アルミニウムゲル、タルク、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム、無水リン酸水素カルシウム、ショ糖脂肪酸エステル、ロウ類、水素添加植物油、ポリエチレングリコールが挙げられる。 Specific examples of lubricants include wheat starch, rice starch, corn starch, stearic acid, calcium stearate, magnesium stearate, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, dry aluminum hydroxide gel, talc, Examples thereof include magnesium aluminate metasilicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sucrose fatty acid ester, waxes, hydrogenated vegetable oil, and polyethylene glycol.
流動性促進剤の具体例としては、含水二酸化ケイ素、軽質無水ケイ酸、乾燥水酸化アルミニウムゲル、合成ケイ酸アルミニウム、ケイ酸マグネシウムが挙げられる。 Specific examples of the fluidity promoter include hydrous silicon dioxide, light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.
また、本発明の抗腫瘍剤は、液剤、シロップ剤、懸濁剤、乳剤、エリキシル剤として投与する場合には、矯味矯臭剤、着色剤を含有してもよい。 Moreover, the antitumor agent of this invention may contain a flavoring agent and a coloring agent, when administering as a liquid agent, a syrup agent, a suspension agent, an emulsion, and an elixir.
以下、実施例により本発明を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples.
(実施例1)
1.ヒプティス・ヴェルチシラータの抽出物、その処理物の調製及び化合物(A)−(E)の単離
ATL患者由来の白血病細胞株S1T細胞に対する抗腫瘍活性を指標として行った。抗腫瘍活性は、下記3に示す方法で測定した。
Example 1
1. The extract of Hiptis vertisirata, the preparation of the treated product, and the antitumor activity of compound (A)-(E) against leukemia cell line S1T cells derived from isolated ATL patients were used as indicators. Antitumor activity was measured by the method shown in 3 below.
ヒプティス・ヴェルチシラータ(被子植物門 双子葉植物網 キク亜綱 シソ目 シソ科 イガニガクサ属)はジャマイカで採取された。 Hyptis Verticillata (Angiospermia dicotyledonous net, Chrysophyceae Lamiaceae Lamiaceae) was collected in Jamaica.
ヒプティス・ヴェルチシラータのメタノール抽出物(S1T細胞に対するIC50値0.1μg/mL)をエーテルと水で二層分配した。エーテル可溶部(IC50値0.125μg/mL)をさらに90%メタノール水溶液とヘキサンで分配し、得られた90%メタノール水溶液可溶部(IC50値0.03μg/mL)を減圧濃縮した。この抽出スキームを図2に示す。 Hyptis verticillata methanol extract (IC 50 value for S1T cells 0.1 μg / mL) was partitioned into two layers with ether and water. The ether soluble part (IC 50 value 0.125 μg / mL) was further partitioned between 90% aqueous methanol solution and hexane, and the obtained 90% methanol aqueous solution soluble part (IC 50 value 0.03 μg / mL) was concentrated under reduced pressure. . This extraction scheme is shown in FIG.
90%メタノール水溶液可溶部(1.07g)をシリカゲルカラムクロマトグラフィー(移動相:5%酢酸エチル/ヘキサン−100%酢酸エチル(画分1〜18)、塩化メチレン:メタノール:水=7:3:0.5(画分19)、100%メタノール(画分20)を用いて分取した。
Silica gel column chromatography (mobile phase: 5% ethyl acetate / hexane-100% ethyl acetate (
60%酢酸エチル/ヘキサンで溶出した9番目の画分53.2mg(IC50値3ng/mL)をさらにHPLC(Cosmosil 5C18−AR、φ10×250mm、移動相:50%メタノール/水、18画分)を用いて分取した。得られた6番目の画分からさらにHPLC(Cosmosil 5C18−MS−II、φ4.6×250mm、移動相:30%アセトニトリル/水)を用いて化合物(B)1.6mg(IC50値2.5ng/mL)を、10番目の画分から化合物(C)2.2mg(IC50値22ng/mL)を単離した。また、12番目の画分からHPLC(Cosmosil 5C18−MS−II、φ10×250mm、移動相:43%メタノール/水)を用いて化合物(D)0.5mg(IC50値0.15ng/mL)と、化合物(E)1.3mg(IC50値15.0ng/mL)をそれぞれ単離した。さらに17番目の画分から化合物(A)1.7mg(IC50値3.0ng/mL)を単離した。 93.2 fraction (IC 50 value 3 ng / mL) eluted with 60% ethyl acetate / hexane was further added to HPLC (Cosmosil 5C18-AR, φ10 × 250 mm, mobile phase: 50% methanol / water, 18 fractions). ). From the obtained sixth fraction, 1.6 mg (IC 50 value: 2.5 ng) of Compound (B) was further obtained using HPLC (Cosmosil 5C18-MS-II, φ4.6 × 250 mm, mobile phase: 30% acetonitrile / water). / ML) and 2.2 mg (IC 50 value 22 ng / mL) of compound (C) was isolated from the 10th fraction. From the twelfth fraction, 0.5 mg (IC 50 value 0.15 ng / mL) of Compound (D) was measured using HPLC (Cosmosil 5C18-MS-II, φ10 × 250 mm, mobile phase: 43% methanol / water). Compound (E) 1.3 mg (IC 50 value 15.0 ng / mL) was isolated. Furthermore, 1.7 mg (IC 50 value: 3.0 ng / mL) of compound (A) was isolated from the 17th fraction.
