JP7073269B2 - 抗増殖剤としてのddx3阻害剤の使用 - Google Patents
抗増殖剤としてのddx3阻害剤の使用 Download PDFInfo
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- JP7073269B2 JP7073269B2 JP2018549791A JP2018549791A JP7073269B2 JP 7073269 B2 JP7073269 B2 JP 7073269B2 JP 2018549791 A JP2018549791 A JP 2018549791A JP 2018549791 A JP2018549791 A JP 2018549791A JP 7073269 B2 JP7073269 B2 JP 7073269B2
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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Description
DEAD-ボックスヘリカーゼは、あらゆる態様のRNA代謝に関与する。その役割は、RNAの巻き戻し、すなわち二次構造モチーフの除去、短いRNA-RNA相互作用の巻き戻し、また、RNA結合タンパク質の除去と考えられており(Yangら、2006年)、DDX3は、名前の由来となるAsp-Glu-Ala-Asp(D-E-A-D)モチーフを含むRNAヘリカーゼスーパーファミリーのメンバーを特徴とする全9種の保存モチーフを、2つのRecA様ドメインを形成する構造的に保存されたコアエレメント内に含有するATPアーゼ/RNAヘリカーゼである。保存ヘリカーゼモチーフは、ATP結合、ATPアーゼ活性、RNA基質結合及び巻き戻しに関与する(Linderら、2004年)。DDX3の結晶構造は、これらの保存モチーフが、短いフレキシブルリンカーを経由してつながる2つのサブドメインで見出されていることを示す。DDX3は、N末端に核外輸送シグナル(NES)を含有する。アミノ末端ドメイン1は、ATP結合モチーフQ、I(ウォーカーA)及びII(ウォーカーB)並びにRNA結合モチーフIa、Ib及びモチーフIIIを含有する。RNA結合モチーフIV、V及びモチーフVIは、ATPアーゼ及び巻き戻し活性を調和させることができ、カルボキシル末端ドメイン2で見出されている。
DDX3は、異なる細胞の代謝経路に関与する。最近の証拠から、DDX3は、2つの他のシャトルタンパク質、CRM1及びTAPと関連して、mRNA核外輸送に関与することが示唆されている。提起されている機構は、DDX3が核のmRNA及びTAPに結合し、続いて、細胞質へのmRNP輸送の促進を援助する機構である。CRM1との相互作用は、HIVの、スプライシングされていない又はスプライシングが不完全なRNAの輸送にのみ重要と考えられている(Kohler Aら、2007年)。DDX3は、翻訳開始因子eIF4E、eIF4A、eIF4G、PABP及びeIF3と相互作用する。最近、Marsden及び共同研究者により、5'-UTR内に特異的な構造的特徴を保有する細胞及びウイルスmRNAの特異的サブセットの翻訳の向上におけるDDX3の役割が実証された。
DDX3は、E-カドヘリンを下方調節し(Botlaguntaら、2008年)、それぞれのプロモーターとの相互作用によりインターフェロン(IFN)及びp21の発現を刺激する(Schroderら、2008年)。IFNプロモーターにおけるDDX3の効果は、ATPアーゼ活性又は巻き戻し機能とは無関係であるが、ATPアーゼ機能はp21プロモーターの刺激を必要とする。
DDX3は、複数の細胞活性を所有し、これは、細胞周期の進展、アポトーシス、低酸素症に関与すると考えられている。いくつかの論文は、DDX3の癌遺伝子及び癌抑制遺伝子としての潜在的な役割を強調しており、残念ながら、その正確な役割は、実質的に不明である。
Wntシグナル伝達経路は、癌化及び胚の発現における役割に関与する。標準的なWnt経路は、細胞質におけるβカテニンの蓄積、及び、その結果として、タンパク質が転写共役因子として作用する核へのその転座の原因になる。2013年には、Cruciatらは、DDX3-CK1ε結合は、CK1εリン酸化反応、その結果として、β-カテニンの活性化を刺激することを見出した。最近の論文(Chenら、2014年)では、調節軸であるRac1-Wnt/βカテニンにおけるDDX3の役割が調査されている。DDX3によるRac-1 mRNA翻訳の上方調節は、β-カテニンシグナル伝達を増加させ、細胞骨格のリモデリングを引き起こす。
低酸素症は、多種多様な腫瘍の特徴であり、癌の進展及び治療耐性における中心的役割が再確認されている。血管形成は、低酸素濃度に対する適応機構を表し、転写因子HIF-1により誘導される。2011年には、Botlaguntaらは、DDX3が、低酸素症を誘導できる遺伝子であり、実際に、HIF-1αはDDX3のプロモーターに結合し、DDX3の発現を向上させると報告している。2013年には、Bol及び共同研究者は、DDX3の発現、及びHIF-1αに関連したタンパク質の相関を観察した。
