JP2019535699A - 癌幹細胞を含む癌を治療するためのルテニウム錯体 - Google Patents
癌幹細胞を含む癌を治療するためのルテニウム錯体 Download PDFInfo
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- JP2019535699A JP2019535699A JP2019524182A JP2019524182A JP2019535699A JP 2019535699 A JP2019535699 A JP 2019535699A JP 2019524182 A JP2019524182 A JP 2019524182A JP 2019524182 A JP2019524182 A JP 2019524182A JP 2019535699 A JP2019535699 A JP 2019535699A
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- 201000005992 juvenile myelomonocytic leukemia Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
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- 239000008101 lactose Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
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- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
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- 210000002307 prostate Anatomy 0.000 description 1
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- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 1
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 1
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- 150000003254 radicals Chemical class 0.000 description 1
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- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- MYFATKRONKHHQL-UHFFFAOYSA-N rhodamine 123 Chemical compound [Cl-].COC(=O)C1=CC=CC=C1C1=C2C=CC(=[NH2+])C=C2OC2=CC(N)=CC=C21 MYFATKRONKHHQL-UHFFFAOYSA-N 0.000 description 1
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- 239000003813 safflower oil Substances 0.000 description 1
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- 238000003118 sandwich ELISA Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
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- 238000009331 sowing Methods 0.000 description 1
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- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
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- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000012134 supernatant fraction Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- YODZTKMDCQEPHD-UHFFFAOYSA-N thiodiglycol Chemical compound OCCSCCO YODZTKMDCQEPHD-UHFFFAOYSA-N 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- AYNNSCRYTDRFCP-UHFFFAOYSA-N triazene Chemical compound NN=N AYNNSCRYTDRFCP-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 208000025444 tumor of salivary gland Diseases 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 230000009452 underexpressoin Effects 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 208000020416 vascular bone neoplasm Diseases 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 235000019164 vitamin B2 Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