40%〜50%酢酸エチル/ヘキサンで溶出した5番目の画分66.1mg(IC50値0.35μg/mL;シリカゲルTLC(50%酢酸エチル/ヘキサン)のRf値約0.4)をさらにHPLC(Cosmosil 5C18−AR、φ10×250mm、移動相:51%メタノール/水、9画分)を用いて分取した。4番目の画分(IC50値0.25ng/mL;保持時間約80分)及び7番目の画分(IC50値0.25ng/mL;保持時間約140分)を得た。
上記精製、単離スキームを図3に示す。
Fifth fraction 66.1 mg (IC 50 value 0.35 μg / mL; silica gel TLC (50% ethyl acetate / hexane) Rf value approximately 0.4) eluted with 40% to 50% ethyl acetate / hexane It fractionated using HPLC (Cosmosil 5C18-AR, φ10 × 250 mm, mobile phase: 51% methanol / water, 9 fractions). A fourth fraction (IC 50 value 0.25 ng / mL; retention time about 80 minutes) and a seventh fraction (IC 50 value 0.25 ng / mL; retention time about 140 minutes) were obtained.
The above purification and isolation scheme is shown in FIG.
2.構造決定
化合物(A)は、不定形で黄色がかった固体として得られた。FABマススペクトルによる解析から、分子量426であり、分子式C23H22O8であった。また、1H NMRスペクトルによる解析から、リグナン骨格を示していることが分かった。さらに、13C NMR、13C DEPT、HMBC、HMQCスペクトルを含めた解析により、化合物(A)が、4−メトキシ−9−(3,4,5−トリメトキシフェニル)−8,9−ジヒドロフロ[3’,4’:6,7]ナフト[2,3−d][1,3]ジオキソール−6(5H)−オンであると同定した。化合物(A)の構造及びHMBC相関と1H NMRケミカルシフト値及び13C NMRケミカルシフト値を図4に示す。また、化合物(A)の1H NMRスペクトル及び13C NMRスペクトルを、それぞれ図5及び6に示す。化合物(A)は、現在までに単離された報告はなく、今回初めて単離された化合物であった。
2. The structure-determining compound (A) was obtained as an amorphous and yellowish solid. From analysis by FAB mass spectrum, the molecular weight 426, and a molecular formula C 23 H 22 O 8. Moreover, it turned out that the lignan skeleton is shown from the analysis by a < 1 > H NMR spectrum. Furthermore, by analysis including 13 C NMR, 13 C DEPT, HMBC, and HMQC spectra, compound (A) was converted to 4-methoxy-9- (3,4,5-trimethoxyphenyl) -8,9-dihydrofuro [ 3 ′, 4 ′: 6,7] naphtho [2,3-d] [1,3] dioxol-6 (5H) -one. FIG. 4 shows the structure, HMBC correlation, 1 H NMR chemical shift value, and 13 C NMR chemical shift value of compound (A). Further, 1 H NMR spectrum and 13 C NMR spectrum of the compound (A) are shown in FIGS. 5 and 6, respectively. Compound (A) was the first isolated compound this time, with no reports of isolation to date.