DDX3は、細胞周期の進展に関与する。Fukumura及び共同研究者は、G1からS期への移行は、DDX3ノックダウン細胞で遮られたと報告している。この効果は、Laiらにより以前に観察されているサイクリンE1 mRNAの翻訳による。
DDX3は、アポトーシスのシグナル伝達を阻害することもできる。Sunらは、DDX3は、死受容体GSK3及びcIAP-1との複合体を形成することにより、抗アポトーシスタンパク質として作用すると報告している。一方、Chang及び共同研究者は、DDX3の欠失は、細胞増殖を亢進させ、アポトーシスを低下させ、並びにDDX3のp53不活化により、MDM2/Slug/E-カドヘリン経路を経由して悪性腫瘍を引き起こすと報告している(Wuら、2014年)。
X及びYは、それぞれ独立してC又はNであり;
Aは、非置換若しくは置換アリール、又は非置換若しくは置換ヘテロアリールであり、アリール又はヘテロアリールにおける1個又は複数の置換基は、非置換若しくは置換C1~C6アルキル、非置換若しくは置換C2~C6アルケニル、非置換若しくは置換C2~C6アルキニル、ハロアルキル、ハロゲン、ORA、SRA、S(=O)(=O)-RA、SO2NHRA、COORB、OC(O)RB、C(O)RB、NRARB、OP(O)(ORA)2、NHC(O)RA、COONRARB、OS又は
R1、R2、R3、R4、R6、R7及びR10は、H、ハロゲン、アルコキシ、C1~C6アルキル、ハロアルキル、ORA、SRA、S(=O)(=O)-RA、SO2NHRA、COORB、OC(O)RB、NRARB、OP(O)(ORA)2、NHC(O)RA、COONRARB、NO2、CNからそれぞれ独立して選択され;
Zは、
R5は、H、非置換又は置換C1~C10アルキル、非置換又は置換フェニルであり、
C1~C10アルキルにおける1個又は複数の置換基は、ハロゲン、ORA、COORB、OC(O)RB、NRARB、OP(O)(ORA)2、OC(O)NRARB、C(O)RB、NHC(O)ORA、NHC(O)RA、COONRARB、OC(O)CHCHRC、
RA及びRBは、H、置換又は非置換C1~C6アルキル、C1~C6シクロアルキル、非置換又は置換アラルキル、ハロアルキルからそれぞれ独立して選択され、
又はRA及びRBは、それらが結合する窒素と一緒にN、S及びOから独立して選択される1個若しくは複数の追加のヘテロ原子を任意選択で含有する4~7員環の飽和若しくは部分不飽和環を形成し、該環は、ハロゲン、C1~C6アルキル、ハロアルキル、OH、アルコキシから独立して選択される1個、2個若しくはそれ超の基で、任意選択で置換されており;
RCは、置換又は非置換フェニル、1,3ベンゾジオキソリルであり、フェニルにおける1個又は複数の置換基は、ハロゲン、ハロアルキル、アルコキシ、C1~C3アルキル又はOHから独立して選択され;
フェニルにおける1個又は複数の置換基は、ハロゲン、ハロアルキル、アルコキシ、C1~C3アルキル、OHから独立して選択され;
R8及びR9は、H、ハロゲン、アルコキシ、COOH、ニトロからそれぞれ独立して選択され、R8及びR9の少なくとも1つは、
又はそれらの塩、溶媒和物、立体異性体であり:
但し、化合物:
RA及びRBは、それらが結合する窒素と一緒に:
- モルホリニル
- ピペラジニル
から選択される6員環の飽和環を形成し、該環は、C1~C6アルキル、ハロアルキル、OH、アルコキシから独立して選択される1個、2個又はそれ超の基で、任意選択で置換されている。
Aは、フェニル、ピリジニル又はイソキノリニルであり、好ましくは、メチル、イソプロピル、CF3、F、Cl、OH又はOMeから独立して選択される1個、2個又はそれ超の基で、それぞれ独立して置換されており、
R5は、ブチル、tert-ブチル、メチル、エチル、イソペンチル、n-ヘキサニル、フェニル、CH2OH、CH2CH2OH、CH2CH2OCH3、CH2OCH2CH3、CHOHCH(CH3)(CH2CH2CH3)、CH2CH2COOH、CH2CH2CH2N(CH3)2、CH2NRARB、CH2CH2NRARB、CH2CH2CH2NRARB、CH2CH2N(CH3)CH2C6H5、CH2CH2OP(O)(OCH3)2、CH2CH2OC(O)CHCH-(ベンゾ[d][1,3]ジオキソール-5-イル)、CH2CH2OC(O)CH2CH(CH3)2、C4F9、CH2CH2CH2F、CHFCH(CH3)(CH2CH2CH3)又は
RA及びRBは、それらが結合する窒素と一緒に:
- モルホリニル
- ピペラジニル
から選択される6員環の飽和環を形成し、該環は、C1~C6アルキル、ハロアルキル、OH、アルコキシから独立して選択される1個、2個又はそれ超の基で、任意選択で置換されており、
X及びYはCであり、
R1、R3、R4はHであり、
R2は、H、F又はOMeである。
