JP2006282577A - Novel photosensitizer for photodynamic therapy of cancer - Google Patents
Novel photosensitizer for photodynamic therapy of cancer Download PDFInfo
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- 238000002428 photodynamic therapy Methods 0.000 title abstract description 16
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Abstract
Description
本発明は、新規化合物、その製造方法並びに該化合物又はその薬学的に許容可能な塩を光増感剤として含む、ガン光線力学治療用医薬に関する。 The present invention relates to a novel compound, a process for producing the same, and a medicament for cancer photodynamic therapy comprising the compound or a pharmaceutically acceptable salt thereof as a photosensitizer.
ガンの治療には、外科手術、放射線療法、化学療法等の多様な方法があり、治療されるガンの性質、体内における部位などに応じて好ましい方法が選択される。しかしながら、放射線療法、化学療法などの方法の多くは重い副作用を有することが知られており、その主な理由は、これらの方法が比較的無差別な細胞毒性を有するということである。したがって、病気の組織に対してより選択性の高い治療方法である光線力学療法（以下、PDTという。）は、他の多くのガン治療方法に比較して上記の不利益を大きく減少させることのできるものである。 There are various methods for treating cancer, such as surgery, radiation therapy, and chemotherapy, and a preferred method is selected according to the nature of the cancer to be treated, the site in the body, and the like. However, many of the methods such as radiation therapy and chemotherapy are known to have severe side effects, mainly because these methods have relatively indiscriminate cytotoxicity. Therefore, photodynamic therapy (hereinafter referred to as PDT), which is a treatment method that is more selective for diseased tissue, greatly reduces the above disadvantages compared to many other cancer treatment methods. It can be done.
ガンのPDTの原理は、可視光線と光増感剤の組み合わせが、どちらもそれ自体無害であるが両者と酸素が同時に存在すると、光増感剤が光励起され光励起三重項状態となり、これを介してガン細胞を不活性化する致死的な細胞毒性物質を生成するという現象に基づく。そして光増感剤、酸素および光を同時に適用するこの方法は、病気の組織が正常組織に比較して選択的に光増感剤を取り込むこと（約２倍）、及び光照射を病気の組織に限定して正常組織での光増感剤の活性化を制限することによって得られたガン組織に対する２重の選択性によって、専ら病気の組織のみが生成した細胞毒性物質に対して露出され、正常組織を無傷に保ちつつ腫瘍を選択的に破壊することを可能にする。 The PDT principle of Gunn is that the combination of visible light and photosensitizer is both harmless per se, but if both and oxygen are present at the same time, the photosensitizer is photoexcited to a photoexcited triplet state. Based on the phenomenon of producing deadly cytotoxic substances that inactivate cancer cells. And this method of applying photosensitizer, oxygen and light simultaneously is that the diseased tissue selectively takes up the photosensitizer compared to normal tissue (about twice), and the light irradiation is the diseased tissue Due to the dual selectivity to cancer tissue obtained by limiting the activation of photosensitizers in normal tissues exclusively, only the diseased tissue is exposed to cytotoxic substances, Allows selective destruction of tumors while keeping normal tissue intact.
