JP5616798B2 - ミトコンドリア由来の抗ガン化合物 - Google Patents
ミトコンドリア由来の抗ガン化合物 Download PDFInfo
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- JP5616798B2 JP5616798B2 JP2010550000A JP2010550000A JP5616798B2 JP 5616798 B2 JP5616798 B2 JP 5616798B2 JP 2010550000 A JP2010550000 A JP 2010550000A JP 2010550000 A JP2010550000 A JP 2010550000A JP 5616798 B2 JP5616798 B2 JP 5616798B2
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- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
- C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Description
1.絶大なプロオキシダントおよびアポトーシス促進活性を得るために、機能的ドメインIの修飾は、解離した酸または荷電したアンモニウム基からなる親水性頭部基を要求した。
2.機能的ドメインの鎖長および不飽和の程度が、アポトーシス活性を決定した。コンホメーション的制限が、活性を増強するように見えた。
3.機能的ドメインの化学結合は、エステルに限定されず、他の官能基は、誘導体の酵素的分解を防止した。
(Fantin、V.R.、Berardi、M.J.、Babbe、H.、Michelman、M.V.、Manning、C.M. and Leder、P. 2005. A bifunctional targeted peptide that blocks HER-2 tyrosine kinase and disables mitochondrial function in HER-2-positive carcinoma cells. Cancer Res. 65:6891-6900)。
本発明らは、現在、ガン性細胞のミトコンドリア内に蓄積し、それらの細胞死を誘発する傾向がある抗ガン化合物を開発している。1つの実施態様において、このような化合物は、ミトコンドリアデリバリー部分に結合しているプロオキシダント部分を含む。このプロオキシダント部分は、ガン性細胞のミトコンドリア内に活性酸素種を生成し、それらの細胞のアポトーシスを誘発する。もう1つの実施態様において、このような化合物は、ミトコンドリアデリバリー部分に結合しているアポトーシス促進性部分を含む。このアポトーシス促進性部分は、それらの細胞のアポトーシスを誘発する。
本発明の第1の態様は、ガン性細胞の死を誘発するための化合物であって、
(i)ガン性細胞のミトコンドリア内に活性酸素種を生成し、(ii)ガン性細胞のアポトーシスを誘発するためのプロオキシダント部分;ならびに
ガン性細胞のミトコンドリアへプロオキシダント部分をデリバリーするためのデリバリー部分;
を含む化合物を提供する。
(i)ガン性細胞のミトコンドリア内に活性酸素種を生成し、(ii)ガン性細胞のアポトーシスを誘発するためのプロオキシダント部分;ならびに
ガン性細胞のミトコンドリアへプロオキシダント部分をデリバリーするためのデリバリー部分;
を含む化合物を提供する。
(i)ガン性細胞のミトコンドリア内に活性酸素種を生成し、(ii)ガン性細胞のアポトーシスを誘発するためのプロオキシダント部分;ならびに
ガン性細胞のミトコンドリアへプロオキシダント部分をデリバリーするためのデリバリー部分;
を含む化合物の治療有効量を患者に投与するステップを含む方法を提供する。
(i)ガン性細胞のミトコンドリア内に活性酸素種を生成し、(ii)ガン性細胞のアポトーシスを誘発するためのプロオキシダント部分;ならびに
ガン性細胞のミトコンドリアへプロオキシダント部分をデリバリーするためのデリバリー部分;
を含む化合物の治療有効量を患者に投与するステップを含む方法を提供する。
(i)ガン性細胞のミトコンドリア内に活性酸素種を生成し、(ii)ガン性細胞のアポトーシスを誘発するためのプロオキシダント部分;ならびに
ガン性細胞のミトコンドリアへプロオキシダント部分をデリバリーするためのデリバリー部分;
を含む化合物の使用を提供する。
(i)ガン性細胞のミトコンドリア内に活性酸素種を生成し、(ii)ガン性細胞のアポトーシスを誘発するためのプロオキシダント部分;ならびに
ガン性細胞のミトコンドリアへプロオキシダント部分をデリバリーするためのデリバリー部分;
を含む化合物の使用を提供する。
該化合物は、単離された、精製された、実質的に精製された、合成または組換の形体であってよい。