-
- A—HUMAN NECESSITIES
- 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
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
- A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
N1−N1−N1は、N,N,N−三座アザ芳香族配位子を表し;
N2−N2は、N,N−二座アザ芳香族配位子を表し;
Xは、OH2、Cl、Br、I、およびSR1R2から選択され;
R1およびR2は、独立に、置換されていてよいC1−C12アルキルから選択され;
Y−は、一価のアニオンであり;かつ
nは、1または2である]
のルテニウム錯体に関する。
・式(I)のルテニウム錯体、および
・ABCG2基体。
・式(I)のルテニウム錯体、および
・抗腫瘍薬。
N1−N1−N1は、N,N,N−三座アザ芳香族配位子を表し;
N2−N2は、N,N−二座アザ芳香族配位子を表し;
Xは、OH2、Cl、Br、I、およびSR1R2から選択され;
R1およびR2は、独立に、置換されていてよいC1−C12アルキルから選択され;
Y−は、一価のアニオンであり;かつ
nは、1または2である]
のRu(II)錯体に関する。
用語「アルキル」とは、1〜12個(「C1−C12アルキル」)、好ましくは1〜6個(「C1−C6アルキル」)、より好ましくは1〜3個(「C1−C3アルキル」)の炭素原子を含有し、一重結合を通じて分子の残りの部分と結合している直鎖状または分岐状アルカン誘導体を指す。例えば、アルキル基としては、メチル、エチル、n−プロピル、i−プロピル、n−ブチル、i−ブチル、t−ブチル、ペンチル、ヘキシルが挙げられる。
を有する。
本発明者らは、リボフラビンなどのABCG2基体へのルテニウム錯体の結合が、例えば、ルテニウム錯体を癌幹細胞に向けることを可能にすることを観察した。
・式(I)のルテニウム錯体、および
・ABCG2基体。
Raは、OH、C1−C6 O−アルキル、OAc、NH2、NH−C1−C6アルキル、N(C1−C6アルキル)2、およびNHAcから選択され;かつ
各Rbは、独立に、H、C1−C6アルキル、およびAcから選択される]
の化合物である。
・式(I)のルテニウム錯体(式中、Xは、メチオニンである)、
・リボフラビン、および
・場合により、前記ルテニウム錯体の前記メチオニンと、リボフラビンとに共有結合しているリンカー。
本発明のRu錯体およびコンジュゲートは、癌幹細胞を含む癌を治療するための医薬組成物を調製するために使用することができる。従って、本発明の別の側面は、癌幹細胞を含む癌の治療において使用するための、本明細書において定義される式(I)のルテニウム錯体またはコンジュゲートを含んでなる医薬組成物である。
・前記2種の化合物を同時に投与する、同じ医薬調製物または医薬品の一部である組合せとして;または
・同時投与、逐次投与、または個別投与の可能性を生じさせる、各々が一方の物質を含有する2種の投与形の組合せとして
投与することができるということを意味する。
・ナイトロジェンマスタード、例えば、クロルメチン、シクロホスファミド、イホスファミド、メルファラン、クロランブシルなど;
・アルトレタミン、チオテパなどを含む、エチレンアミンおよびメチレンアミン誘導体;
・スルホン酸アルキル、例えば、ブスルファンなど;
・ニトロソ尿素、例えば、カルムスチン、ロムスチンなど;
・トリアゼン、例えば、ダカルバジン、プロカルバジン、テモゾロミドなど;ならびに
・白金を含有する抗悪性腫瘍剤、例えば、アルキル化剤として一般的に分類されるが、DNAをアルキル化するのではなく、異なる方法によってDNAとともに共有結合性金属性付加体を形成することになる、シスプラチン、カルボプラチン、およびオキサリプラチンなど。
・プリン類似体、例えば、アザチオプリン、メルカプトプリン、チオグアニン、フルダラビン、ペントスタチン、クラドリビンなど;
・ピリミジン類似体、例えば、5−フルオロウラシル(5FU)、フロクスウリジン(FUDR)、シトシンアラビノシド(シタラビン)、6−アザウラシル(6−AU)など;または
・葉酸代謝拮抗薬、例えば、メトトレキサート、ペメトレキセド、プログアニル、ピリメタミン、トリメトプリムなど。
・血管新生阻害薬、例えば、アンギオスタチン、エンドスタチン、フマギリン、ゲニステイン、ミノサイクリン、およびスタウロスポリン;
・DNA合成阻害薬、例えば、アミノプテリン、ガンシクロビル、およびヒドロキシ尿素;
・酵素阻害薬、例えば、S(+)−カンプトセシン、クルクミン、2−イミノ−1−イミダゾリジン酢酸(シクロクレアチン)、ヒスピジン、ホルメスタン、およびメビノリン;
・微小管阻害薬、例えば、コルヒチンおよびドラスタチン15;ならびに