光増感剤は、特定の波長の光を吸収し、これを有用なエネルギーに変換する化合物である。特にPDTにおいては、光増感剤は、選択的に病気の組織中に蓄積され、細胞毒性物質を産生することを特徴とする。PDTにおける光増感剤の作用機序は詳しく解明されている。光照射によって、まず、光増感剤が基底状態（S0）から第一励起状態（S1）へ励起され、さらに分子間のクロスリンクを介して、三重項状態（T1）へ変換される。この三重項状態が長く続くことによって、励起された光増感剤と周囲の分子との相互作用及びPDTの間における細胞毒性種の生成も可能となる。具体的には、励起された光増感剤は、以下の２つのタイプの反応のいずれかを介して、究極的にはPDTにおける腫瘍細胞の破壊をもたらす（非特許文献１）：
１）生物学的な溶媒又は他の光増感剤のいずれかとの間で水素原子の除去又は電子伝達を行うことによって、反応性の高いフリーラジカルとラジカルイオンを生成する。これが酸素分子と反応してスーパーオキサイドアニオンなどの反応性の酸素種を生成して酸素による生物学的ダメージを細胞に与える；及び
２）基底状態の酸素分子との間のエネルギー伝達により、第一励起状態の酸素である一重項酸素を生成する。この非常に反応性の高い両性イオン種が、多くの生物学的基質と反応して酸化的ダメージを起こし、細胞死に導く。
A photosensitizer is a compound that absorbs light of a specific wavelength and converts it into useful energy. Particularly in PDT, photosensitizers are characterized by being selectively accumulated in diseased tissues and producing cytotoxic substances. The mechanism of action of photosensitizers in PDT has been elucidated in detail. By photoirradiation, the photosensitizer is first excited from the ground state (S0) to the first excited state (S1), and further converted to the triplet state (T1) via an intermolecular cross-link. The long-lasting triplet state also allows interaction of the excited photosensitizer with surrounding molecules and generation of cytotoxic species between the PDT. Specifically, the excited photosensitizer ultimately leads to tumor cell destruction in PDT via either of the following two types of reactions (Non-patent Document 1):
1) Generation of highly reactive free radicals and radical ions by removal of hydrogen atoms or electron transfer with either biological solvents or other photosensitizers. This reacts with the oxygen molecules to produce reactive oxygen species such as superoxide anions, causing biological damage by oxygen to the cells; and 2) energy transfer between the ground state oxygen molecules and the first Singlet oxygen which is oxygen in an excited state is generated. This highly reactive zwitterionic species reacts with many biological substrates to cause oxidative damage, leading to cell death.
従来使用されてきた光増感剤の多くは、ヘマトポルフィリンを酸で処理して合成した、以下の式（I）：
により表される、フォトフリン（登録商標）などのヘマトポルフィリン誘導体である。ヘマトポルフィリンは、エーテル結合を持つ２０種類以上の混合物からなり、ヘム色素と同様、光増感剤において重要と考えられる以下の式（II）：
A hematoporphyrin derivative such as Photofurin (registered trademark) represented by: Hematoporphyrin is a mixture of 20 or more types having an ether bond, and, like heme dyes, the following formula (II) considered to be important in a photosensitizer:
また、ヘマトポルフィリン誘導体以外の臨床で最近使用されている光増感剤には、生物学的アッセイにおいて着色剤として広く使用されている、以下の式（III）：
我々は先の研究において、「アラレマイシン」と名づけた、以下の式（IV）：
したがって、これらの欠点を克服した新規な光増感剤の開発が必要とされる。 Therefore, development of a novel photosensitizer that overcomes these drawbacks is required.
上記のように知られた化合物である５−アセタミド−４−オキソ−５−ヘキセン酸の類縁体の中でも、以下の式（VII）：
上記エチルエステルに対応するメチルエステルである本発明の化合物、５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルは、新規化合物であって、上記エチルエステルを記載した非特許文献５にも記載されておらず、したがって、該メチルエステルの合成方法は知られていない。さらに、５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルの合成に上記反応を適用することは、反応の選択性及び収率の低下が予想された。また、上記方法に関する記載には、出発物質の合成方法が含まれていない等の不明な点があった。 The compound of the present invention, which is a methyl ester corresponding to the ethyl ester, 5-acetamido-4-oxo-5-hexenoic acid methyl ester is a novel compound, and is also described in Non-Patent Document 5 describing the ethyl ester. Therefore, the synthesis method of the methyl ester is not known. Furthermore, applying the above reaction to the synthesis of 5-acetamido-4-oxo-5-hexenoic acid methyl ester was expected to reduce the selectivity and yield of the reaction. In addition, the description relating to the above method has some unclear points such as not including a synthesis method of the starting material.
本発明の目的は、ヘマトポルフィリン誘導体に代わる新規光増感剤用新規化合物又は薬学的に許容可能なその塩、該化合物の製造方法、並びに該化合物又は塩を含む、ガン光線力学治療用医薬を提供することである。 An object of the present invention is to provide a novel compound for a photosensitizer or a pharmaceutically acceptable salt thereof in place of a hematoporphyrin derivative, a method for producing the compound, and a medicament for cancer photodynamic therapy containing the compound or salt. Is to provide.