テトラフェニルホスホニウムカチオンが、適当なデリバリー部分のもう1つの例である。
適当なデリバリー部分のさらなる例は、Hoye、Adam T.、Davoren、Jennifer E.、Wipf、Peter、Fink、Mitchell P.、and Kagan、Valerian E.、(Targeting Mitochondria、Acc. Chem. Res.、41、1、87-97、2008)に記載されている。
化合物は、1つ以上のプロオキシダント部分を有することができ、該部分は、呼吸鎖の異なる領域/成分を、中断/標的化することができる。
する場合、たとえば、α-トコフェロール(α-TOH)などの抗酸化(酸化還元)活性があるビタミンE類縁体である。したがって、プロオキシダントビタミンE類縁体および抗酸化性ビタミンE類縁体の生物活性は、正反対である。
ガン性細胞のアポトーシスを誘発するためのアポトーシス促進性部分;および
ガン性細胞のミトコンドリアへアポトーシス促進性部分をデリバリーするためのデリバリー部分;
を含む化合物を提供する。
ガン性細胞のアポトーシスを誘発するためのアポトーシス促進性部分;および
ガン性細胞のミトコンドリアへアポトーシス促進性部分をデリバリーするためのデリバリー部分;
を含む化合物を提供する。
ガン性細胞のアポトーシスを誘発するためのアポトーシス促進性部分;および
ガン性細胞のミトコンドリアへアポトーシス促進性部分をデリバリーするためのデリバリー部分;
を含む化合物の治療有効量を患者に投与するステップを含む方法を提供する。
ガン性細胞のアポトーシスを誘発するためのアポトーシス促進性部分;および
ガン性細胞のミトコンドリアへアポトーシス促進性部分をデリバリーするためのデリバリー部分;
を含む化合物の治療有効量を患者に投与するステップを含む方法を提供する。
細胞培養:
本実験に用いた以下の細胞は、他に特記しない限り、ATCCから入手した:ヒトTリンパ腫細胞 ジャーカット、ヒト中皮腫細胞 Meso-I、MM-BI、Ist-Mes、Ist-Mes-2(Pass、H.I. ら、Characteristics of nine newly derived mesothelioma cell lines. Ann. Thorac. Surg. 59、835-844(1995))、ヒト乳ガン細胞 MCF-7(erbB2-low)およびMDA-MB-453(erbB2-high)、ヒト結腸直腸細胞 HCT-116、ヒト肝細胞ガン細胞 Huh-7、マウス中皮腫細胞 AE17(Jackaman、C. ら、L-2 intratumoral immunotherapy enhances CD8+ T cell that mediate destruction of tumor cell and tumor-associated vasculature: a novel mechanism for IL-2. J. Immunol. 171、505150-505163(2003)、ヒト良性中皮細胞 Met-5A、ラット心室筋細胞様細胞 HL-1(Claycomb、W.C. ら、HL-1 cell: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc. Natl. Acad. Sci. USA 95、2979-2984(2001))およびH9c2、ならびにヒト内皮様細胞 EAhy926(Edgell、C.J.、McDonald、C.C. & Graham、J.B. Permanent cell line expressing human factor VIII-related antigen established by hybridization. Proc. Natl. Acad. Sci. USA 80、3734-3737(1983))。10% FCSおよび抗生物質を補足して、RPMI培地中でジャーカット細胞を増殖させ、他の悪性細胞株およびMet-5A細胞には、DMEMを用いた。ノルアドレナリンを補足したクレイコーム(Claycomb)培地中でフィブロネクチン/ゼラチンコーティング皿中で維持したHL-1細胞を増殖させ(Claycomb、W.C. ら、HL-1 cell: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc. Natl. Acad. Sci. USA 95、2979-2984(2001))、HATを補足した完全DMEM中でEAhy926細胞を増殖させた(Edgell、C.J.、McDonald、C.C. & Graham、J.B. Permanent cell line expressing human factor VIII-related antigen established by hybridization. Proc. Natl. Acad. Sci. USA 80、3734-3737(1983))。 Weber、T.