JP2014210742A - 持続性磁性抗がん剤 - Google Patents
持続性磁性抗がん剤 Download PDFInfo
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A61K47/48—
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/02—Iron compounds
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
鉄サレン錯体(化1)−パクリタキセル(タキソール)の複合体の合成
化合物1、無水酢酸(acetic anhydride)、H2SO4を室温で1時間混合した。混合中の反応は、薄層クロマトグラフィー(TLC:Thin-Layer Chromatography)で確認した。詳細確認後、酢酸エチル(EtOAc)/ホスファチジルエタノールアミン(P.E.)で再結晶化した後、化合物2を得た。化合物2であることは質量分析で分子量を測定し確認した。
鉄サレン錯体(化2)−パクリタキセル(タキソール)の複合体の合成
この合成のための方法は、実施例1のステップ8において、金属サレン錯体部分の金属キレートを生成する段階で使用される金属ハロゲンを“FeCl24H2O”から“FeCl3”に変更した以外は、ほぼ実施例1と同じである。得られた化合物が鉄サレン錯体(2量体)−パクリタキセル複合体(化4)であることを質量分析よって確認した。質量分析結果は同じくAPI−ES法で測定したところ計算値2478.74に対して、 2481.6であった。
次に、実施例1で得られた、鉄サレン錯体−パクリタキセル複合体(化3)と、実施例2で得られた、鉄サレン錯体−パクリタキセル複合体(化4)について、それぞれの化合物を丸型シャーレ内の精製水に分散し、ネオジウム永久磁石(表面磁束密度800mT)を近づけて、夫々の化合物が磁石で誘導できるか否かを確認した。図1の「磁石なし」の写真に示すように、磁力が適用されない場合には、精製水に化合物が分散された状態に成るのに対して、「磁石あり」の写真では、化合物が、磁場が及ぶ領域に集合することが確認された。即ち、各化合物は、鉄サレン錯体に由来する磁力を失わず、維持していることが確認された。
鉄サレン錯体−パクリタキセル複合体(化3)を、放射線医学総合研究所分子イメージセンターに設置してあるMRI装置(7.0T Burker社製)で撮影した。撮影結果としての写真を図2に示す。市販薬剤であるタキソール(Taxol)はシグナル変化なしの白色を呈するのに対して、化3の化合物(EI-2574M)の水溶液は1.5mMから187mMへと濃度が高くなるにつれて白色のシグナルが得られることがわかった。よって、金属サレン錯体−パクリタキセル複合体(化3)は、MRI造影剤としても機能することが分かった。
実施例4と同様にして、鉄サレン錯体−パクリタキセル複合体(化4)の水溶液をMRI装置で撮影した。撮影結果としての写真を図3に示す。化4の化合物(EI-2573M)は1.5mMから187mMへと濃度が高くなるにつれて白色のシグナルが得られることがわかった。よって、金属サレン錯体−パクリタキセル複合体(化4)は、MRI造影剤としても機能することが分かった。
鉄サレン錯体−パクリタキセル複合体(化3)のがん細胞に対する殺傷効果の確認試験を実施した。実験材料及び試験方法は次のとおりである。
1.材料
細胞株:理化学研究所から譲渡された乳がん細胞株(MCF−7)
2.試験試薬
XTT cell proliferation assay kit (American Type Culture Collection社製)
3.試験方法
(1)細胞培養
乳がん細胞株(MCF-7)を、10%非働化ウシ血清(GIBCO, USA)、100units/mlペニシリン・ストレプトマイシン(Wako大阪)を添加したRPMI−1640(Wako、大阪)を用いて摂氏37度、5%CO2の条件下で培養した。
(2)XTTアッセイ
鉄サレン錯体−パクリタキセル複合体(化3)の抗腫瘍効果を評価するためXTTアッセイ法を用いた。各細胞をマイクロプレート(組織培養用、96穴、平底)に各ウェル100μlをCO2インキュベーターで摂氏37度、5%CO2条件下で3時間培養した。
実施例6と同様にして、鉄サレン錯体−パクリタキセル(タキソール)の複合体(磁性化タキソール:化4)の抗がん効果の試験を行った。なお、1.9μM、3.8μM、7.5μM、15μM、30μM、60μMの濃度の鉄サレン錯体−パクリタキセル複合体(化4)でがん細胞を24、48、72時間刺激し、夫々の時点での吸光度を実施例6と同様にして求めた。測定結果に基づいて、時間経過に応じたがん細胞の成長率を算出した。結果を図5に示す。図5から分かるように、鉄サレン錯体−パクリタキセル複合体は、パクリタキセル(タキソール)に鉄サレン錯体が結合した構造にも拘わらず、タキソールの抗がん効果を維持していることが分かった。なお、磁場環境では、鉄サレン錯体−パクリタキセル複合体の濃度はパクリタキセルに比べて数倍高いために、前者の抗がん効果は後者に比較して顕著に向上される。また、金属サレン−パクリタキセル複合体の抗がん効果は、パクリタキセル単独に比較して顕著に向上された。