Aはフェニルであり、好ましくは、メチル、イソプロピル、CF3、F、Cl、OH又はOMeで置換されている。
Aはフェニルであり、好ましくは、メチル、イソプロピル、CF3、F、Cl、OH又はOMeで置換されており、
R5は、H、ブチル、イソペンチル又はCH2OCH2CH3であり、
X及びYはCであり、
R6、R7及びR10はHである。
Aはフェニルであり、好ましくは、メチル、イソプロピル、CF3、F、Cl、OH又はOMeで置換されており、
R5は、H、ブチル、イソペンチル又はCH2OCH2CH3であり、
X及びYはCであり、
R6、R7及びR10はHである。
Aはイソキノリニルであり、
R5は、H、ブチル、イソペンチル又はCH2OCH2CH3であり、
X及びYはCであり、
R6、R7及びR10はHである。
R8又はR9のもう一方はHであり、
Aはフェニルであり、好ましくは、メチル、イソプロピル、CF3、F、Cl、OH又はOMeで置換されており
R5はHであり、
X及びYはCであり、
R6、R7及びR10はHである。
X及びYはCであり、
R6、R7及びR10はHである。
「置換されている」という用語は、特定された基又は部分が、独立して炭素原子、窒素原子又は他の原子の少なくとも1個において、水素原子を有し、独立して置換基で置き換えられ得ることを意味する。
合成
概要
試薬は、商業的供給業者(例えばSigma-Aldrich社)から得た。すべての市販の化学物質を、更なる精製をせずに購入したままで使用した。CH3CNは、水素化カルシウムで脱水し、CH2Cl2は、水素化カルシウムで脱水し、THFは使用する前にNa/ベンゾフェノンで脱水したが、DMFは既に無水で入手した。無水反応は正圧の乾燥N2又はアルゴン下で、実行した。TLCは、Merck社TLCプレートシリカゲル60 F254を使用して実行した。クロマトグラフの精製は、フラッシュ技術のためのMerck社のシリカゲル60、23-400メッシュをパックしたカラムで行った。1H-NMR及び13C-NMRスペクトルを、400MHzのBrucker社Avance DPX400分光計で記録した。化学シフトは、0.00ppmでのテトラメチルシランに対して、報告されている。1Hパターンは、以下の略語:s=一重線、d=二重線、t=三重線、q=四重線、quint=五重線、sx=六重線、sept=七重線、m=多重線、br=幅広シグナル、br s=幅広一重線を使用して記載されている。
マイクロ波照射実験は、CEM社Discover Synthesis Unit(CEM Corp.社、Matthews、NC)を使用して実施した。この機械は、連続フォーカスマイクロ波電力伝送系と、操作者が選択可能な0から300Wの出力からなる。反応容器下に取り付けた較正した赤外温度コントロールを使用して、内容器の温度をモニターした。これにより容器の内容物が、マイクロ波空洞の底面下に位置する、回転する磁気プレート及び容器中のテフロン(登録商標)コーティングした電磁撹拌棒によって撹拌されることによる撹拌オプションを使用して、すべての実験を行った。
適正なアニリン2又は72(3.62mmol)を、無水CH2Cl2(10mL)中の適正なイソシアネート1又は1a(5.43mmol)の溶液に一度に添加した。溶液を窒素雰囲気下で60℃にて4時間撹拌した。黄色沈殿物を濾過し、冷DCM及び石油エーテルで洗浄し、高真空下で乾燥させて、望ましい生成物を白色固体として得た。
適正な尿素3a又は3b(1.10mmol)を、30mLの無水MeOH中で可溶化し、炭上パラジウム(50mg)を添加した。反応混合物を水素雰囲気下で1時間撹拌し、次いで、混合物をセライトパッドで濾別し、溶媒を減圧で蒸発し、残留物をアセトニトリルから結晶化した。
適正なアニリン4a又は4b(0.41mmol)を、CH3CNに溶解し、氷塩浴で0℃に冷却した。この撹拌した溶液に、tBuONO(0.61mmol)を添加し、混合物を10分間撹拌し、この後、TMSN3(65μL、0.49mmol)を10分間滴下添加し、生じた褐色溶液を室温にて撹拌した。1時間後、溶媒を減圧で除去し、残留物をフラッシュクロマトグラフィーによりシリカゲル上で精製した。
適切なアルキン(0.10mmol)及びアジド5(25mg、0.09mmol)を、小型電磁撹拌棒を備えた10mLガラスバイアル中において、水及びt-BuOH(各1.5mL)の1:1の混合物中で懸濁した。これに、アスコルビン酸ナトリウム(0.1当量)及び硫酸銅(II)五水和物(0.10mmol)を添加した。次いで、混合物を、マイクロ波照射下で125℃にて、300Wの照射電力を使用して10分間加熱した。この後、沈殿物を濾別し、シリカ上で精製して、最終生成物8a、8b、8c、8d又は8eを得た。
