JP2011527679A - シグナル伝達性転写因子(stat)の増殖及び活性化の新規の抑制剤 - Google Patents
シグナル伝達性転写因子(stat)の増殖及び活性化の新規の抑制剤 Download PDFInfo
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Abstract
Description
なし
なし
なし
又は、その薬学的に許容される塩、若しくは溶媒和化合物であり、式中、
nは、1、2、又は3から選択される整数であり、
R0は、R1であるか、又はR0は、R1−Z1−であり、式中、Z1はアルキルであり、特に、m3=0、1、2、3、又は4である、−(CH2)m3−などの低級アルキルであってよく、
R1は、
であり、
式中、X1、X2、X3、及びX4は、それぞれ独立して、水素、ハロゲン、アルキル、アルコキシ、OH、トリハロメチル、又はNO2であり、Y1は、OH、特にBr及びClを含むハロゲン、又はO2Nであり、
R2は、アルキル、アルケニル、アルキニル、アルコキシ、アルキルアリール、ハロゲン、水素、OH、NO2、チオエーテル、アミン、SH、又はNH2であり、
R3は、
であり、
式中、m1は、1、2、3、又は4から選択される整数であり、
X5及びX6は、それぞれ独立して、水素、アルキル、高級アルキル、低級アルキル、アリール、アルコキシル、アリールオキシル、環式アルキル、シクロアルキル、シクロアリールアルキル、アラルキル、アルキルエステル、アルキルエステルアルキル、アルキルアセトキシル、ヒドロキシル、ヒドロキシルアルキル、シクロプロピル、シクロブチル、−CH3、−CH2OH、シクロペンチル、−CH2OAc、−CH2OC(O)C(CH3)3、−CH2C6H5、又はシクロヘキシルであり、
Zは、NH、S、又はOであり、
Z3は、アルキル又は低級アルキルであり、
R4は、CN、置換アミン、CH2S−アルキル、アルキル、又はCH2N3であり、
R5及びR6は、それぞれ独立して、
単糖(例えば、グルコース、フルクトース、ガラクトース等)、多糖、単糖誘導体(例えば、アセチル化ガラクトースなどのアセチル化単糖、1,2,3,4−ジイソプロピリデノ−D−ガラクトース)置換及び非置換アリール、並びに置換及び非置換アルキルアリール
からなる群から選択される。
又はその薬学的に許容される塩、若しくは溶媒和化合物を有し、式中
nは、1、2、又は3から選択される整数であり、
R0は、R1であるか、又はR0は、R1−Z1−であり、式中、Z1は、アルキルであり、特に、m3=0、1、2、3、又は4である−(CH2)m3−などの低級アルキルであってよく、
R1は、
であり、
式中、X1、X2、X3、及びX4は、それぞれ独立して、水素、ハロゲン、アルキル、アルコキシ、OH、トリハロメチル、又はNO2であり、Y1は、OH、特にBr及びClを含むハロゲン、又はO2Nであり、
R2は、アルキル、アルケニル、アルキニル、アルコキシ、アルキルアリール、ハロゲン、水素、OH、NO2、チオエーテル、アミン、SH、又はNH2であり、
R3は、
であり、
式中、m1は、1、2、3、又は4から選択される整数であり、
X5及びX6は、それぞれ独立して、水素、アルキル、高級アルキル、低級アルキル、アリール、アルコキシル、アリールオキシル、環式アルキル、シクロアルキル、シクロアリールアルキル、アラルキル、アルキルエステル、アルキルエステルアルキル、アルキルアセトキシル、ヒドロキシル、ヒドロキシルアルキル、シクロプロピル、シクロブチル、−CH3、−CH2OH、シクロペンチル、−CH2OAc、−CH2OC(O)C(CH3)3、−CH2C6H5、又はシクロヘキシルであり、
Zは、NH、S、又はOであり、
Z3は、アルキル又は低級アルキルであり、
R4は、CN、置換アミン、CH2S−アルキル、アルキル、又はCH2N3であり、
R5及びR6は、それぞれ独立して、
単糖(例えば、グルコース、フルクトース、ガラクトース等)、多糖、単糖誘導体(例えば、アセチル化ガラクトースなどのアセチル化単糖、1,2,3,4−ジイソプロピリデノ−D−ガラクトース)、置換及び非置換アリール、並びに置換及び非置換アルキルアリールからなる群から選択される。