本発明によれば、以下の式（IX）：
本発明によれば、上記新規化合物５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルの製造方法であって、以下のステップ：
以下の式（X）：
を含む、前記方法が提供される。
According to the present invention, there is provided a process for producing the novel compound 5-acetamido-4-oxo-5-hexenoic acid methyl ester, comprising the following steps:
The following formula (X):
Wherein said method is provided.
さらに、本発明によれば、５‐アセタミド‐４‐オキソ‐５‐ヘキセン酸メチルエステル又は薬学的に許容可能なその塩を光増感剤として含む、ガン光線力学治療用医薬が提供される。 Further, according to the present invention, there is provided a medicament for cancer photodynamic therapy comprising 5-acetamido-4-oxo-5-hexenoic acid methyl ester or a pharmaceutically acceptable salt thereof as a photosensitizer.
本発明者らは、抗生物質のスクリーニングにおいて見出された５−アセタミド−４−オキソ−５−ヘキセン酸の合成過程において、新規化合物５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルの合成に成功した。 In the process of synthesizing 5-acetamido-4-oxo-5-hexenoic acid found in antibiotic screening, the present inventors synthesized a novel compound 5-acetamido-4-oxo-5-hexenoic acid methyl ester. succeeded in.
合成された５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルは、従来の光増感剤ALAに比べて高い光感受性増大効果を示した。 The synthesized 5-acetamido-4-oxo-5-hexenoic acid methyl ester showed a higher photosensitivity increasing effect than the conventional photosensitizer ALA.
用語の説明
本明細書において、「ガン光線力学治療」及び「PDT」という用語は交換可能に使用され、いずれも光増感剤をガン患者に投与し、レーザー光照射を行うことにより、腫瘍を壊死させる方法を意味する（非特許文献１）。
Explanation of Terms In this specification, the terms “cancer photodynamic therapy” and “PDT” are used interchangeably, and both of them are used to administer a photosensitizer to a cancer patient and perform laser light irradiation to treat the tumor. It means a method of necrosis (Non-Patent Document 1).
本明細書において、「光増感剤」という用語は、特定の波長の光を吸収し、これを有用なエネルギーに変換する化合物を意味する。 As used herein, the term “photosensitizer” means a compound that absorbs light of a specific wavelength and converts it into useful energy.
本発明者らは、５−アセタミド−４−オキソ−５−ヘキセン酸の合成過程において上記新規化合物５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルを合成することに成功した（図１参照）。その方法においては、まず４−ペンチニルカルボン酸を出発物質として用い、慣用方法によって合成の中間体である以下の式（X）：
当初、発明者らは次のステップとして、上記式（X）のアジ化ケトンにエタノール中でナトリウムエトキシドを加えて、該アジ化ケトンのアジド基をアミノ基に変換し且つ５位と６位の炭素の間に二重結合を形成することによって、以下の式（XI）：
そこで、本発明者らは、上記式（X）のアジ化ケトン中のアジド基に対して同時に還元とアセチル化を行うステップによって、他の中間体として式（IX）のアミド（５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステル）を合成することを考案し、得られた該アミドを用いて式（IV）のカルボン酸アミドを合成することに成功した（図１参照）。 Therefore, the present inventors carried out reduction and acetylation simultaneously on the azide group in the azide ketone of the above formula (X), whereby the amide (5-acetamido- 4-oxo-5-hexenoic acid methyl ester) was devised, and the resulting amide was used to successfully synthesize a carboxylic acid amide of formula (IV) (see FIG. 1).