L-プロリン(1.9mg、0.01mmol)、CuCl(8.2mg、0.08mmol)、K2CO3(13.7mg)、アジド(20mg、0.08mmol)、適切なアルキン酸(0.08mmol)を順次、電磁撹拌機を備えた10mLガラスバイアルに添加した。バイアルを隔壁で閉鎖し、65℃にて照射した。15分後、混合物を、水20mLとAcOEt(40mL)との間で分配し、有機層を分離し、乾燥させ(Na2SO4)、溶媒を真空で除去して、褐色残留物を得、これを、フラッシュクロマトグラフィーによりシリカゲル(DCM-MeOH、98:2)上で精製して、望ましいトリアゾール化合物8e又は8fを得た。
適切なアルキン(0.10mmol)及びアジド13(25mg、0.09mmol)を、小型電磁撹拌棒を備えた10mLガラスバイアル中において、水及びt-BuOH(各1.5mL)の1:1の混合物中で懸濁した。これに、アスコルビン酸ナトリウム(0.1当量)及び硫酸銅(II)五水和物(0.10mmol)を添加した。次いで、混合物を、マイクロ波照射下で80℃にて、300Wの照射電力を使用して5分間加熱した。この後、沈殿物を濾別し、シリカ上で精製して、最終生成物15a又は15bを得た。
適切なアルキン30a~h(4.34mmol)及びアジド16(594.11mg、3.62mmol)を、小型電磁撹拌棒を備えた10mLガラスバイアル中において、水及びt-BuOH(各1.5mL)の1:1の混合物中で懸濁した。これに、アスコルビン酸ナトリウム(1.81mmol)及び硫酸銅(II)五水和物(1.81mmol)を添加した。次いで、混合物を、マイクロ波照射下で120℃にて、300Wの照射電力を使用して10分間加熱した。この後、沈殿物を濾別し、シリカ上で精製して、望ましいトリアゾール化合物17a、17b、17c、17d、17e、17f、17g又は17hを得た。
適正なトリアゾール化合物17a~f又は18g(400mg、1.60mmol)を、30mLの無水MeOH中で可溶化し、10%炭上パラジウム(25mg)を添加した。反応混合物を水素雰囲気下で1時間撹拌し、次いで、混合物をセライトパッドで濾別し、溶媒を減圧で蒸発し、残留物を、適正な溶離液を用いるフラッシュクロマトグラフィーにより、シリカゲル上で精製した。
適正なアニリン19a~h(100mg、0.46mmol)を、無水CH2Cl2(10mL)中の適切なイソシアネート(85μL、0.65mmol)の溶液に一度に添加した。溶液を窒素雰囲気下で、室温にて4時間撹拌した。溶媒を減圧で除去し、残留物を、適正な溶離液を使用するフラッシュクロマトグラフィーにより精製した。
300mLの水中のNaOHの200gの撹拌溶液(0.3mol、16.8g)に、適正なアルコール(2.5mL、33.02mmol)を添加した。これに、対応する硫酸塩(15mmol、2082mg)を2時間でゆっくり滴下添加し、混合物を50℃にて加熱した。最終生成物を留去し、蒸留を95℃にて止め、次いで受け皿の内容物を冷NH4Cl水溶液で洗浄し、分離した。
適切なアルキン(6.08mmol)及びアジド16(831mg、5.07mmol)を、小型電磁撹拌棒を備えた10mLガラスバイアル中において、水及びt-BuOH(各1.5mL)の1:1の混合物中で懸濁した。これに、アスコルビン酸ナトリウム(2.5mmol)及び硫酸銅(II)五水和物(2.50mmol)を添加した。次いで、混合物を、マイクロ波照射下で125℃にて、300Wの照射電力を使用して10分間加熱した。この後、溶媒を減圧で除去し、水を添加し、混合物をEtOAc(3×20mL)で抽出した。有機層を収集し、ブラインで洗浄し、Na2SO4で脱水した。粗製物を、適正な溶離液を使用するフラッシュクロマトグラフィーによりシリカゲル上で精製して、望ましいトリアゾール化合物31a、31b、31c、31d又は31eを得た。
塩化トシル(1.88mmol、359.00mg)、KOH(4.28mmol、240.39mg)及び適正なアルコールを、窒素雰囲気下で0℃にて、氷塩浴中の15mLの無水THF中で撹拌した。30分後、反応混合物を室温にて撹拌した。12時間後、溶媒を減圧で除去し、水を添加し、反応混合物をDCM(100mL×3)で抽出した。合わせた有機層をブラインで洗浄し、乾燥させ(Na2SO4)、濃縮した。残留物を、フラッシュクロマトグラフィーによりシリカゲル(PE/EtOAc、5:3)上で精製した。
適正なトシレートの溶液に、0℃にて対応するアミンを添加した。反応混合物を封管中で80℃にて撹拌した。24時間後、溶媒を減圧で除去し、残留物を、フラッシュクロマトグラフィーによりシリカゲル上で精製した。
適正なトリアゾール化合物31a~d、又は33e~i(400mg、1.60mmol)を、30mLの無水MeOH中で可溶化し、10%炭上パラジウム(25mg)を添加した。反応混合物を水素雰囲気下で1時間撹拌し、次いで、混合物をセライトパッドで濾別し、溶媒を減圧で蒸発した。
適正なアニリン34a~i(0.10mmol)を、無水MeOH(10mL)中の適切なイソシアネート1又は24(0.15mmol)の溶液に一度に添加した。溶液を、窒素雰囲気下で室温にて9時間撹拌した。溶媒を減圧で除去し、残留物をシリカ上で精製して、最終生成物35a、35b又は35gを白色固体として得た。或いは、残留物をMeOHから結晶化して、化合物35e又は35fを得た。