ら(Mitochondria play a central role in apoptosis induced by α-tocopheryl succinate、an agent with anticancer activity. Comparison with receptor-mediated pro-apoptotic signaling. Biochemistry 42、4277-4291(2003))が詳述しているように、mtDNA(ρ0 表現型)を欠いている細胞を調製した。mtDNAにコードされたチトクロームCオキシダーゼサブユニットII(COXII、図示せず)の細胞による発現の欠如によって、ρ0表現型の獲得を確認した。10% FCS、抗生物質、10 mg/mlのグルコースおよび非必須アミノ酸を補足したDMEM中で、複合体Iを欠いているチャイニーズハムスター肺線維芽細胞(B10細胞)(Seo、B.B. ら、Molecular remedy of complex I defects: rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria restores the NADH oxidase activity of complex I-deficient mammalian cell. Proc. Natl. Acad. Sci. USA 95、9167-9171(1998))および複合体II(CybL-/-;B9細胞)(Oostveen、F.G.、Au、H.C.、Meijer、P.J. & Scheffler、I.E. A Chinese hamster mutant cell line with a defect in the integral membrane protein CII-3 of complex II of the mitochondrial electron transport chain. J. Biol. Chem. 270: 26104-26108(1995))ならびに親細胞(B1細胞)(Oostveen、F.G.、Au、H.C.、Meijer、P.J. & Scheffler、I.E. A Chinese hamster mutant cell line with a defect in the integral membrane protein CII-3 of complex II of the mitochondrial electron transport chain. J. Biol. Chem. 270: 26104-26108(1995))を増殖させた。
国際出願番号PCT/NZ98/00173およびPCT/NZ02/00154の明細書に記載の方法にしたがって、以下の化合物(大部分を図1に記載する)を一般的に合成した:- MitoVE11S、S-MitoVE11S、R-MitoVE11S、MitoVE9S、MitoVE7S、MitoVE5S、MitoVE3S、MitoVE11AE、MitoVE11F and VES4TPP。
Turanek、J.、ら、((2008). Liposomal formulation of vitamin E analogs as an efficient and selective anti-cancer treatment. Clin. Cancer Res. (submitted))に詳述されている通り、IC50に基づいて、ガン細胞に対するα-TOS、VE11S(VES)、MitoVE3S、MitoVE5S、MitoVE7S、MitoVE9S、MitoVE11S(MitoVES)、MitoVE11AE(MitoVEAE)、MitoVE11F(MitoVEF)、MitoVE11M(MitoVEM)およびVES4TPPの毒性を評価した。アネクシンV法を用いてアポトーシスを評価し(Weber、T. ら、Mitochondria play a central role in apoptosis induced by α-tocopheryl succinate、an agent with anticancer activity. Comparison with receptor-mediated pro-apoptotic signaling. Biochemistry 42、4277-4291(2003))、多色プローブJC-1(Molecular Probes)を用いてミトコンドリア内膜電位の消失を評価した(Weber、T. ら、Mitochondria play a central role in apoptosis induced by α-tocopheryl succinate、an agent with anticancer activity. Comparison with receptor-mediated pro-apoptotic signaling. Biochemistry 42、4277-4291(2003))。