上記のように、本発明の新規化合物５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルは、５−アセタミド−４−オキソ−５−ヘキセン酸の合成中間体として得られたものであるが、これを従来技術によって対応するエチルエステルと同様に合成することが適当でないと予想されたことは既に述べたとおりである。これに対して、本発明の方法は、上記従来技術とは出発物質、各反応ステップともに全く異なるものであり、目的のメチルエステルを容易な反応により高収率で合成することのできるものであった。加えて、上記メチルエステルから合成されるアラレマイシン（５−アセタミド−４−オキソ−５−ヘキセン酸）の６位の炭素をさらに水素化することを介して、多様なα−カルボニル化合物を合成することができ、上記ステップは、α−カルボニル化合物の製造過程においても広く適用できると考えられる。 As described above, the novel compound 5-acetamido-4-oxo-5-hexenoic acid methyl ester of the present invention was obtained as a synthetic intermediate of 5-acetamido-4-oxo-5-hexenoic acid. As already mentioned, it was expected that it would not be suitable to synthesize it in the same way as the corresponding ethyl ester by the prior art. On the other hand, the method of the present invention is completely different from the above-described prior art in starting materials and reaction steps, and the target methyl ester can be synthesized in a high yield by an easy reaction. It was. In addition, various α-carbonyl compounds are synthesized through further hydrogenation of the 6-position carbon of araremycin (5-acetamido-4-oxo-5-hexenoic acid) synthesized from the above methyl ester. The above steps can be widely applied in the production process of α-carbonyl compounds.
本発明の好ましい実施態様によれば、上記ステップにおいて溶媒であり且つアセチル基の供給源である無水酢酸とともに使用される溶媒は、ハロゲン性の溶媒であり、好ましくはクロロホルム、塩化メチレン又は四塩化炭素のいずれかであり、より好ましくは四塩化炭素である。また、本発明の方法中では、アジ化ケトンからアミドへの変換反応に通常用いられるEtOH中のNaOEtの代わりに、NaReO4を触媒として用いることにより、５−アジド−４−オキソ−ヘキサン酸メチルエステルから５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルを合成することに成功した。NaReO4の使用量は、０．００５〜０．０３当量、より好ましくは０．０１３当量である。 According to a preferred embodiment of the present invention, the solvent used in the above step together with acetic anhydride which is a solvent and a source of acetyl groups is a halogenated solvent, preferably chloroform, methylene chloride or carbon tetrachloride. More preferably, carbon tetrachloride is used. In the method of the present invention, methyl 5-azido-4-oxo-hexanoate was obtained by using NaReO 4 as a catalyst instead of NaOEt in EtOH usually used for the conversion reaction from azide ketone to amide. Succeeded in synthesizing 5-acetamido-4-oxo-5-hexenoic acid methyl ester from the ester. The amount of NaReO 4 is 0.005 to 0.03 equivalents, more preferably 0.013 eq.
得られた５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルが細胞内で光感受性増大効果を有するためには、上記合成ステップによって導入されたアセタミド基中のアセチル部分による水溶液中での該化合物の安定化及びメチレン部分による細胞内でのラジカル生成が必要とされ、有効な光増感剤としての特徴を該化合物に与えるこれらの部分を効率よく導入することのできる上記合成方法は、非常に有益なものである。加えて、細胞へ効率よく取り込まれるためには、細胞膜透過性の高い脂溶性の化合物であることも必要であり、その点でも本発明のメチルエステルは優れたものといえる。 In order for the obtained 5-acetamido-4-oxo-5-hexenoic acid methyl ester to have a photosensitivity increasing effect in cells, the acetyl moiety in the acetamide group introduced by the synthesis step described above in an aqueous solution was used. The above synthesis method, which requires the stabilization of the compound and the generation of radicals in the cell by the methylene moiety, can efficiently introduce these moieties that give the compound characteristics as an effective photosensitizer, It is useful for. In addition, in order to be efficiently taken up into cells, it is also necessary to be a fat-soluble compound having a high cell membrane permeability, and the methyl ester of the present invention is also excellent in this respect.
さらに、上記メチルエステルから慣用方法によって、５−アセタミド−４−オキソ−５−ヘキセン酸をはじめとしたその誘導体が合成可能である。上述の５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステル及びその誘導体の新規合成法により、新規光増感剤開発のためのこれら新規リード化合物の安定供給が可能となった。 Furthermore, derivatives thereof including 5-acetamido-4-oxo-5-hexenoic acid can be synthesized from the above methyl ester by a conventional method. The above novel synthesis method of methyl 5-acetamido-4-oxo-5-hexenoate and its derivatives has made it possible to stably supply these new lead compounds for the development of new photosensitizers.
