JP2006282577A - ガン光線力学治療用新規光増感剤 - Google Patents
ガン光線力学治療用新規光増感剤 Download PDFInfo
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 20
- 201000011510 cancer Diseases 0.000 title claims abstract description 16
- 238000002428 photodynamic therapy Methods 0.000 title abstract description 16
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
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。
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):
以下の式(X):
を含む、前記方法が提供される。
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)。
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)
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。
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。
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。
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。
Claims (3)
- 請求項1に記載の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。
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011246362A (ja) * | 2010-05-24 | 2011-12-08 | Tokyo Institute Of Technology | アラレマイシン誘導体 |
WO2012063487A1 (ja) | 2010-11-10 | 2012-05-18 | 国立大学法人東京工業大学 | アラレマイシン又はその誘導体を有効成分とする抗マラリア薬 |
JP5669111B2 (ja) * | 2010-11-10 | 2015-02-12 | 国立大学法人東京工業大学 | アラレマイシン又はその誘導体を有効成分とする抗マラリア薬 |
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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