化合物(B)は、不定形無色の固体として得られた。FABマススペクトルによる解析から、分子量414であり、分子式C22H22O8であった。さらに、1H NMR、13C NMR、13C DEPT、HMBC、HMQCスペクトルによる構造解析、及び、B.Konuklugil,Chem.Nat.Compd.,2005,41,306−307及びD. E. Jackson and P. M. Dewick, Phytochemistry, 1984, 23, 1147−1152との比較により、化合物(B)がβ−ペルタチン(β−peltatin)((5R)−5,8,8aβ,β−テトラヒドロ−10−ヒドロキシ−5−(3,4,5−トリメトキシフェニル)フロ[3’,4’:6,7]ナフト[2,3−d]−[1,3]−ジオキソール−6(5aαH)−オン)であると同定した。化合物(B)の構造及び1H NMRケミカルシフト値(ppm)を図7に示す。
Compound (B) was obtained as an amorphous colorless solid. From analysis by FAB mass spectrum, the molecular weight 414, and a
化合物(C)は、不定形で黄色がかった固体として得られた。FABマススペクトルによる解析から、分子量384であり、分子式C21H20O7であった。さらに、1H NMR、13C NMR、13C DEPT、HMBC、HMQCスペクトルによる構造解析、及び、D. E. Jackson and P. M. Dewick, Phytochemistry, 1984, 23, 1147−1152との比較により、化合物(C)が4’−デメチルデスオキシポドフィロトキシン(4’−demethyldesoxypodpphyllotoxin)((5R)−5β−[3,4,5−トリメトキシフェニル]−5aα-ヒドロキシ-5,8,8aβ,9−テトラヒドロフロ[3’,4’:6,7]ナフト[2,3−d]−1,3−ジオキソール-6(5aH)-オン))であると同定した。化合物(C)の構造及び1H NMRケミカルシフト値(ppm)を図8に示す。
Compound (C) was obtained as an amorphous and yellowish solid. From analysis by FAB mass spectrum, the molecular weight 384, and a
化合物(D)は、不定形無色の固体として得られた。FABマススペクトルによる解析から、分子量396であり、分子式C22H20O7であった。さらに、1H NMR、13C NMR、13C DEPT、HMBC、HMQCスペクトルによる構造解析、及び、M. Kuhnt et al, Phytochemistry, 1994,36,485−489との比較により、化合物(D)がヒプチニン(hyptinin)(9α−(3,4,5−トリメトキシフェニル)−5,9−ジヒドロフロ[3’,4’:6,7]ナフト[2,3−d]−[1,3]−ジオキソール−6(8H)−オン)であると同定した。化合物(D)の構造及び1H NMRケミカルシフト値(ppm)を図9に示す。
Compound (D) was obtained as an amorphous colorless solid. From analysis by FAB mass spectrum, the molecular weight 396, and a
化合物(E)は、不定形無色の固体として得られた。FABマススペクトルによる解析から、分子量398であり、分子式C22H22O7であった。さらに、1H NMR、13C NMR、13C DEPT、HMBC、HMQCスペクトルによる構造解析、及び、Y. Inamori et al. Chem. Pharm. Bull., 1985, 33, 704−709との比較により、化合物(E)がデオキシピクロポドフィリン(Deoxypicropodophyllin)((5R)−5,8,8aβ,9−テトラヒドロ−5β−(3,4,5−トリメトキシフェニル)フロ[3’,4’:6,7]ナフト[2,3−d]−[1,3]−ジオキソール−6(5aβH)−オン)であると同定した。化合物(E)の構造及びHMBC相関と1H NMRケミカルシフト値及び13C NMRケミカルシフト値を図10に示す。
Compound (E) was obtained as an amorphous colorless solid. From analysis by FAB mass spectrum, the molecular weight 398, and a
3.抗腫瘍活性の測定
抗腫瘍活性は、ATL細胞株であるS1T細胞に対する細胞障害性をWST法で測定することにより行った。
3. Measurement of antitumor activity Antitumor activity was measured by measuring cytotoxicity against S1T cells, which are ATL cell lines, by the WST method.
RPMI−1640 10%FCS培養液を用いて、96穴平底マルチプレートにS1T細胞1×104/100μL/ウェルと10倍希釈系列の分画液(100μL/ウェル)を入れ、72時間37℃、5%CO2存在下で培養した。
Using RPMI-1640 10% FCS culture medium, placed in a 96-well flat-bottom multi-plate fractionation
最後の4時間、テトラゾリウム塩WST−8試薬を20μL/ウェル添加し、培養を継続した。次いで450nmの吸光度を測定した。細胞生存率はコントロール群を100%として、各濃度分画液のコントロールに対する割合で評価した。抗腫瘍活性の表現として、50%の細胞障害作用を引き起こす化合物の濃度をIC50とした。IC50はμg/mL及びnMで表した。 During the last 4 hours, 20 μL / well of tetrazolium salt WST-8 reagent was added, and the culture was continued. The absorbance at 450 nm was then measured. The cell viability was evaluated based on the ratio of each concentration fraction to the control with the control group as 100%. As an expression of antitumor activity was the concentration of compound causing 50% of the cytopathic effect as IC 50. IC 50 was expressed in μg / mL and nM.