・他の抗腫瘍剤、例えば、17−(アリルアミノ)−17−デメトキシゲルダナマイシン、アピゲニン、シメチジン、黄体形成ホルモン放出ホルモン、およびピフィスリンα。
・式(I)のルテニウム錯体、および
・抗腫瘍薬。
本発明の一側面は、癌幹細胞を含む癌を治療するための医薬品を製造するための、本明細書において定義される、ルテニウム錯体またはコンジュゲートの使用である。
・慢性骨髄増殖性腫瘍(MPN):慢性骨髄性白血病BCR−ABL陽性、慢性好中球性白血病、真性赤血球増加症、原発性骨髄線維症、本態性血小板減少症、慢性好酸球性白血病、全身性肥満細胞症、および分類不能の骨髄増殖性腫瘍を含む。
・好酸球増加症およびPDGFRA、PDGFRB、またはFGFR1異常を伴う骨髄性およびリンパ系新生物。
・骨髄異形成症候群(MDS):単系統異形成を伴う不応性血球減少症、鉄芽球性不応性貧血、多系統異形成を伴う不応性血球減少症、芽球増加を伴う不応性貧血、単独del(5q)染色体異常を伴う骨髄異形成症候群(myelodysplastic syndrome with isolated del(5q))、分類不能の骨髄異形成症候群、および小児骨髄異形成症候群を含む。
・骨髄異形成/骨髄増殖性腫瘍(MDS/MPN):慢性骨髄単球性白血病、非定型慢性骨髄性白血病BCR−ABL陰性、若年性骨髄単球性白血病、および分類不能の 骨髄異形成/骨髄増殖性腫瘍を含む。
・急性骨髄性白血病(AML):反復する遺伝子異常を伴うAML、t(8;21)(q22;q22)RUNX1を伴うAML、骨髄異形成に関連した変化を伴うAML、治療関連AML、前述のカテゴリーに典型的な特徴をもたないAML、骨髄様肉腫、ダウン症候群関連骨髄増殖、および芽球性形質細胞様樹状細胞腫瘍を含む。
・系統不明な急性白血病。
・前駆細胞のリンパ系新生物:B細胞リンパ芽球性リンパ腫/白血病およびT細胞リンパ芽球性リンパ腫/白血病を含む。
・成熟B細胞新生物。
・成熟T細胞およびNJ細胞新生物。
・ホジキンリンパ腫。
a)A:0.1%TFAを含有するH2O、B:0.1%TFAを含有するACN。
勾配1:40分間でB 0%→50%。
b)A:100mM TEAAを含有する95:5 H2O:ACN、B:100mM TEAAを含有する70:30 ACN:H2O。
勾配2:B 0%で5分間、続いて、55分間でB 0%→100%。
勾配3:40分間でB 10%→50%。
実施例1A.錯体1の合成
この合成では、暗所で80℃の水中でアコ錯体2と1のチオエーテル配位子の等量を混合する必要がある。反応の経過は、RP−HPLCを用いてモニタリングすることができる。RP−HPLCによる精製後、褐色の粉末として化合物[10]・TFA2を得た。
照射を用いてDNAを金属化するためのアッセイの一般的方法
オリゴヌクレオチド(10μM)を、100mM KClを含む10mMリン酸カリウムバッファー(pH=7.5)中で室温で30分間ルテニウム錯体で処理した。この溶液を暗所でインキュベートするかまたは高出力LEDで照射した。照射のために、サンプルをサンプル支持体内の標準的な10mmキュベットに入れ、高出力LEDユニットを用いて900mWで455nmで30分間照射した(Thorlabs, Inc.、カタログ番号:M455L3)。LEDの光は、照射パワーを最大にする目的で短い焦点距離を有する平凸レンズによって視準する。
最初に、錯体1のグアノシン一リン酸(GMP)金属化能力を研究した。その目的で、錯体1(250μM)を、10mMリン酸バッファー(pH=7.5)および100mM NaCl中で3当量のGMP(750μM)と混合した。室温で30分後に、アコ[Ru(terpy)(bpy)H2O]2+錯体(2)の部分的形成(50%を超える)が観察されたが、一方、GMPは本質的に未反応のままであった(図1、線b)。その後の2時間のサンプルインキュベーションによって、金属化生成物3およびアコ錯体2が生じ、開始時の塩素錯体は完全に消費された(図1、線d)。サンプルへの30分間の照射(λ=455nm)によって、モノ付加体3の排他的形成が起こった(GMPの消失に基づいて約80%の転化率、図1、線c)。
平行c−MYC四重鎖d[TTGAG3TG3TAG3TG3TA3](配列番号1)の10μM溶液を、10mMリン酸バッファー(pH=7.5)および100mM KCl中で5当量のルテニウム錯体1で処理し、この混合物に室温で30分間照射した(λ=455nm)。81%の転化率での、モノ付加誘導体MYC−[Ru]に相当する質量を有する生成物の形成が観察された(図4、線c)。光不在下での反応もまた、室温で30分後に約41%の転化率で観察された(図4、線b)。
錯体4(250μM)を、10mMリン酸バッファー(pH=7.5)および100mM NaCl中で3当量のGMP(750μM)と混合した。暗所、室温で30分後に、新たな生成物の形成は観察されなかった(図5、線b)。しかしながら、最初のサンプルに30分間照射すると(λ=455nm)、モノ付加体3の排他的形成が観察された(図5、線c)。
四重鎖c−MYCの10μM溶液を、10mMリン酸バッファー(pH=7.5)および100mM KCl中で5当量のルテニウム錯体4で処理した。この混合物への室温で30分間の照射(λ=455nm)によって、生成物MYC−[Ru]の形成が起こった(図6、線c)。この反応を暗所で行った場合には、30分後に金属化生成物の形成は観察されなかった(図6、線b)。
錯体5(250μM)を、10mMリン酸バッファー(pH=7.5)および100mM NaCl中で3当量のGMP(750μM)と混合した。暗所、室温で30分後に、新たな生成物の形成は観察されなかった(図7、線b)。しかしながら、最初のサンプルに30分間照射すると(λ=455nm)、モノ付加体3の排他的形成が観察された(図7、線c)。