さらに、Hela細胞を用いた実験によって、５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルが、従来の光増感剤ALAに比較して優れた光感受性の増大を示すことを明らかにした。インビトロで癌細胞と光増感剤を接触させ、光（又はレーザー）を照射することによって示される、光増感剤の癌細胞生存率（光感受性）に及ぼす効果と、同じ光増感剤がインビボでマウスの固形腫瘍に対して及ぼす成長抑制効果との間に正の相関関係のあることはすでに証明されている（非特許文献２）。したがって、上記メチルエステルは、新規光増感剤開発のリード化合物として期待される。また、構造的類縁体である、５−アセタミド−４−オキソ−５−ヘキセン酸（アラレマイシン）が抗菌活性を有するが、本発明の上記メチルエステルも抗菌活性を示す。 In addition, experiments using Hela cells revealed that 5-acetamido-4-oxo-5-hexenoic acid methyl ester exhibits superior photosensitivity compared to the conventional photosensitizer ALA. . The effect of photosensitizer on cancer cell viability (photosensitivity) shown by contacting cancer cell with photosensitizer in vitro and irradiating with light (or laser) is the same as photosensitizer It has already been proved that there is a positive correlation between the growth inhibitory effect on solid tumors in mice in vivo (Non-patent Document 2). Therefore, the methyl ester is expected as a lead compound for developing a new photosensitizer. Further, 5-acetamide-4-oxo-5-hexenoic acid (araremycin), which is a structural analog, has antibacterial activity, but the methyl ester of the present invention also exhibits antibacterial activity.
特記されない限り、以下の実施例中において使用した反応物質は、商業的に入手した。 Unless otherwise noted, the reactants used in the following examples were obtained commercially.
実施例１ ５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルを中間体として介する、５−アセタミド−４−オキソ−５−ヘキセン酸の合成
図１に示した合成スキームにしたがって以下のステップを実施することにより、５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルを中間体として介する、５−アセタミド−４−オキソ−５−ヘキセン酸の合成を行った（図１参照）。
１）ラクトン（図１中の式（XIII）により表されるテトラヒドロ−２−エチリデン−５−フラノン）の合成
PDCl2(PhCN)2（54ｍｇ、0.14mmol）の入っているフラスコの中にMeCN（25mL）、Et3N（0.060mＬ、0.43mmol）、及びカルボン酸（図１中の式（XII）により表される４−ペンチニルカルボン酸）（0.16ｇ、14.3mmol）をこの順に入れ、５時間加熱還流した。溶媒を減圧下留去し、粗生物をシリカゲルクロマト（メルク社製のシリカゲル６０）に付すと、式（XIII）のラクトンが1.36ｇ得られた（収率85％）：1H NMR δ1.68(dt, J=7.2 Hz, 3H), 2.54-2.70(m, 2H), 2.76-2.86(m, 2H), 4.62(tq, J=1.5, 7 Hz, 1H)
Example 1 Synthesis of 5-acetamido-4-oxo-5-hexenoic acid via 5-acetamido-4-oxo-5-hexenoic acid methyl ester as an intermediate The following steps were performed according to the synthetic scheme shown in FIG. By carrying out the synthesis, 5-acetamido-4-oxo-5-hexenoic acid was synthesized through the use of 5-acetamido-4-oxo-5-hexenoic acid methyl ester as an intermediate (see FIG. 1).