の構造を有するアルキルアリールであってよく、
式中、mは、0、1、2、3、4、5、6、又は7から選択される整数であり、
X5及びX6は、それぞれ独立して、水素、アルキル、高級アルキル、低級アルキル、アリール、アルコキシル、アリールオキシル、環式アルキル、シクロアルキル、シクロアリールアルキル、アラルキル、アルキルエステル、アルキルエステルアルキル、アルキルアセトキシル、ヒドロキシル、ヒドロキシルアルキル、シクロプロピル、シクロブチル、−CH3、−CH2OH、シクロペンチル、−CH2OAc、−CH2OC(O)C(CH3)3、−CH2C6H5、又はシクロヘキシルであり、
R7、R8、R9、R10、及びR11は、それぞれ独立して、水素、ハロゲン、アルキル、アルコキシ、OH、トリハロメチル、及びNO2からなる群から選択される。
のいずれか1つであり得る。
であってよく、
式中、X1は、Br又はClなどのハロゲンであってよく、
X2、X3、及びX4は、それぞれ独立して、水素、ハロゲン、アルキル、アルコキシ、OH、トリハロメチル、又はNO2である。
以下の方法は、本発明を実施するために使用できる。
(E)−3−(6−ブロモピリジン−2−イル)アクリルアルデヒドの合成
6−ブロモ−2−カルボキシピリジン溶液(3g、16.1ミリモル)を、ジクロロメタン(100mL)中に溶解した。(トリフェニルホスホラニリデン)アセトアルデヒド(4.9g、16.1ミリモル)を加え、得られた混合物を室温で5時間攪拌した。ジクロロメタンを、(体積約50mLまで)部分的に蒸発させ、反応混合物をクロマトグラフィーカラム(シリカゲル60)にかけた。生成物をジクロロメタンで溶出した。生成物を含む画分を合せ、蒸発させて白色粉末2.3gを得た(収率67%)。
1HNMR(CDCl3、δ)ppm:9.81(d,1H,J=7.6Hz,CHO),7.63(dd,1H,J=J=7.7Hz,H4),7.51(dd,2H,J=J=7.7Hz,H−3,5),7.45(d,1H,J=15,8Hz,Ar−CH=CH−CHO),7.12(dd,1H,1H,J=15.8Hz,J=7.6Hz,Ar−CH=CH−CHO)
無水エタノール中の(1)(2.1g、9.9ミリモル)及びピペリジン(0.2mL)の溶液を調製した。アルデヒド(10.6ミリモル)を加え、反応混合物を室温で攪拌した。3時間後に得られた固体を濾過し、エタノールで洗浄し、乾燥させた。以下の例において説明される化合物を作製した。
(2E,4E)−5−(6−ブロモピリジン−2−イル)−2−シアノ−N−[(1S)−1−フェニルエチル]ペンタ−2,4−ジエンアミド
収率67%(2E,4E)−5−(6−ブロモピリジン−2−イル)−2−シアノ−N−((S)−1−フェニルエチル)ペンタ−2,4−ジエンアミド
(2E,4E)−5−(6−クロロピリジン−2−イル)−2−シアノ−N−[(1S)−1−フェニルエチル]ペンタ−2,4−ジエンアミド
(2E,4E)−5−(6−クロロピリジン−2−イル)−2−シアノ−N−[(1R)−1−フェニルエチル]ペンタ−2,4−ジエンアミド
(2E,4E)−N−ベンジル−5−(6−ブロモピリジン−2−イル)−2−シアノペンタ−2,4−ジエンアミド
(2E,4E)−5−(6−クロロピリジン−2−イル)−2−シアノ−N−[(1R)−1−フェニルエチル]ペンタ−2,4−ジエンアミド
(2E,4E)−N−ベンジル−5−(6−クロロピリジン−2−イル)−2−シアノペンタ−2,4−ジエンアミド
(2E,4E)−5−(6−ブロモピリジン−2−イル)−2−シアノ−N−[(S)−シクロプロピル(フェニル)メチル]ペンタ−2,4−ジエンアミド
(2E,4E)−5−(6−ブロモピリジン−2−イル)−2−シアノ−N−[(1S)−1−フェニルプロピル]ペンタ−2,4−ジエンアミド
(2E,4E)−5−(6−ブロモピリジン−2−イル)−2−シアノ−N−[(1S)−1−フェニルブチル]ペンタ−2,4−ジエンアミド