四重鎖c−MYCの10μM溶液を、10mMリン酸バッファー(pH=7.5)および100mM KCl中で5当量のルテニウム錯体5で処理した。この混合物への室温で30分間の照射(λ=455nm)によって、生成物MYC−[Ru]の形成が起こった(図8、線c)。この反応を暗所で行った場合には、30分後に金属化生成物の形成は観察されなかった(図8、線b)。
10mMリン酸バッファー(pH=7.5)および100mM NaCl中の錯体1(250μM)は暗所でゆっくりとアコ2誘導体に変化することが観察された。30分後に完全な転化が観察されたことを考え合わせると、この加水分解は、照射(λ=455nm)によって著しく促進される(図9、線c)。暗所での、10mMリン酸バッファー(pH=7.5)および100mM NaCl中でのアコ2誘導体(250μM)と3当量のGMP(750μM)との反応によって、30分後に63%の転化が起こった(図10、線b)。光照射(λ=455nm)によってプロセスが加速され、30分後に完全な転化が起こった(図10、線c)。
材料と方法
細胞培養物
細胞株は、10%(v/v)のFCS(ウシ胎仔血清、Gibco)、ペニシリン(100U/mL)、およびストレプトマイシン(100U/mL)を添加したDMEM中で培養した。細胞培養物は、5%CO2中、湿度を保ち、37℃で維持した。
1ウェルあたり3×105個のHeLa細胞(子宮頸癌細胞株)またはVero細胞(腎上皮細胞株)を6ウェルプレートに播種した。1日後、アッセイする化合物を細胞培養培地に添加し、細胞を16時間または48時間インキュベートした。市販のキット(Qiagen Rneasy Mini Kit)を用いて製造業者の推奨に従って全RNAを抽出した。RNAは、Nanodrop ND−1000で定量した。同量のRNAを、CFX96リアルタイムシステム装置(Bio−Rad)でのqRT−PCR(Promega Gotaq 1−Step RT−qPCR System)に使用した。使用したプライマーは以下の通りであった:c−MYC:センス:5’−CTG AGG AGG AAC AAG AAG ATG AG−3 '(配列番号2)、アンチセンス:5’−TGT GAG GA GGT TTG CTG TG−3’(配列番号3);ALAS:センス:5’−GTT TGG AGC AAT CAC CTT CG−3'(配列番号4)、アンチセンス:5’−ACC CTC CAA CAC AAC AAC AG−3’(配列番号5);GAPDH:センス:5’−GGT GTG AAC CAT GAG AAG TAT GA-3'(配列番号6)、アンチセンス:5’−GAG TCC TTC GAT CAC CAC AAA G−3'(配列番号7)。
指示された濃度のアッセイする物質の存在下で、50%のコンフルエンスになるまでHeLa細胞を16時間インキュベートした。細胞をSDS−PAGE Laemmli法用バッファー中に溶解し、標準的な方法に従ってSDS−PAGEおよびウエスタンブロットに供した。c−MYCタンパク質は、抗MYC抗体(Santa−Cruz Biotechnologies)によって検出した。免疫反応性タンパク質のシグナルを検出するために、化学発光法に従った(ECL、Amersham Biosciences)。
HeLa細胞を、1ウェルあたり3×105個の細胞の密度で6ウェルプレートに播種した。翌日、錯体1を100μMの濃度で細胞培養培地に添加し、細胞を16時間インキュベートした。細胞を新鮮培地で2回洗浄し、70%HNO3/H2O中に溶解した。サンプルを全容量3mLの水に希釈し、ICP−MS(7,700× Agilent)によって分析した。
1ウェルあたり4000個の細胞を96ウェルプレートに播種し、24時間インキュベートした。異なる濃度のアッセイする物質を培養培地に添加し、さらに72時間、細胞をインキュベーター内に残した。次いで、MTTを終濃度0.5mg/mlで添加し、4時間インキュベートした。細胞を溶解し、水中0.1M HClおよび10%SDSを含有する可溶化溶液をある容量添加することによってホルマザン沈殿物を可溶化した。吸光度は、Tecan Infinito F200 Proプレートリーダーにより570nmで決定した。
HeLa細胞を、1ウェルあたり3×105個の細胞の密度で6ウェルプレートに播種した。翌日、錯体1を100μMの濃度で細胞培養培地に添加し、細胞を16時間インキュベートした。核の単離については以下のプロトコールに従った:細胞をPBSで洗浄し、遠心分離によって沈降させた。次いで、それらを細胞溶解バッファー[HEPES 10mM;pH=7.5、KCl 10mM、EDTA 0.1mM、ジチオトレイトール 1mM(DTT)、および0.5%ノニデット−40]中に再懸濁し、間欠的に混合しながら氷上で15〜20分間放置した。チューブを激しく撹拌して細胞膜を破壊し、次に、4℃で10分間12,000gで遠心分離した。堆積した核の完全性は、Nikon Eclipse TiE装置の位相差顕微鏡によって確認した。細胞質を含有する上清画分および核を含有する沈降物を70%HNO3/H2O中でホモジナイズし、上記のように、ICP−MSによって分析した。クロマチン抽出のために、市販のキットを使用した(Chromatin Extraction Kit、Abcam)。単離したクロマチンを70%HNO3/H2O中に再懸濁し、ICP−MSによって分析した.