1) Synthesis of lactone (tetrahydro-2-ethylidene-5-furanone represented by the formula (XIII) in FIG. 1)
In a flask containing PDCl 2 (PhCN) 2 (54 mg, 0.14 mmol), MeCN (25 mL), Et 3 N (0.060 mL, 0.43 mmol), and carboxylic acid (represented by the formula (XII) in FIG. 1). 4-pentynylcarboxylic acid) (0.16 g, 14.3 mmol) was added in this order and heated to reflux for 5 hours. The solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel chromatography (
２）ブロモケトン（図１中の式（IVX）により表される５−ブロモ−４−オキソヘキサン酸メチルエステル）の合成
式（XIII）のラクトン(850mg, 7.58mmol)をCCl4(10mL)に溶かし、０℃に冷却後、その中にBr2(0.39mL, 7.57mmol)のCCl4(2mL)溶液を滴下した。３０分たってから濃縮し、MeOH（10mＬ）とEt3Nを少量加えた。室温下、１時間攪拌し、濃縮した。こうして合成した粗生成物をシリカゲルクロマトに付すと、式（IVX）のブロモケトンが1.20ｇ得られた（収率 71%）:1H NMR δ1.77(d, Ｊ=７Hz, 3H), 2.49-2.78(m, 2H), 2.91(ddd, J=18, 7.5, 6Hz, 1H),3.14(ddd J=18, 6.5, 6Hz, 1H), 3.69(s, 3H), 4.49(q, J=7Hz, 1H);13C NMR δ20.2, 28.4, 33.6, 47.5, 52.0, 172.8, 202.9。
2) Synthesis of bromoketone (5-bromo-4-oxohexanoic acid methyl ester represented by formula (IVX) in FIG. 1) Lactone (850 mg, 7.58 mmol) of formula (XIII) was dissolved in CCl 4 (10 mL). After cooling to 0 ° C., a solution of Br 2 (0.39 mL, 7.57 mmol) in CCl 4 (2 mL) was added dropwise thereto. After 30 minutes, it was concentrated and a small amount of MeOH (10 mL) and Et 3 N were added. The mixture was stirred at room temperature for 1 hour and concentrated. The crude product thus synthesized was subjected to silica gel chromatography to obtain 1.20 g of bromoketone of formula (IVX) (yield 71%): 1 H NMR δ1.77 (d, J = 7 Hz, 3H), 2.49- 2.78 (m, 2H), 2.91 (ddd, J = 18, 7.5, 6Hz, 1H), 3.14 (ddd J = 18, 6.5, 6Hz, 1H), 3.69 (s, 3H), 4.49 (q, J = 7Hz , 1H); 13 C NMR δ20.2, 28.4, 33.6, 47.5, 52.0, 172.8, 202.9.
３）アジ化ケトン（式（X）により表される５−アジド−４−オキソ−ヘキサン酸メチルエステル）の合成
式（IVX）のブロモケトン（1.20g,5.38mmol）をDMF(5mL）に溶解し、この中にNaN3(699mg,10.8mmol)を加えた。室温下、１時間攪拌した後、水を加えた。生成物を３回Et2O抽出した。抽出液をMgSO4で乾燥し、濃縮した。粗生成物をシリカゲルクロマトに付すと式（X）のアジ化ケトンが976mg得られた（収率 98%):1H NMR δ1.41(d, J＝7Hz、3H），2.56-2.62(m, 2H)， 2.77‐2.83(m, 2H), 3.63(s, 3H), 3.97(q, Ｊ＝7Hz, 1H）；13C NMRδ15.8, 27.6, 33.7, 51.9, 63.2, 172.6, 205.8。
3) Synthesis of azide ketone (5-azido-4-oxo-hexanoic acid methyl ester represented by formula (X)) Bromoketone of formula (IVX) (1.20 g, 5.38 mmol) was dissolved in DMF (5 mL). To this, NaN 3 (699 mg, 10.8 mmol) was added. After stirring at room temperature for 1 hour, water was added. The product was extracted 3 times with Et 2 O. The extract was dried over MgSO 4 and concentrated. The crude product was subjected to silica gel chromatography to obtain 976 mg of azide ketone of formula (X) (yield 98%): 1 H NMR δ1.41 (d, J = 7 Hz, 3H), 2.56-2.62 (m , 2H), 2.77-2.83 (m, 2H), 3.63 (s, 3H), 3.97 (q, J = 7 Hz, 1H); 13 C NMR δ 15.8, 27.6, 33.7, 51.9, 63.2, 172.6, 205.8.