細胞生存率及び薬剤用量反応の測定のためのMTT法
様々な細胞型を96ウェルプレート上に1ウェルにつき50,000セル/100μlの濃度で播種し、密集状態に到達するまでDMEM培地で24〜48時間培養した。密集状態に、様々な濃度(0から100μM)で、WP1220を含む新鮮な培地25μlをウェルに加え、37℃で72時間インキュベートした。複合体を除去し、新鮮な培地100μを加え、細胞を一晩インキュベートした。培地を除去し、37℃でさらに4時間、細胞をインキュベートする前に、(20μlの)MTT溶液(PBS中に5mg/ml)と一緒に、各ウェルへ新鮮な培地(100μl)を加えた。590nmでマイクロプレートリーダーを使用し、対照細胞と比較して、生成物を定量する前に、一晩、0.01N HCl中のドデシル硫酸ナトリウム(100μl、10%w/v)によって、反応生成物を可溶化した。実験を3通り(n=3)で実行した。
タンパク質及びリン酸化タンパク質含有量を測定するためのウエスタンブロット法
リン酸化チロシンSTAT3(Y705)、リン酸化チロシンJak2(Y1007/1008)、全てのSTAT3、全てのJak2、BcI−xL、アクチン(Cell Signaling Technology、Danvers、MA)、及びサバイビン(R&D Systems、Minneapolis、MN)抗体を使用して、以下の方法を使用しウエスタンブロット法を実施した。手短に述べると、(1)対象のタンパク質を分解から保護する緩衝液中でホモジナイズした細胞から、試料を調製し、(2)次に、SDS−PAGE(10〜15μgタンパク質/ウェル)を使用して、試料を分離し、次に検出のための膜へ移動し、(3)膜を、一般的なタンパク質(乳タンパク質)によってインキュベートして、任意の残りの部位へ結合させた。次に、一次抗体を、その抗体の特異なタンパク質へ結合させることができる溶液へ加え、(4)次に、一次抗体を認識する、二次抗体−酵素複合体を加えて、一次抗体が結合した位置を発見した。
Claims (5)
- 構造式I
の化合物、又はその薬学的に許容される塩、若しくは溶媒和化合物[式中、
nは、1、2、又は3から選択される整数であり、
R0は、R1であるか、又はR0は、R1−Z1−であり、式中、Z1は、アルキルであり、特に、m3=0、1、2、3、又は4である−(CH2)m3−などの低級アルキルであってよく、
R1は、
であり、
式中、X1、X2、X3、及びX4は、それぞれ独立して、水素、ハロゲン、アルキル、アルコキシ、OH、トリハロメチル、又はNO2であり、Y1は、OH、特にBr及びClを含むハロゲン、又はO2Nであり、
R2は、アルキル、アルケニル、アルキニル、アルコキシ、アルキルアリール、ハロゲン、水素、OH、NO2、チオエーテル、アミン、SH、又はNH2であり、
R3は、
であり、
式中、m1は、1、2、3、又は4から選択される整数であり、
X5及びX6は、それぞれ独立して、水素、アルキル、高級アルキル、低級アルキル、アリール、アルコキシル、アリールオキシル、環式アルキル、シクロアルキル、シクロアリールアルキル、アラルキル、アルキルエステル、アルキルエステルアルキル、アルキルアセトキシル、ヒドロキシル、ヒドロキシルアルキル、シクロプロピル、シクロブチル、−CH3、−CH2OH、シクロペンチル、−CH2OAc、−CH2OC(O)C(CH3)3、−CH2C6H5、又はシクロへキシルであり、
Zは、NH、S、又はOであり、
Z3は、アルキル又は低級アルキルであり、
R4は、CN、置換アミン、CH2S−アルキル、アルキル、又はCH2N3であり、
R5及びR6は、それぞれ独立して、
単糖(例えば、グルコース、フルクトース、ガラクトース等)、多糖、単糖誘導体(例えば、アセチル化ガラクトースなどのアセチル化単糖、1,2,3,4−ジイソプロピリデノ−D−ガラクトース)、置換及び非置換アリール、並びに置換及び非置換アルキルアリール
からなる群から選択される]。 - 請求項1に記載の(又は式I及び定義の)化合物と癌細胞を接触させるステップを含む、STAT3の活性化を抑制する方法。