本発明者らは、c−MYC癌遺伝子の発現レベルに対する本発明の錯体の効果を、メッセンジャー発現レベルおよびタンパク質発現レベルの両方において分析した。
膵腺癌は、癌幹細胞(CSC)の亜集団を含む不均一な腫瘍細胞集団を含む膵臓癌である。
Claims (30)
- 癌が癌幹細胞を含む癌である場合の、癌を治療するための医薬品を製造するための、式(I):
N1−N1−N1は、N,N,N−三座アザ芳香族配位子を表し;
N2−N2は、N,N−二座アザ芳香族配位子を表し;
Xは、OH2、Cl、Br、I、およびSR1R2から選択され;
R1およびR2は、独立に、置換されていてよいC1−C12アルキルから選択され;
Y−は、一価のアニオンであり;かつ
nは、1または2である]
のルテニウム錯体の使用。 - N1−N1−N1が、以下:
からなる群から選択される、請求項1に記載の使用。 - N1−N1−N1が、以下:
- N2−N2が、以下:
からなる群から選択される、請求項1〜3のいずれか一項に記載の使用。 - N2−N2が、以下:
- N1−N1−N1が
- 前記ルテニウム錯体が、下式:
Xは、OH2、Cl、Br、I、およびSR1R2から選択され;
R1およびR2は、独立に、置換されていてよいC1−C12アルキルから選択され;
Y−は、一価のアニオンであり;かつ
nは、1または2である]
を有する、請求項1〜6のいずれか一項に記載の使用。 - XがOH2を表し、かつnが2である、請求項1〜7のいずれか一項に記載の使用。
- XがSR1R2を表し、ここで、R1およびR2は、独立に、ハロゲン、OR’’、N(R’’)2、N(R’’)COR’’、CN、NO2、COR’’、CO2R’’、OCOR’’、OCO2R’’、OCONHR’’、OCON(R’’)2、CONHR’’、CON(R’’)2、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、C6−C14アリール、および3員〜10員のヘテロシクリルから選択される1個以上の基で置換されていてよいC1−C12アルキルから選択される、請求項1〜7のいずれか一項に記載の使用。
- 前記ルテニウム錯体が、以下:
からなる群から選択される、請求項1〜9のいずれか一項に記載の使用。 - Y−が、PF6 −、Cl−、Br−、BF4 −、CF3SO3 −、CH3SO3 −、およびCH3C6H4SO3 −からなる群から選択される、請求項1〜10のいずれか一項に記載の使用。
- 前記癌が、乳癌、肺癌、結腸癌、前立腺癌、卵巣癌、膵臓癌、子宮頸癌、および腎臓癌から選択される、請求項1〜11のいずれか一項に記載の使用。
- 前記癌が、膵臓癌、好ましくは膵腺癌である、請求項12に記載の使用。
- 以下:
・請求項1〜11のいずれか一項に記載の式(I)のルテニウム錯体、および
・ABCG2基体
を含んでなるコンジュゲート。 - 前記ABCG2基体が、イマチニブ、ゲフィチニブ、フラボピロドール、トポテカン、イリノテカン、SN−38、ミトキサントロン、シメチジン、プラゾシン、スタチン類、ジドブジン、エストロン、17β−エストラジオール、プロトポルフィリンIX、2−アミノ−1−メチル−6−フェニルイミダゾ[4,5−b]ピリジン、アムサクリン、アスパラギナーゼ、アザチオプリン、ビサントレン、ブレオマイシン、ブスルファン、カペシタビン、カルボプラチン、カルムスチン、クロランブシル、シスプラチン、クラドリビン、クロファラビン、シクロホスファミド、シタラビン、ダカルバジン、ダクチノマイシン、ダウノルビシン、ドセタキセル、ドキソルビシン、エピルビシン、エトポシド、フラボピリドール、フルダラビン、フルオロウラシル、ゲムシタビン、イダルビシン、イホスファミド、イリノテカン、ヒドロキシ尿素、ロイコボリン、リポソームダウノルビシン、リポソームドキソルビシン、ロムスチン、クロルメチン、メルファラン、メルカプトプリン、メスナ、メトトレキサート、マイトマイシン、ミトキサントロン、オキサリプラチン、パクリタキセル、ペメトレキセド、ペントスタチン、プロカルバジン、サトラプラチン、ストレプトゾトシン、テガフール・ウラシル、テモゾロミド、テニポシド、チオグアニン、チオテパ、トレオスルファン、トポテカン、ビンブラスチン、ビンクリスチン、ビンデシン、SN−38、ビノレルビン、リボフラビン、D−ルシフェリン、ローダミン123、フェオホルビドa、BODIPY−プラゾシン、およびヘキスト33342から選択される、請求項14に記載のコンジュゲート。