ELISA比色分析キット(Roche)を用いて細胞増殖を測定し、使用説明書を用いる5-ブロモ-2-デオキシウリジン(BrdUrd)のDNA取り込みに基づいて、細胞周期のS期にある細胞の数を決定した。細胞周期分析のために、24時間の回復後に、細胞が〜50%、70%および100%集密に達するように、24ウエルプレートに細胞を置いた。次いで、細胞を採取し、クエン酸ナトリウム(1%)、トリトンX-100(0.1%)、RNアーゼA(0.05 μg/mL)および5 μg/mLのヨウ化プロピジウムを含む緩衝液に再懸濁し、4℃にて30分間インキュベートし、フローサイトメトリーによって分析した。
複合体II基質2,6-ジクロロフェノールインドフェノール(DCIP)の減少の時間的経過を、反応体積1 mlを含む1 cmキュベット中600 nmにおける吸光度を測定することによって追跡した(ε600=21x103 M-1cm-1)。反応成分は、NADH、0.5 mM;コハク酸エステル、5 mM;KCN、10 mM;DCIP、50 μM;フェナジンメトスルフェート(PMS)、50 μMを含んだ。各アッセイの時点のために、0.5 mgのサンプルタンパク質を用い、示すとおり、100または300 μMのいずれかにてα-TOSを加えた。分光光度計(UVIKON XL、Secomam)を用いて、DCPIPの吸光度の変化を測定し、複製サンプルを検定した(n=3)。複合体Iを測定する場合(NADHデヒドロゲナーゼ活性)、PMSは含めなかった。α-TOSの無いコントロール反応のために、最終濃度が<0.1%(v/v)になるように希釈DMSOを加えた。
図の説明に示すとおり、α-TOSで細胞を処理し、フローサイトメトリーによって間接的に、および電子常磁性共鳴(EPR)分光分析によって間接的に、細胞ROSを検出した。幾つかの実験において、2 μMのミトコンドリアに標的化された補酵素Q(MitoQ)で1時間細胞を前処理するか(Kelso、G.F.、ら、Selective targeting of a redox-active ubiquinone to mitochondria within cell: antioxidant and antiapoptotic properties. J. Biol. Chem. 276、4588-45896(2001))、または750ユニット/mlのスーパーオキシドジスムターゼ(SOD;Sigma S4636;EC 1.15.1.1)とともに共インキュベートした。間接的評価のために、細胞をα-TOSで処理し、ジヒドロジクロロフルオレセイン二酢酸(DCF;Molecular Probes)と30分間反応させ、蛍光が強い細胞に対するフローサイトメトリーによって評点を付け、平均蛍光強度における増加に基づいて評価した。ラジカルトラップである5,5-ジメチルl-1-ピロリン N-オキシド(DMPO;Sigma)の使用に基づいて、ROS生成のEPR分光分析を行った。簡単に言うと、T25フラスコで細胞を培養し、60-70%集密(〜5x106細胞/フラスコ)に到達させた。細胞を洗浄し、PSS培地で覆い(Thomas、S.R.、Chen、K.、& Keaney、J.F. Hydrogen peroxide activates endothelial nitric-oxide synthase through coordinated phosphorylation and dephosphorylation via a phosphoinositide 3-kinase-dependent signaling pathway. J. Biol. Chem. 277、6017-6024(2002))、10 mMのDMPOを加えた後、50 μMのα-TOSとともに5分間インキュベートした。石英フラットセル(Wilmad)へ移された細胞懸濁液ならびに細胞馴化培地から採取したサンプルで、DMPO付加物の分析を行った。次いで、次の分光計パラメーター(場掃引 10 mT、マイクロ波電力 20 mW、マイクロ波周波数 100 kHz、振幅変調 0.1 mT、掃引時間 83.9秒)をもつ293 KにセットしたBruker EMX 卓上分光計の空洞内に石英セルを置いた。安定な窒素酸化物(TEMPO)の検出限界は、〜50 nMであった。