適正なアルコール35b~c(25mg、0.07mmol)、酸(10μL、0.07mmol)、N,N'-ジシクロヘキシルカルボジイミド(22mg、0.11mmol)及びDMAP(3mg、0.01mmol)を0℃にて、CH2Cl2 10mL及びDMF 2mLの混合物中で30分間撹拌した。この後、反応混合物を室温に到達させ、12時間撹拌した。次いで、溶媒を減圧で除去し、EtOAcを添加し、混合物を5%LiCl水溶液で洗浄し、無水Na2SO4で脱水し、真空で濃縮した。残留物を、適正な溶離液を用いるフラッシュクロマトグラフィーにより、シリカゲル上で精製した。
適正なアルコール31a、31c又は31d(400mg、1.38mmol)を、15mLのCH2Cl2に溶解し、Deoxo-Fluor(登録商標)(533μL、2.48mmol)を、-40℃にて添加した。-40℃にて2時間撹拌した後で、反応混合物を室温まで温め、終夜撹拌した。溶媒を減圧で除去し、残留物を、フラッシュクロマトグラフィーによりシリカゲル上で精製した。
適正なトリアゾール化合物40a、40b又は40c(100mg、0.34mmol)を、10mLの無水MeOH中で可溶化し、10%炭上パラジウム(30mg)を添加した。反応混合物を水素雰囲気下で1時間撹拌し、次いで、混合物をセライトパッドで濾別し、溶媒を減圧で蒸発した。
適正なアニリン化合物41a~c(100mg、0.46mmol)を、無水CH2Cl2(10mL)中の0-(トリフルオロメチル)フェニルイソシアネート24(85μL、0.65mmol)の溶液に一度に添加した。溶液を窒素雰囲気下で、室温にて4時間撹拌した。溶媒を減圧で除去し、残留物を、適正な溶離液を使用するフラッシュクロマトグラフィーにより精製した。
尿素誘導体55a~qは、Table 1(表2)で報告されている。
5mLのCH2Cl2中の適正な芳香族アミン(41mg、0.3835mmol)及びDMAP(19mg、0.1534mmol)の溶液を、CH2Cl2中の氷冷したトリホスゲン溶液に30分間滴下添加し、次いで、適正なアニリン17a~cを一度に添加し、反応混合物を室温にて12時間撹拌した。この後、2M HClを添加し、混合物をCH2Cl2(3×20mL)で抽出した。有機層を収集し、ブラインで洗浄し、Na2SO4で脱水した。粗製物を、適正な溶離液を使用するフラッシュクロマトグラフィーによりシリカゲル上で精製した。
5mLの無水ピリジン中の適正な芳香族アミン(1当量)の撹拌した溶液に、0℃にて、対応する塩化スルホニル(1.1当量)を添加した。対応する溶液を、窒素雰囲気下で室温にて5時間撹拌した。反応の完了後、混合物を20mLの2N HClで酸性化し、水性相を数回抽出し、合わせた有機相を乾燥させ(Na2SO4)、濃縮した。
適正なスルホンアミド(400mg、1.35mmol)を、20mLの無水EtOH中で可溶化し、炭上パラジウム(60mg)を添加した。反応混合物を水素雰囲気下で1時間撹拌した。次いで、混合物をセライトパッドで濾別し、真空で濃縮し、粗生成物を、適切な溶離液を用いるフラッシュクロマトグラフィーにより、シリカゲル上で精製した。
アミン(100mg、0.41mmol)を、CH3CNに溶解し、氷塩浴で0℃に冷却した。この撹拌した溶液に、tBuONOを添加し、混合物を10分間撹拌し、この後、TMSN3を10分間滴下添加し、生じた褐色溶液を室温にて撹拌した。1時間後、溶媒を減圧で除去し、残留物を、適切な溶離液を用いるフラッシュクロマトグラフィーにより、シリカゲル上で精製した。
適切なアルキン(6.08mmol)及び適正なアジド(5.07mmol)を、小型電磁撹拌棒を備えた10mLガラスバイアル中において、水及びt-BuOH(各1.5mL)の1:1の混合物中で懸濁した。これに、アスコルビン酸ナトリウム(2.5mmol)及び硫酸銅(II)五水和物(2.50mmol)を添加した。次いで、混合物を、マイクロ波照射下で125℃にて、300Wの照射電力を使用して10分間加熱した。この後、溶媒を減圧で除去し、水を添加し、混合物をEtOAc(3×20mL)で抽出した。有機層を収集し、ブラインで洗浄し、Na2SO4で脱水した。粗製物を、適正な溶離液を使用するフラッシュクロマトグラフィーによりシリカゲル上で精製して、望ましいトリアゾール化合物64a、64b、64c、64d、64e、64f、65a、65c、66d、67d及び68を得た。
適正な4-ニトロアニリン(7.24mmol)を、CH3CNに溶解し、氷塩浴で0℃に冷却した。この撹拌した溶液に、tBuONO(8.69mmol)を添加し、混合物を10分間撹拌し、この後、TMSN3(10.86mmol)を10分間滴下添加し、生じた褐色溶液を室温にて撹拌した。1時間後、溶媒を減圧で除去し、残留物をフラッシュクロマトグラフィーによりシリカゲル上で精製した。