- 前記ABCG2基体がリボフラビンである、請求項14または15に記載のコンジュゲート。
- 以下:
・請求項1〜11のいずれか一項に記載の式(I)のルテニウム錯体、および
・抗腫瘍薬
を含んでなる、コンジュゲート。 - 前記ルテニウム錯体が式(I’):
の錯体である、請求項14〜17のいずれか一項に記載のコンジュゲート。 - 式(I)のルテニウム錯体中のXがSR1R2を表し、ここで、R1およびR2は、独立に、置換されていてよいC1−C12アルキルから選択される、請求項18に記載のコンジュゲート。
- Xが、メチオニンまたはメチオニン誘導体から選択される、請求項18または19に記載のコンジュゲート。
- Xが式:
Raは、OH、C1−C6 O−アルキル、OAc、NH2、C1−C6 NH−アルキル、N(C1−C6アルキル)2、およびNHAcから選択され;かつ
各Rbは、独立に、H、C1−C6アルキル、およびAcから選択される]
の化合物である、請求項18〜20のいずれか一項に記載のコンジュゲート。 - 前記ルテニウム錯体と、前記ABCG2基体または前記抗腫瘍薬とに共有結合しているリンカーを含んでなる、請求項14〜21のいずれか一項に記載のコンジュゲート。
- 前記リンカーが1〜20個の原子長の炭化水素鎖であり、ここで、該鎖の炭素原子の1個以上は、NR’、O、およびSから選択されるヘテロ原子で置き換えられていてもよく、ここで、R’は、H、C1−C6アルキル、およびアセチルから選択され;かつ前記鎖の炭素原子の1個以上は、=O、OH、SH、NH2、COOH、CH3、およびPhから選択される置換基で置換されていてもよい、請求項22に記載のコンジュゲート。
- 前記リンカーが、アミノ酸またはペプチド結合を介して結合している複数のアミノ酸の配列から選択される、請求項22または23に記載のコンジュゲート。
- 以下:
・請求項1〜11のいずれか一項に記載の式(I)のルテニウム錯体(式中、Xはメチオニンである)、
・リボフラビン、および
・任意で、前記ルテニウム錯体の前記メチオニンと、リボフラビンとに共有結合しているリンカー
を含んでなる、請求項14〜16および18〜24のいずれか一項に記載のコンジュゲート。 - 下記の構造:
を有する、請求項25に記載のコンジュゲート。 - 医療において使用するための、請求項14〜26のいずれか一項に記載のコンジュゲート。
- 癌幹細胞を含む癌の治療において使用するための、請求項14〜26のいずれか一項に記載のコンジュゲート。
- 前記癌が、乳癌、肺癌、結腸癌、前立腺癌、卵巣癌、膵臓癌、子宮頸癌、および腎臓癌から選択される、請求項28に記載の使用のためのコンジュゲート。
- 前記癌が、膵臓癌、好ましくは膵腺癌である、請求項28または29に記載の使用のためのコンジュゲート。
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BIOTHERAPY, vol. 21, no. 4, JPN6021034575, 2007, pages 209 - 216, ISSN: 0004982563 * |
CHEM. EUR. J., vol. 17, JPN6021034572, 2011, pages 9924 - 9929, ISSN: 0004982561 * |
CHEM. EUR. J., vol. 22, JPN6021034571, 4 July 2016 (2016-07-04), pages 10960 - 10968, ISSN: 0004982559 * |
CYTOMETRY RESEARCH, vol. 26, no. 2, JPN6022024895, 15 December 2016 (2016-12-15), pages 7 - 13, ISSN: 0004982566 * |
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