JP2005534625A - 光毒性を調節する方法 - Google Patents
光毒性を調節する方法 Download PDFInfo
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- JP2005534625A JP2005534625A JP2003585662A JP2003585662A JP2005534625A JP 2005534625 A JP2005534625 A JP 2005534625A JP 2003585662 A JP2003585662 A JP 2003585662A JP 2003585662 A JP2003585662 A JP 2003585662A JP 2005534625 A JP2005534625 A JP 2005534625A
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
本出願は、2002年4月19日出願の仮出願第60/374,033号の優先権を主張する。この出願の全開示をここに参考文献として合体させる。
本発明は、皮膚細胞の光毒性のモジュレーターとして有用な分子および組成物に関する。具体的には、ここでの使用において「モジュレーター」とは、光に対する露出によって生じる、細胞、例えば皮膚細胞、の障害を加速又は遅延させることが可能な物質をいう。
コラーゲンに対する前記内因性皮膚成分の成分が、光毒性障害の原因物質および/又はその抑制物質である可能性が非常に高いと考えられた。従って、それらの分子を調べた。
上述したものに類似する実験において、複数のヒドロキシピリジン誘導体の集団を調べた。簡単に説明すると、2,3および4−ヒドロキシピリジンを、N−エチル−3−ヒドロキシピリジンと同様に、テストした。全ての構造を図1に示す。
上述した実験に続いて、悪性メラノーマ細胞(G−361細胞)と悪性乳癌細胞(MCF−7)とを使用した追加の実験を行った。これらの実験において、UVA光を9.9J/cm2として、前述したN−エチル誘導体を、種々の濃度でテストした。前記処理の2日後に生存度を測定した。コントロールとして、N−エチル誘導体のみ、と、UVA光のみとで実験を行った。
本発明の有効物質は小さな分子である。小分子は有用ではあるが、時に、そのような分子をより大きな分子、例えば、タンパク質、と複合化することが望ましい。これによって、もしもそれが例えば、細胞上の特定のマーカーに対して特異的な抗体、特定のレセプターに対するリガンド、核会合タンパク質(nuclear associated protein)等、と複合化される場合に、その小分子の標的化が促進される。
例4に記載した複合物の抗増殖作用を、何も添加しないか (コントロール)、又はBSAもしくは前記BSA−B6複合物を添加して、そして、HaCaTケラチン生成細胞のサンプルをSSLで処理するか、もしくは処理しないことによってテストした。前記BSAとBSA−B6とを、10mg/ml添加し、SSLは2.3J/cm2のUVAと0.12J/cm2のUVBとから構成されたものであった。処理の三日後、増殖を、コールターカウンターと標準法を使用して測定した。
上述の例1−5に記載したデーターは、細胞破壊を促進する分子に関するものである。しかし、これは必ずしも望ましいものではなく、この例と、以下の例とにおいては、このプロセスを抑制する分子について説明する実験が記載される。これらの分子を、以降、光励起状態のクエンチャー、又は“QPES”と称する。これらの化合物は、その後、上述したようなタイプの細胞死を誘発することになる分子の光励起状態を失活させる能力によって特徴付けられる。
ΦX174プラスミドは、人工太陽光からの照射と、UV感作物質として作用するAGE−色素濃縮(enriched)タンパク質との組み合わせの作用によってのみ開裂されることがよく知られている。AGE−BSA(「終末糖化産物」改変ウシ血清アルブミン)は、前述したタイプの内因性皮膚感作物質の蓄積のモデルである。これを示すアッセイの詳細は、ここにその全部を参考文献として合体させるワンドラック(Wondrak)他 Photochem. Photobiol. Sci. 1:355-363(2002)に見られる。このアッセイをこの例において使用した。
上述したように、光励起された酸素、即ち、基底状態の、三重項酸素又は“3O2”のスピン対相同物、である一重項酸素、“1O2”が、光毒性に関与していることが知られている最も重要な励起状態の分子である。特に、細胞DNA、膜脂質、およびケラチンやコラーゲン等の構造タンパク質、に対する光酸化障害における一重項酸素の関与は、十分に記載されてきた。一重項酸素を失活させることにおける、上述したプロリンおよびプロリン誘導体の有効性を測定するためのアッセイが開発された。ここにその全体を参考文献として合体させるライオン(Lion)他,Nature 263:442-443(1976)を参照。
これらの実験は、クエンチャーであることが証明された前記化合物が皮膚細胞を保護するのに有効であるか否かを調べるために構成された。
QPES-化合物: L-Pro 6.2±5.4
L-Pro-OCH3 83.8±10.9
4-OH-L-Pro 7.3±2.5
4-OH-L-Pro-OCH371.0±13.4
%増殖 ((TB+光+QPES)- %増殖(TB+光)
保護(%)= X100
%増殖(コントロール)- %増殖(TB+光)
上述した化合物4−OH−L−プロリンメチルエステルは、新規なグループの化合物を代表する新規な化合物であると考えられる。この化合物の合成、このファミリーの他のメンバーの合成のガイドラインについて次に記載する。
Claims (20)
- それを必要とする対象体における光障害を調節する方法であって、前記対象体の皮膚に、紫外線光によって生じる光障害を調節するのに十分な量の光障害モジュレーターを供与する工程を有する、光障害を調節する方法。
- 前記モジュレーターは、光障害を促進する請求項1の方法。
- 前記モジュレーターは、コラーゲン由来である請求項2の方法。
- 前記モジュレーターは、3−ヒドロキシピリジン ファルマコフォアから成る構造を有する請求項2の方法。
- 前記モジュレーターは、N−アルキル−3−ヒドロキシピリジン又はその塩である請求項4の方法。
- 前記N−アルキル−3−ヒドロキシピリジン又はその塩は、2−20の炭素原子のアルキル部分(モアエティ:moiety)を含む請求項5の方法。
- 前記アルキル部分は、エチル基である請求項6の方法。
- 前記モジュレーターは、キャリア分子に接続される請求項2の方法。
- 前記モジュレーターは、ビタミンB6、ピリジノリン、又は3−ヒドロキシピリジンである請求項2の方法。
- 前記モジュレーターは、光障害を抑制する請求項1の方法。
- 前記モジュレーターは、プロリン、4−ヒドロキシプロリン又はそのアルキルエステルである請求項10の方法。
- 前記プロリンアルキルエステルは、1−24の炭素原子のアルキル部分を含む請求項11の方法。
- 前記プロリンアルキルエステルは、L−プロリン−OCH3又は4−OH−L−Pro−OCH3である請求項12の方法。
- 前記モジュレーターを、クリーム、ローション、シャンプー、スプレー、又はパッチの形態で供与することを含む請求項1の方法。
- 1−24の炭素原子を含むアルキル鎖を有する4−ヒドロキシ−L−プロリンアルキルエステル化合物。
- 約−1.00〜約+8.00のlog P値を有する請求項15の化合物。
- 前記アルキル鎖は、1−10の炭素原子を含む請求項15の化合物。
- 前記アルキル鎖は、16−22の炭素原子を含む請求項15の化合物。
- 前記アルキル鎖は、11−24の炭素原子を含む請求項15の化合物。
- 4−ヒドロキシ−L−プロリンメチルエステルとして指定される請求項15の化合物。
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