適切なアルキン14a又は14b(0.10mmol)及び適正なアジド(0.09mmol)を、小型電磁撹拌棒を備えた10mLガラスバイアル中において、水及びt-BuOH(各1.5mL)の1:1の混合物中で懸濁した。これに、アスコルビン酸ナトリウム(0.1当量)及び硫酸銅(II)五水和物(0.10mmol)を添加した。次いで、混合物を、マイクロ波照射下で125℃にて、300Wの照射電力を使用して10分間加熱した。この後、沈殿物を濾別し、シリカ上で精製して、最終生成物76又は77を得た。
適正なトリアゾール化合物76又は78(1.60mmol)を、30mLのMeOH中で可溶化し、10%炭上パラジウム(25mg)を添加した。反応混合物を水素雰囲気下で1時間撹拌し、次いで、混合物をセライトパッドで濾別し、溶媒を減圧で蒸発して、78又は79を純粋化合物として得た。
適正なアニリン78又は79(0.10mmol)を、無水DCM(15mL)中の2-(トリフルオロメチル)フェニルイソシアネート(0.15mmol)の溶液に一度に添加した。溶液を、窒素雰囲気下で室温にて9時間撹拌した。溶媒を減圧で除去し、残留物をシリカ上で精製して、最終生成物80又は81を得た。
93(500mg、3.26mmol)を、窒素雰囲気下で無水DMF(3mL)に溶解した。これに、NaH(86mg、3.58mmol)を0℃にて一度に添加した。20分後、DMF(1mL)中の適正なハロゲン誘導体(3.9mmol)の溶液(94aの場合、ヨウ化シクロペンチル、又は94bの場合、クロロメチルメチルエーテル)をカニューレにより添加した。生じた溶液を室温にて2時間撹拌した。反応の完了後、水を添加し、混合物をEtOAcで数回抽出し、5%LiCl(水溶液)で洗浄し、合わせた有機相を乾燥させ(Na2SO4)、濃縮した。
適正なニトロ化合物94a又は94b(0.40mmol)を、30mLのMeOH中で可溶化し、10%炭上パラジウム(5mg)を添加した。反応混合物を水素雰囲気下で1時間撹拌し、次いで、混合物をセライトパッドで濾別し、溶媒を減圧で蒸発して、54a又は54bを純粋化合物として得た。
in vitroのADME研究
化合物のADME特性は、最も重要なものである。溶解度及び透過性の低さは、薬物開発中の失敗の中でも主な原因である。一般に、経口投与後の受動的拡散による胃腸の吸収に影響を与える脂質二分子膜透過性と溶解度との良好なバランスを見出すことは重要な試みである。こうした理由から、当該化合物の物理化学的性質を、QikProp(QP)予測プログラム(QikProp、バージョン3.3、Schrodinger, LLC社、New York、NY、2010年)を使用して第1フェーズから開始して、予測した。
化学物質。すべての溶媒、試薬は、Sigma-Aldrich Srl社(Milan、Italy)からのものであった。ドデカンは、Fluka社(Milan、Italy)から購入した。男性ドナーからプールした20mg mL-1 HLMは、BD Gentest-Biosciences社(San Jose、California)からのものであった。Milli-Q quality water(Millipore社、Milford、MA、USA)を使用した。疎水性フィルタープレート(MultiScreen-IP、Clear Plates、細孔径0.45μm)、96ウェルマイクロプレート及び96ウェルUV透過マイクロプレートはMillipore社(Bedford、MA、USA)から得た。
ヘリカーゼアッセイ
二重らせん構造(ds)RNA(蛍光性の6-FAMを有するらせん構造の一方の5'末端で標識)の単一らせん構造(ss)核酸への変換を測定することにより、DDX3 wtのヘリカーゼ活性をモニターした。特に指定のない限り、25nMの最終濃度のRNA基質を実験に使用した。反応は、50mMトリスHCl、pH7.5、1mM DTT、0.2mg/ml BSA、5%グリセロール及び100μM ATP、10mM MgCl2中で、37℃にて10分間で行い、EDTA 50mM pH8を添加することにより止めた。生成物を、4℃にて、5Wで4時間にわたるTBE緩衝液中での非変性8%PAGEで分離した。基質及び生成物を、レーザースキャニングデンシトメトリー(Thyphoon-TRIO、GE Healthcare社)により定量した。
ヒト組換えDDX3を、(Francaら、Proteins 2007年、67、1128~37頁)に記載されているようにクローニングし、発現させ、精製した。