CybL遺伝子を保持するTopo pCR3.1 Uniプラスミドを用いて、B9細胞をトランスフェクトさせ(Slane BG、Aykin-Burns N、Smith BJ、Kalen AL、Goswami PC、Domann FE、Spitz DR. (2006). Mutation of succinate dehydrogenase subunit C results in increased oxidative stress、and genomic instability. Cancer Res 66: 7615-7620)、次の文献に記載の通り選択した(Weber T、Dalen H、Andera L、Negre-Salvayre A、Auge N、Sticha M ら(2003). Mitochondria play a central role in apoptosis induced by α-tocopheryl succinate、an agent with anticancer activity. Biochemistry 42: 4277-4291)。安定にトランスフェクトされ、SDH活性およびSDHC発現について、siRNA処理された細胞を評価した。抗SDHC免疫グロブリンG(IgG)(クローン3E2;Novus Biologicals)を用い、ローディングコントロールとして抗β-アクチンIgG (Santa Cruz Biotechnology、Santa Cruz、CA、USA)を用いて、次の文献に記載の通りウエスタンブロッティングを行った(Wang XF、Birringer M、Dong LF、Veprek P、Low P、Swettenham E ら(2007). A peptide adduct of vitamin E succinate targets breast cancer細胞 with high erbB2 expression. Cancer Res 67: 3337-3344)。標準的プロトコルを用いてRT-PCRを行った。公表されたヒトCybL(Slane BG、Aykin-Burns N、Smith BJ、Kalen AL、Goswami PC、Domann FE、Spitz DR. (2006). Mutation of succinate dehydrogenase subunit C results in increased oxidative stress、and genomic instability. Cancer Res 66: 7615-7620)およびチャイニーズハムスターグリセルアルデヒド三リン酸デヒドロゲナーゼプライマー(Sever ら、2004)を用いた。
EAhy926細胞の創傷治癒活性におけるα-TOSの効果を評価するために、3.5 mmペトリ皿に細胞を播種し、完全集密に到達させた。滅菌した黄色のピペットチップを用いて細胞を除去して細胞の単層に傷を付け、直径0.4-0.5 mmの露出領域を作成した。接眼レンズにグリッドを備えた顕微鏡において、露出裂け目を狭くすることの動力学を追跡することによって、「裂け目を満たす速度」として表される治癒を治癒速度(μm/時間)として、α-TOSまたはα-TEAの存在下での細胞の再増殖(創傷治癒)を評価した。
先の記載(Weber、T. ら、Mitochondria play a central role in apoptosis induced by α-tocopheryl succinate、an agent with anticancer activity. Comparison with receptor-mediated pro-apoptotic signaling. Biochemistry 42、4277-4291(2003))の通り、透過電子顕微鏡法に付す培養物を調製した。簡単に言えば、 0.1 Mスクロース−カコジル酸ナトリウム−HCl緩衝液(pH 7.2;Sigma、St Louis、MO、USA)中の2%グルタルアルデヒド(Agar Scientic、Essex、UK)の添加によってジャーカット細胞の培養物を固定し、オスミウム(Johnson Matthey Chemicals、Roystone、UK)中で後固定した。その後、2 %寒天中で細胞をペレット化した後、脱水し、酢酸ウラニル(Sigma)で染色し、Epon-812(Fluka AG、Buchs、Switzerland)に包埋した。治癒したブロックの薄い切片をダイヤモンドナイフ(DIATOME、Bienne、Switzerland)で切断し、クエン酸鉛(Sigma)で染色し、審査し、JEOL 1230-EX電子顕微鏡(Tokyo、Japan)で100 kVにて写真を撮った。
Brookhaven Protein Databank(code 1ZOY)(Sun F、Huo X、Zhai Y、Wang A、Xu J、Su D、Bartlam M、Rao Z. 2005. Crystal structure of mitochondrial respiratory membrane protein 複合体II. Cell 121:1043-1057)から、ブタ心臓由来のミトコンドリア呼吸膜タンパク質複合体IIの結晶構造を入手した。複合体は、4個のタンパク質を含む。この複合体における3個のサブユニットである鉄イオウタンパク質(鎖B)、大(鎖C)および小(鎖D)膜貫通タンパク質は、UbQへの結合に関与する。NCBIウェブサイトからのBLAST調査は、ブタおよびヒト複合体IIの間の配列同一性が、鉄イオウタンパク質について97%、大膜貫通タンパク質について90%および小膜貫通タンパク質について94%と非常に高いことを示した。