化合物(A)について、上記抗腫瘍活性試験を行った結果を表1及び図11に示す。白血病細胞株であるK3T(ATL細胞)、Jurkat(急性リンパ性白血病細胞)、HL60及びK562(骨髄性白血病細胞)、並びにA549(肺癌細胞)及びSW480(結腸癌細胞)に対する細胞障害性についてもS1T細胞と同様に測定した。 The results of the antitumor activity test for compound (A) are shown in Table 1 and FIG. S1T for cytotoxicity against the leukemia cell lines K3T (ATL cells), Jurkat (acute lymphocytic leukemia cells), HL60 and K562 (myeloid leukemia cells), and A549 (lung cancer cells) and SW480 (colon cancer cells). Measurement was performed in the same manner as the cells.
さらに、化合物(A)について、S1T(ATL細胞)及びActT(活性化T細胞)に対して抗腫瘍活性試験を行った結果を表2に示す。抗腫瘍活性試験は細胞障害性をWST法で測定することにより行った。96穴マルチプレートを用いて化合物(A)を最終濃度10μg/mLから10倍希釈系列で希釈し、それにS1T細胞又はActT細胞1×105/ウェルを添加し、37℃、5%CO2の条件で72時間培養し、上記と同様にWST法で発色させ細胞障害活性を測定した。50%細胞障害作用を引き起こす濃度をIC50とした。
Furthermore, Table 2 shows the results of antitumor activity tests performed on S1T (ATL cells) and ActT (activated T cells) for compound (A). The antitumor activity test was performed by measuring cytotoxicity by the WST method. Compound (A) is diluted from a final concentration of 10 μg / mL to a 10-fold dilution series using a 96-well multiplate, and S1T cells or
表2より、化合物(A)は、ATL細胞であるS1Tに対し、ActTの12倍の抗腫瘍活性を有することがわかる。 From Table 2, it can be seen that the compound (A) has 12 times the antitumor activity of ActT against S1T which is an ATL cell.
以上より、本発明の化合物(A)は、癌細胞、特に白血病細胞であるATL細胞に対して非常に高い抗腫瘍活性を有することがわかった。 From the above, it was found that the compound (A) of the present invention has very high antitumor activity against cancer cells, particularly ATL cells which are leukemia cells.
4.薬剤耐性細胞株に対する抗腫瘍活性の測定
薬剤耐性細胞株に対して化合物(A)、エトポシド及びミトキサントロンの抗腫瘍活性試験を行った結果を表3に示す。薬剤耐性細胞としては、類上皮癌KB3−1とそれに薬剤耐性遺伝子MRP−1を移入した細胞KB/MRP、同様に薬剤耐性遺伝子P−糖蛋白質遺伝子を移入したKB−G2、骨髄性白血病細胞株K562とそれに薬剤耐性遺伝子BCRPを移入したK562/BCRPを用いた。MRP−1、P−糖蛋白質遺伝子及びBCRPはいずれも、多種類の抗癌剤耐性に関与している。MRP−1とP−糖蛋白質の遺伝子移入株についてはエトポシドをコントロール薬剤として用い、BCRP移入株においてはミトキサントロンをコントロール薬剤として用いた。抗腫瘍活性試験は細胞障害性をWST法で測定することにより行った。
4). Measurement of antitumor activity against drug resistant cell line Table 3 shows the results of antitumor activity tests of compound (A), etoposide and mitoxantrone on drug resistant cell lines. Drug resistant cells include epithelioid carcinoma KB3-1 and cell KB / MRP transfected with the drug resistant gene MRP-1, KB-G2 similarly transfected with the drug resistant gene P-glycoprotein gene, myeloid leukemia cell line K562 and K562 / BCRP into which the drug resistance gene BCRP was transferred were used. MRP-1, P-glycoprotein gene and BCRP are all involved in various types of anticancer drug resistance. For gene transfer strains of MRP-1 and P-glycoprotein, etoposide was used as a control agent, and for BCRP transfer strains, mitoxantrone was used as a control agent. The antitumor activity test was performed by measuring cytotoxicity by the WST method.