４）アミド（式（IX）により表される５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステル）の合成
Ac2O（0.5ｍL）とCCl4(0.5mＬ）の混合溶液の中にNaReO4(1mg、0.0037mmol)、CF3SO3H
（0.001mL,0.011mmol）、及び式（X）のアジ化ケトン(50mg, 0.27mmol)を加え、１０時間加熱還流した。溶液を減圧下濃縮し、粗生成物をシリカゲルクロマトに付すと、式（IX）のアミドが34mg得られた（収率63％）：1H NMR δ2.12(ｓ, 3H), 2.68（ｔ, J=6.5Hz, 2H）3.11(t, J=6.5Hz, 2H), 3.70(s,3H), 5.84(t, J=1Hz, 1H), 6.93(d, J=1Hz, 1H), 7.99(br s, 1H);13C NMR δ24.8, 28.1, 30.8, 52.0, 109.5, 137.7, 169.0, 172.7, 194.9。
５）カルボン酸アミド（式（IV）により表される５−アセタミド−４−オキソ−５−ヘキセン酸）の合成
氷冷したMeOH(1.1mL)とH2O(1.1mL)の混合溶媒中に式（IX）のアミド (180mg, 0.904mmol)と1N水酸化リチウム(1.2mL)を加えた。この溶液を30分間そのままの温度で攪拌し、その後、溶液を10％酒石酸を加えて弱酸性にした。生成物を酢酸エチルで３回抽出し、抽出液をMgSO4で乾燥し、濃縮した。最後に粗生成物をシリカゲルクロマトに付すと、式（IV）のカルボン酸アミド６148mgが得られた（収率88％）：1H NMR((CD3)2SO中)δ2.02(s, 3H), 2.46-2.51(m, 2H), 2.96(t, J=6Hz, 2H), 5.79(s, 1H), 6.46(s, 1H), 9.10(br s, 1H), 12.15(bs s, 1H); 13C NMR(CD3OD中)δ24.0, 28.9, 32.2, 110.6, 140.1, 172.0, 176.0, 196.6。
4) Synthesis of amide (5-acetamido-4-oxo-5-hexenoic acid methyl ester represented by formula (IX))
In a mixed solution of Ac 2 O (0.5 mL) and CCl 4 (0.5 mL), NaReO 4 (1 mg, 0.0037 mmol), CF 3 SO 3 H
(0.001 mL, 0.011 mmol) and an azide ketone of formula (X) (50 mg, 0.27 mmol) were added and heated to reflux for 10 hours. The solution was concentrated under reduced pressure and the crude product was subjected to silica gel chromatography to obtain 34 mg of the amide of formula (IX) (yield 63%): 1 H NMR δ2.12 (s, 3H), 2.68 (t , J = 6.5Hz, 2H) 3.11 (t, J = 6.5Hz, 2H), 3.70 (s, 3H), 5.84 (t, J = 1Hz, 1H), 6.93 (d, J = 1Hz, 1H), 7.99 (br s, 1H); 13 C NMR δ 24.8, 28.1, 30.8, 52.0, 109.5, 137.7, 169.0, 172.7, 194.9.
5) Synthesis of carboxylic acid amide (5-acetamido-4-oxo-5-hexenoic acid represented by formula (IV)) In a mixed solvent of ice-cooled MeOH (1.1 mL) and H 2 O (1.1 mL) The amide of formula (IX) (180 mg, 0.904 mmol) and 1N lithium hydroxide (1.2 mL) were added. The solution was stirred for 30 minutes at the same temperature, after which the solution was made weakly acidic by adding 10% tartaric acid. The product was extracted 3 times with ethyl acetate and the extract was dried over MgSO 4 and concentrated. Finally, the crude product was subjected to silica gel chromatography to obtain 6148 mg of carboxylic acid amide of formula (IV) (yield 88%): 1 H NMR (in (CD 3 ) 2 SO) δ2.02 (s, 3H), 2.46-2.51 (m, 2H), 2.96 (t, J = 6Hz, 2H), 5.79 (s, 1H), 6.46 (s, 1H), 9.10 (br s, 1H), 12.15 (bs s, 1H); 13 C NMR (in CD 3 OD) δ 24.0, 28.9, 32.2, 110.6, 140.1, 172.0, 176.0, 196.6.