細胞を、American Type Culture Collection(ATCC、Manassas社、VA、USA)から購入した。LNCaP(ATCC(登録商標)CRL-1740(商標))、A549(ATCC(登録商標)CCL-185(商標))、MDA-MB-231(ATCC(登録商標)CRM-HTB-26(商標))、22Rv1(ATCC(登録商標)CRL-2505(商標))、HCT-116(ATCC(登録商標)CCL-247(商標))及びPC3(ATCC(登録商標)CRL-1435(商標))細胞を、5%CO2/空気雰囲気下で37℃にて、10%ウシ胎仔血清(Euroclone社;ECS0180L)、2mM L-グルタミン、100単位/mLペニシリン及び100mg/mLストレプトマイシンを補充したRoswell Park Memorial Institute 1640培地(RPMI;Euroclone社、ECB9006L)で維持した。DU145(ATCC(登録商標)HTB-81(商標))及びDAOY(ATCC(登録商標)HTB-186(商標))細胞を、5%CO2/空気雰囲気下で37℃にて、10%ウシ胎仔血清(Euroclone社;ECS0180L)、2mM L-グルタミン、100単位/mlペニシリン及び100mg/mLストレプトマイシンを補充したイーグル最小必須培地(EMEM;Euro-clone社、ECM0445L)で維持した。SH-SY5Y(ATCC(登録商標)CRL-2266(商標))、DBRTG(ATCC(登録商標)CRL-2020(商標))、HeLa(ATCC(登録商標)CCL-2(商標))、HN6細胞(Dr Silvio Gutkind、UCSD Medical Center、Moores Cancer Center USAの好意により提供された、Chen J.Jら、Oncotarget 2013年、4、206~217頁))、U2OS(ATCC(登録商標)HTB-96(商標))、RD18細胞(Dr P. Boccuni Memorial Sloan-Kettering Cancer Center、New York、USAの好意により提供された、Vella S.ら、Clin Epigenetics. 2015年、6;7~82頁)細胞を、5%CO2/空気雰
囲気下で37℃にて、10%ウシ胎仔血清(Euroclone社;ECS0180L)、2mM L-グルタミン、100単位/mlペニシリン及び100 mg/mLストレプトマイシンを補充したダルベッコ改変イーグル培地で維持した(DMEM;Euroclone社、ECB7501L)。
細胞株を、阻害剤化合物で処置する24時間前に、6ウェル培養プレート中の2mL増殖培地に適切な密度でシードした。24時間後、培地を除去し、濃度が上昇した化合物を含有する新しい培地を、細胞に添加した。固定最終濃度は、0.1μM、1μM、10μM、100μMであった。DMSOは、化合物の希釈に使用されるビヒクルであり、細胞に対する最終濃度は0.2%未満であった。培地のみを含有するウェルは、対照として含まれた。細胞を、薬物と48時間インキュベートし、次いで、細胞生存能力を評価した。
細胞を、300μLのトリプシンを有する6ウェルプレートの各ウェルから剥がし、培地中で1mLの最終体積に懸濁した。次いで、細胞計数で細胞生存能力を評価した。細胞を、等張緩衝希釈剤、Isoton(Backman Coulter社)で、製造者の指示に従い、1:50の比に希釈し、自動細胞計数器(Z2 series Coulter Counter、Beckman Coulter社)を使用して計数した。細胞計数を、それぞれ3回繰り返し行った。単一濃度での各化合物の存在下における、細胞の相対生存率に対応する値を、未処理の対照に対して標準化した。次いで、in vitroで50%増殖阻害を導入するのに必要とされる薬物濃度を表す最大半減阻害濃度(IC50)値を、GraphPad Prism 6.0ソフトウェアで、最良適合シグモイド曲線を使用して計算した。
DDX3ヘリカーゼに対する、代表的な化合物の抗酵素活性は、Table 5(表6)で報告されている。
Table 5(表6)から選択した化合物を、DDX3が関与する過剰増殖障害に対して試験した。
1)RNA結合部位と相互反応し、続いて触媒工程に干渉することによりヒトDDX3タンパク質のヘリカーゼ活性を阻害できる;
2)ヒト前立腺腺癌細胞株-LNCaP、脳転移に由来するヒト前立腺癌細胞株DU-145、ヒト前立腺癌上皮細胞株22Rv1、ヒト前立腺癌細胞株(PC3)、ヒト神経芽細胞腫細胞株SH-SY5Y、ヒト乳腺癌細胞株MDA-MB-231、ヒト子宮頸癌細胞株HeLa、ヒト膠芽腫細胞株U87、ヒト肺胞基底上皮腺癌細胞A549、ヒト結腸直腸癌細胞株HCT116、ヒト骨肉腫細胞株U2OS、ヒト頭頸部扁平上皮癌細胞株HN6、ヒト横紋筋肉腫細胞株RD18、ヒト脳膠芽腫細胞株DBTRG、ヒト髄芽腫細胞株DAOYにおける細胞増殖を抑制できることが示される。
Claims (23)
- DDX3により調節される癌の処置における使用のための、式:
X及びYが、それぞれ独立してC又はNであり;
Aが、非置換若しくは置換アリール、又は非置換若しくは置換ヘテロアリールであり、アリール又はヘテロアリールにおける1個又は複数の置換基が、独立して、非置換若しくは置換C1~C6アルキル、非置換若しくは置換C2~C6アルケニル、非置換若しくは置換C2~C6アルキニル、ハロアルキル、ハロゲン、ORA、SRA、S(=O)(=O)-RA、SO2NHRA、OC(O)RB、C(O)RB、NRARB、OP(O)(ORA)2、NHC(O)RA、COONRARB、又は