図2は、ビタミンEのミトコンドリアに標的化された酸化還元サイレント類縁体が、そのガン細胞に対する選択性を維持しながら、その非標的化α-TOS対応物と比べて、ガン細胞に対する極めて高いアポトーシス効果および抗ガン活性を有することを示す。特に、MitoVE11S(Mito-α-TOS)は、ガン細胞中の原型のα-TOSよりも、50倍まで高いアポトーシス性を見出された。
第V表
aジャーカット細胞は、0.5x106個/mlにて処理し、他の細胞株(EAhy926細胞以外)は、〜60%集密にて処理した。
bIC50値は、MTT生存能力アッセイを用いて生存能力曲線から誘導され、μmol/lで表わされる。
cEAhy926細胞は、100%集密(上段)または〜50%集密(下段)にて処理した。
第VI表
aジャーカット細胞は、0.5x106個/mlで処理し、EtOH溶液として加えた、表に示した類縁体に曝露した。
bIC50値は、MTT生存能力アッセイを用いて生存能力曲線から誘導され、μmol/lで表わされる。
パネルJにおけるα-TOS-およびMitoVE11S-処理ジャーカット細胞の顕微鏡写真は、アポトーシスの典型的な特徴的兆候を表す。
図6の結果から、MitoVES(MitoVE11S)は、ROSの蓄積により、増殖している内皮細胞においてアポトーシスを引き起こすが、停止内皮細胞においては引き起こさないことが示され、したがって、強力な抗血管新生薬としてのその潜在力が明らかとなる。よって、MitoVE11Sは、血管新生の有効なインヒビターであり、アポトーシスを介してガン細胞を殺すことによって直接的抗ガン効果を有する。
図7の創傷治癒、管形成およびアポトーシスアッセイから、MitoVES(MitoVE11S)は、インビトロにおいて血管新生を阻害することが示され、したがって、抗血管新生薬としての、その潜在的能力が再確認される。
α-TOSと同様に、MitoVE11Sは、増殖している内皮細胞を標的化し、殺すことにおいて非常に強力な抗血管新生活性を有する。しかしながら、MitoVE11Sは、抗血管新生薬として、驚くべき5倍大きい効力を示す。同じ内皮細胞型における同程度の効果のために、α-TOSが約25-50マイクロモル必要であるのに対し、MitoVE11Sは約5-10マイクロモル必要である(α-TOSレベルは、次の文献からのものである;Lan-Feng Dong、Emma Swettenham、Johanna Eliasson、Xiu-Fang Wang、Mikhal Gold、Yasmine Medunic、Marina Stantic、Pauline Low、Lubomir Prochazka、Paul K. Witting、Jaroslav Turanek、Emmanuel T. Akporiaye、Stephen J. Ralph、and Jiri Neuzil、Vitamin E Analogues Inhibit Angiogenesis by Selective Induction of Apoptosis in Proliferating Endothelial cell: The Role of Oxidative Stress、Cancer Res 2007;67:(24). December 15、2007.)
本発明者らによる先の研究から、α-TOSは、複合体IIの呼吸鎖におけるUbQ部位を妨げることによってROSを誘発することが明らかにされている。本実施例から、複合体IIを遺伝的に欠損している突然変異ガン細胞株は、MitoVESに反応しないことが示され、したがって、MitoVES(MitoVE11S)が、複合体IIの呼吸鎖におけるUbQ部位を妨げることによってROSを誘発することが確認される。
MitoVESがUbQ結合部位を介して複合体IIと相互作用するという結果を理論的に説明するために、本発明者らは、を用いる分子モデリング研究に着手した
(Morris G M、 Goodsell DS、 Halliday RS、Huey R、Hart W E、 Belew RK、Olson AJ(1998) Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function. J Comp Chem 19: 1639-1662)。ブタ心臓ミトコンドリアCIIの結晶構造が報告されている(Sun F、Huo X、Zhai Y、Wang A、Xu J、Su D、Bartlam M、Rao Z. 2005. Crystal structure of mitochondrial respiratory membrane protein complex II. Cell 121:1043-1057)。それは、ヒトCII(個々のサブユニットに対して、95-97%)との高い配列同一性を示し、したがって、本発明者らは、モデリング研究のための基準として、この構造(1ZOY)および関連する構造(1ZP0)とインヒビターTTFAを用いた。図5に示す通り、ドッキング実験は、複合体IIの空間充填モデルに示されるように棒線画構造として同定されるMitoVE11Sとの結合構造を生み出した。複合体IIの鎖B(鉄−イオウタンパク質)の表面および鎖CおよびD(膜貫通部分)の表面を図示するが、鎖A(フラビンタンパク質−コハク酸レダクターゼ)は、図示せず。