Claims (7)
- (N,N,O,O)を4座配位子として金属を配位させた金属サレン錯体に、タキサン系抗がん性分子を結合した複合体を有効成分として含有し、細胞周期の複数のフェーズで作用する、持続性磁性抗がん剤。
- 前記金属サレン錯体は、
(Mは、Fe、Cr、Mn、Co、Ni、Mo、Ru、Rh、Pd、W、Re、0s、Ir、Pt、Nd、Sm、Eu、又は、Gdである。)
である、請求項1記載の持続性磁性抗がん剤。 - 前記金属錯体は、
(Mは、Fe、Cr、Mn、Co、Ni、Mo、Ru、Rh、Pd、W、Re、0s、Ir、Pt、Nd、Sm、Eu、又は、Gdである。)
である、請求項1記載の持続性磁性抗がん剤。 - 前記タキサン系抗がん分子がパクリタキセルである、請求項1記載の持続性磁性抗がん剤。
- 前記複合体が、
である、請求項1記載の持続性磁性抗がん剤。 - 前記複合体が、
である、請求項1記載の持続性磁性抗がん剤。 - 前記複合体は投与後、外部磁場が適用された患部領域で保持されて、持続的な抗がん作用を発揮する、請求項1から6の何れか一項記載の持続性磁性抗がん剤。
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016046989A1 (ja) * | 2014-09-26 | 2016-03-31 | 株式会社Ihi | 抗がん剤、がん細胞殺傷方法 |
JP2016169182A (ja) * | 2015-03-12 | 2016-09-23 | 株式会社Ihi | 磁性抗体 |
WO2016161903A1 (zh) * | 2015-04-08 | 2016-10-13 | 厦门大学 | 锇杂稠环化合物及其制备方法、含有该化合物的组合物以及应用 |
JP2017128552A (ja) * | 2016-01-22 | 2017-07-27 | 株式会社Ihi | 抗癌剤、抗癌剤の制御方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010058280A1 (ja) * | 2008-11-20 | 2010-05-27 | 株式会社Ihi | 自己磁性金属サレン錯体化合物 |
-
2013
- 2013-04-19 JP JP2013088559A patent/JP2014210742A/ja active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010058280A1 (ja) * | 2008-11-20 | 2010-05-27 | 株式会社Ihi | 自己磁性金属サレン錯体化合物 |
Non-Patent Citations (3)
Title |
---|
CLINICAL JOURNAL OF ONCOLOGY NURSING, vol. 17, no. 1, JPN6016047743, 2013, pages 9 - 14 * |
EXPERIMENTAL AND MOLECULAR PATHOLOGY, vol. Vol.89, JPN6016030906, 2010, pages 334 - 342 * |
TOXICOLOGY IN VITRO, vol. Vol.26, JPN6016030904, 2012, pages 480 - 484 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016046989A1 (ja) * | 2014-09-26 | 2016-03-31 | 株式会社Ihi | 抗がん剤、がん細胞殺傷方法 |
US10030039B2 (en) | 2014-09-26 | 2018-07-24 | Ihi Corporation | Anti-cancer agent and cancer cell killing method |
JP2016169182A (ja) * | 2015-03-12 | 2016-09-23 | 株式会社Ihi | 磁性抗体 |
WO2016161903A1 (zh) * | 2015-04-08 | 2016-10-13 | 厦门大学 | 锇杂稠环化合物及其制备方法、含有该化合物的组合物以及应用 |
JP2017128552A (ja) * | 2016-01-22 | 2017-07-27 | 株式会社Ihi | 抗癌剤、抗癌剤の制御方法 |
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