C1~C6アルキル又はC2~C6アルケニル又はC2~C6アルキニルにおける1個又は複数の置換基が、ORA、COORB、OC(O)RB、C(O)RB、NRARB、OP(O)(ORA)2、NHC(O)RA、NHC(O)ORA、COONRARB、SRA、S(=O)(=O)-RA、SO2NHRAから独立して選択され;
R1、R2、R3、R4、R6、R7及びR10が、H、ハロゲン、アルコキシ、C1~C6アルキル、ハロアルキル、ORA、SRA、S(=O)(=O)-RA、SO2NHRA、COORB、OC(O)RB、NRARB、OP(O)(ORA)2、NHC(O)RA、COONRARB、NO2、CNからそれぞれ独立して選択され;
Zが、
R5が、H、非置換又は置換C1~C10アルキル、非置換又は置換フェニルであり、
C1~C10アルキルにおける1個又は複数の置換基が、ハロゲン、ORA、COORB、OC(O)RB、NRARB、OP(O)(ORA)2、OC(O)NRARB、C(O)RB、NHC(O)ORA、NHC(O)RA、COONRARB、OC(O)CHCHRC、
RA及びRBが、H、置換又は非置換C1~C6アルキル、C1~C6シクロアルキル、非置換又は置換アラルキル、ハロアルキルからそれぞれ独立して選択され、
又はRA及びRBが、それらが結合する窒素と一緒に、N、S及びOから独立して選択される1個若しくは複数の追加のヘテロ原子を任意選択で含有する4~7員環の飽和若しくは部分不飽和環を形成し、該環が、ハロゲン、C1~C6アルキル、ハロアルキル、OH、アルコキシから独立して選択される1個、2個若しくはそれ超の基で、任意選択で置換されており;
RCが、置換又は非置換フェニル、1,3ベンゾジオキソリルであり、フェニルにおける1個又は複数の置換基が、ハロゲン、ハロアルキル、アルコキシ、C1~C3アルキル又はOHから独立して選択され;
R8及びR9が、H、ハロゲン、アルコキシ、COOH、ニトロからそれぞれ独立して選択され、R8及びR9の少なくとも1つが、
又はそれらの塩、溶媒和物、立体異性体であり:
但し、化合物:
- X及びYがCである、請求項1に記載の組成物。
- Aが置換アリールである、請求項1又は2に記載の組成物。
- 置換アリールがフェニルである、請求項3に記載の組成物。
- フェニルが、メチル、イソプロピル、CF3、F、Cl、OH、OMeから独立して選択される1個、2個又はそれ超の基で置換されている、請求項4に記載の組成物。
- Aが、非置換又は置換ヘテロアリールである、請求項1又は2に記載の組成物。
- 置換ヘテロアリールが、ピリジニル又はイソキノリニルである、請求項6に記載の組成物。
- X及びYがCであり、Aが非置換又は置換ヘテロアリールである、請求項1に記載の組成物。
- ヘテロアリールが、ピリジニル又はイソキノリニルである、請求項8に記載の組成物。
- ピリジニル又はイソキノリニルが、メチル、イソプロピル、CF3、F、Cl、OH、OMeから独立して選択される1個、2個又はそれ超の基で置換されている、請求項9に記載の組成物。
- RA及びRBが、それらが結合する窒素と一緒に、N及びOから独立して選択される1個又は複数の追加のヘテロ原子を含有する6員環の飽和環を形成し、該環が、C1~C6アルキル、ハロアルキル、OH、アルコキシから独立して選択される1個、2個又はそれ超の基で、任意選択で置換されているモルホリニル又はピペラジニルから選択される、請求項1に記載の組成物。
- 癌が、乳癌、前立腺癌、肺癌、膠芽腫、多形性膠芽腫、腎臓癌、口腔癌、結腸直腸癌、神経芽細胞腫、髄芽腫、頭頸部扁平上皮癌、横紋筋肉腫、骨肉腫、ユーイング肉腫、子宮頸癌、橋腫瘍、肝細胞癌、網膜芽細胞腫、肝芽腫、胆嚢癌、黒色腫、肉腫及び白血病からなる群から選択される、請求項1から14のいずれか一項に記載の組成物。
- 癌が、原発癌又は転移癌である、請求項15に記載の組成物。
- 前記組成物が更なる抗過剰増殖処置と併用されるためのものである、及び/又は前記組成物が、さらなる治療剤と併用される、請求項1から16のいずれか一項に記載の組成物。
- 更なる抗過剰増殖処置が、放射線治療及び化学治療からなる群から選択される、請求項17に記載の組成物。
- 化学治療が、前アポトーシス剤、モノクローナル抗体、インターロイキン又はインターフェロンからなる群から選択される、請求項18に記載の組成物。
- 更なる治療剤が、鎮痛剤、制吐剤(アプレピタント、ホスアプレピタント、ドラセトロン、グラニセトロン、オンダンセトロン、パロノセトロン、トロピセトロン又はラモセトロン、デキサメタゾンなど)の群から選択される、請求項17から19のいずか一項に記載の組成物。
- 癌の処置及び/又は予防における使用のための、請求項1から20のいずれか一項に記載の組成物、及び薬学的に許容される賦形剤を含む医薬組成物。
- 治療剤を更に含む、請求項21に記載の医薬組成物。
- 前記医薬組成物が、抗過剰増殖処置と組み合わせて使用するためのものである、請求項21又は22に記載の医薬組成物。
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