実施例２ ５−アミノレブリン酸及び５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルによる光感受性の増大
ヒト子宮癌細胞Hela細胞を、35mmシャーレに２×１０4となるように播種し、１０-4M、１０-5M濃度の５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルを、単独で及び１０-3MのALAの共存下、暗所で１時間接触させた後に洗浄した。この処理後の細胞をさらに光照射した群及び暗所に維持した群に分けた（１群３例）。光照射は５００Wハロゲンランプ（東芝、425WN-EH）で５００nm以上の光を照射し、光量は２８J／ｃｍ2であった。照射２４時間後に、MTT法（非特許文献６）で細胞生存率を決定した（図２参照）。光照射することによって、１０-4モル濃度の５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステル単独処理後の細胞生存率が約３０％低下し、１０-3モル濃度でも光照射後に約９０％の細胞生存率を示す５−アミノレブリン酸に比較して顕著な光照射による細胞毒性の増大を示した。また、１０-4モル濃度の５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルを１０-3モル濃度の５−アミノレブリン酸と併用しても、光照射によって暗所においた場合に比べて顕著に細胞生存率が低下した。このことにより、５−アセタミド−４−オキソ−５−ヘキセン酸メチルエステルの細胞に対する光感受性の増大作用が確認された。
Example 2 Increased photosensitivity by 5-aminolevulinic acid and 5-acetamido-4-oxo-5-hexenoic acid methyl ester Human uterine cancer cell Hela cells were seeded in a 35 mm petri dish at 2 × 10 4. -4 M, 10 -5 M concentrations of 5-acetamido-4-oxo-5-hexenoic acid methyl ester alone and in the presence of 10 -3 M ALA were contacted in the dark for 1 hour before washing. . The cells after this treatment were further divided into a group irradiated with light and a group maintained in the dark (3 cases per group). Light irradiation 500W halogen lamp (Toshiba, 425WN-EH) irradiating light of at least 500nm, the light intensity was 28 J / cm 2. 24 hours after irradiation, cell viability was determined by the MTT method (Non-patent Document 6) (see FIG. 2). By light irradiation, 10-4 molar concentrations of 5-acetamido-4-oxo-5-hexenoic acid methyl ester alone after treatment of cell viability decreased by about 30%, about the after irradiation with 10 -3 molar Compared to 5-aminolevulinic acid, which shows 90% cell viability, it showed a marked increase in cytotoxicity due to light irradiation. In addition, even when 10-4 molar concentration of 5-acetamido-4-oxo-5-hexenoic acid methyl ester is used in combination with 10-3 molar concentration of 5-aminolevulinic acid, compared with the case where it is placed in the dark by light irradiation. The cell viability was significantly reduced. This confirmed that photosensitivity of 5-acetamido-4-oxo-5-hexenoic acid methyl ester to cells was increased.
Claims (3)
以下の式（X）：
を含む、前記方法。 A method of synthesizing 5-acetamido-4-oxo-5-hexenoic acid methyl ester according to claim 1, comprising the following steps:
The following formula (X):
Said method.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2011246362A (en) * | 2010-05-24 | 2011-12-08 | Tokyo Institute Of Technology | Alaremycin derivative |
| WO2012063487A1 (en) | 2010-11-10 | 2012-05-18 | 国立大学法人東京工業大学 | Antimalarial drug comprising alaremycin or derivative thereof as active ingredient |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011246362A (en) * | 2010-05-24 | 2011-12-08 | Tokyo Institute Of Technology | Alaremycin derivative |
| WO2012063487A1 (en) | 2010-11-10 | 2012-05-18 | 国立大学法人東京工業大学 | Antimalarial drug comprising alaremycin or derivative thereof as active ingredient |
| JP5669111B2 (en) * | 2010-11-10 | 2015-02-12 | 国立大学法人東京工業大学 | Antimalarial drugs containing araremycin or its derivatives as active ingredients |
| US9295660B2 (en) | 2010-11-10 | 2016-03-29 | Tokyo Institute Of Technology | Antimalarial drug comprising alaremycin or derivative thereof as active ingredient |
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