ガン療法における近年の重要な発見は、腫瘍を再定着させるための源となりうるガン幹細胞が存在するということである。腫瘍の大部分を殺すが、身体に幹細胞を生存させたままにする治療は、腫瘍が再増殖するために失敗するので、この発見は、ガンを治療することの困難さも強調する(LouおよびDean、Oncogene 2007)。ガン幹細胞は、通例、療法に対して耐性があり(O'Brien ら、2008、Li ら.、2008)、そして、薬物耐性があり、ガン幹細胞における蓄積から化学療法薬を妨げるのに関与する、細胞膜上の多剤耐性(MDR)/ABC輸送糖タンパク質を発現するので、非常に重要な標的でもある。ガン幹細胞は、高いDNA損傷修復能力があるので、放射線耐性があることも発見されている(Neuzil ら.、2007 BBRC;EylerおよびRicj、2008)。
1) MitoVES(MitoVE11S)は、α-TOSと比べて、選択的ガン細胞殺活性において〜50倍という驚くほど強い効力を有する;
2) MitoVESは、1)の結果として、正常細胞における毒性はかなり低く、特異性は改善される;
3) MitoVESは、α-TOSと比べて、細胞死に対してミトコンドリア経路をより特異的に誘発する;
4) α-TOSと同様に、MitoVESは、増殖中の内皮細胞を標的化し、殺すことにおいて非常に強力な抗血管新生活性を有するが、MitoVES(MitoVE11S)は、驚くべきことに、α-TOSと比べて、抗血管新生薬として5倍強い効力を示す;そして
5) MitoVESは、それが、中皮腫、乳ガン、結腸ガン、リンパ腫細胞株およびガン幹細胞を殺すことを考慮すると、ガン療法において非常に広く適用できる可能性が高い。
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Claims (9)
- ガン性細胞の死を誘発するため、またはガンを治療するための化合物であって、
(i)ガン性細胞のミトコンドリア内に活性酸素種を生成し、(ii)ガン性細胞のアポトーシスを誘発し、そして(iii)ガン性細胞のミトコンドリア複合体IIと相互作用するためのプロオキシダント部分;ここで、プロオキシダント部分は、ミトコンドリア複合体IIのQpユビキノン結合部位と相互作用することができる置換クロマノール環のC6位における機能的ドメイン、置換クロマノール環を含むドメイン、および少なくとも7個の炭素原子の長さの脂肪族鎖を含む疎水性ドメイン、を含むビタミンE類縁体を含む;
ならびに
ガン性細胞のミトコンドリアへプロオキシダント部分をデリバリーするため、およびQpユビキノン結合部位との相互作用のための機能的ドメインを正確に位置づけるためのデリバリー部分;ここで、デリバリー部分は、脂溶性トリフェニルホスホニウムカチオンを含み、
該ビタミンE類縁体は、α-コハク酸トコフェリル、α-マレイン酸トコフェリル、α-トコフェリルマレイルアミドおよび2,5,7,8-テトラメチル-2R-(4R,8R,12-トリメチルトリデシル)-クロマン-6-イルオキシ酢酸(α-トコフェリルオキシ酢酸)から選ばれる;
を含む化合物。 - プロオキシダントビタミンE類縁体が、α-コハク酸トコフェリル(α-TOS)である請求項1に記載の化合物。
- 請求項1または2に記載の化合物またはその生理学的に許容しうる塩および生理学的に許容しうる担体を含む医薬組成物または獣医用組成物。
- プロオキシダントビタミンE類縁体が、α-コハク酸トコフェリル、α-マレイン酸トコフェリルおよびα-トコフェリルマレイルアミドから選ばれ、担体が、経皮適用可能なクリームである請求項3に記載の医薬組成物または獣医用組成物。
- プロオキシダントビタミンE類縁体が、α-トコフェリルオキシ酢酸であり、担体が、経口投与に適している請求項3に記載の医薬組成物または獣医用組成物。
- ガン性細胞の死を誘発するための医薬の製造における請求項1または2に記載の化合物の使用。
- ガン性細胞の死を誘発するための医薬の製造における請求項3〜5のいずれか1つに記載の医薬組成物の使用。
- ガンの予防または治療用医薬の製造における請求項1または2に記載の化合物の使用。
- ガンの予防または治療用医薬の製造における請求項3〜5のいずれか1つに記載の医薬組成物の使用。
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