RPMI−1640 10%FCS培養液を用いて、96穴平底マルチプレートに各細胞1×104/100μL/ウェルと10倍希釈系列の分画液(100μL/ウェル)を入れ、72時間37℃、5%CO2存在下で培養した。
Using RPMI-1640 10% FCS culture medium, placed fraction solution of each
テトラゾリウム塩WST−8試薬を20μL/ウェル添加し、同条件で4時間培養した後、450nmの吸光度を測定した。細胞生存率はコントロール群を100%として、各濃度分画液のコントロールに対する割合で評価した。50%細胞障害作用を引き起こす濃度をIC50とした。 After adding 20 μL / well of tetrazolium salt WST-8 reagent and culturing for 4 hours under the same conditions, absorbance at 450 nm was measured. The cell viability was evaluated based on the ratio of each concentration fraction to the control with the control group as 100%. The concentration causing 50% cell cytotoxicity was IC 50.
KB/MRP細胞はKB3−1に比べて、エトポシドに対し28.6倍の薬剤耐性を示すが、化合物(A)に対しては1.17倍の薬剤耐性を示すに過ぎない。KB−G2細胞はKB3−1に比べて、エトポシドに対して20.8倍の薬剤耐性を示すが、化合物(A)に対しては耐性を全く示さない。K562/BCRP細胞はK562に比べて、ミトキサントロンに対して約15倍の薬剤耐性を示すが、化合物(A)に対しては約1.9倍という極めて低い薬剤耐性を示すに過ぎない。 KB / MRP cells are 28.6 times more resistant to etoposide than KB3-1, but only 1.17 times more resistant to compound (A). KB-G2 cells are 20.8 times more resistant to etoposide than KB3-1, but not to compound (A) at all. K562 / BCRP cells are about 15 times more resistant to mitoxantrone than K562, but only about 1.9 times less resistant to compound (A).
以上より、化合物(A)は、多剤耐性遺伝子である、MRP−1、P−糖蛋白質遺伝子及びBCRPの関与する薬剤耐性を超えて、癌細胞株に作用することが明らかとなった。 From the above, it has been clarified that compound (A) acts on cancer cell lines beyond drug resistance involving MRP-1, P-glycoprotein genes and BCRP, which are multidrug resistance genes.
Claims (7)
1H NMRスペクトル(CDCl3、300K、mult.,J=Hz)が、δ 6.34(s)、6.34(brs)、5.89(brs)、4.86(d,17.2)、4.76(d,6.0)、4.76(dd,17.2,2.3)、4.07(s)、3.76(s)、3.76(s)、3.64(dd,22.5,4.5)、3.60(dd,22.5,4.1)にピークを有し;
13C NMRスペクトル(CDCl3、300K)が、δ 172.2、158.0、153.2、148.8、140.1、138.2、137.9、134.5、130.5、127.6、116.2、105.5、103.3、100.9、71.1、60.7、59.3、56.1、42.7、24.3にピークを有する化合物であって、
ヒプティス・ヴェルチシラータのメタノール抽出物をエーテルと水で分配して得られたエーテル層を85〜95%メタノール水溶液とヘキサンで分配した場合の前記メタノール水溶液抽出物を、シリカゲルカラムクロマトグラフィーにより処理して得られる、上記化合物。 From an analysis by FAB mass spectrum, it has a molecular weight of 426 and a molecular formula of C 23 H 22 O 8 ;
1 H NMR spectrum (CDCl 3 , 300K, multit., J = Hz) was found to be δ 6.34 (s), 6.34 (brs), 5.89 (brs), 4.86 (d, 17.2). ), 4.76 (d, 6.0), 4.76 (dd, 17.2, 2.3), 4.07 (s), 3.76 (s), 3.76 (s), 3 .64 (dd, 22.5, 4.5) with a peak at 3.60 (dd, 22.5, 4.1);
13 C NMR spectra (CDCl 3 , 300K) are shown by δ 172.2, 158.0, 153.2, 148.8, 140.1, 138.2, 137.9, 134.5, 130.5, 127. a compound having a peak in .6,116.2,105.5,103.3,100.9,71.1,60.7,59.3,56.1,42.7,24.3 ,
When the ether layer obtained by partitioning the methanol extract of Hyptis verticillata with ether and water was partitioned with 85-95% aqueous methanol and hexane, the aqueous methanol extract was treated by silica gel column chromatography. And the above compound obtained .
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