- それを必要とする患者への、請求項1に記載の(又は式I及び定義の)化合物の治療有効量の投与を含む、STAT3仲介疾患の治療の方法。
- 請求項1に記載の(又は式I及び定義の)化合物と癌細胞を接触させるステップを含む、STAT5の活性化を抑制する方法。
- それを必要とする患者への、請求項1に記載の(又は式I及び定義の)化合物の治療有効量の投与を含む、STAT5仲介疾患の治療の方法。
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2020165991A (ja) * | 2014-09-26 | 2020-10-08 | ナショナル ユニバーシティ オブ シンガポール | Th−gm細胞の機能を調節するための方法および組成物 |
JP7106604B2 (ja) | 2014-09-26 | 2022-07-26 | ナショナル ユニバーシティ オブ シンガポール | Th-gm細胞の機能を調節するための方法および組成物 |
JP2021502374A (ja) * | 2017-11-10 | 2021-01-28 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | 過剰増殖性疾患を処置するためのコーヒー酸誘導体 |
JP7428642B2 (ja) | 2017-11-10 | 2024-02-06 | ボード オブ リージェンツ,ザ ユニバーシティ オブ テキサス システム | 過剰増殖性疾患を処置するためのコーヒー酸誘導体 |
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JP5675606B2 (ja) | 2015-02-25 |
US20140228414A1 (en) | 2014-08-14 |
EP2307367A4 (en) | 2012-04-18 |
ZA201100536B (en) | 2012-06-27 |
US20110053992A1 (en) | 2011-03-03 |
MX2011000268A (es) | 2011-04-27 |
EP2307367A2 (en) | 2011-04-13 |
CN102143947A (zh) | 2011-08-03 |
CN102143947B (zh) | 2015-06-24 |
NZ590372A (en) | 2012-09-28 |
WO2010005807A2 (en) | 2010-01-14 |
AU2009268841A1 (en) | 2010-01-14 |
IL210423A0 (en) | 2011-03-31 |
BRPI0915697A2 (pt) | 2016-02-10 |
EA201170160A1 (ru) | 2011-08-30 |
WO2010005807A3 (en) | 2010-03-25 |
ES2521676T3 (es) | 2014-11-13 |
PL2307367T3 (pl) | 2015-03-31 |
EP2307367B1 (en) | 2014-09-24 |
CR20110074A (es) | 2011-06-24 |
US8143412B2 (en) | 2012-03-27 |
US9000179B2 (en) | 2015-04-07 |
UA103492C2 (ru) | 2013-10-25 |
AU2009268841B2 (en) | 2014-02-06 |
CA2729943A1 (en) | 2010-01-14 |
EA020766B1 (ru) | 2015-01-30 |
US8637675B2 (en) | 2014-01-28 |
KR20110033922A (ko) | 2011-04-01 |
AU2009268841A8 (en) | 2011-02-03 |
US20120149738A1 (en) | 2012-06-14 |
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