JP6304594B2 - 芳香環含有化合物並びに癌の予防剤および/または治療剤 - Google Patents
芳香環含有化合物並びに癌の予防剤および/または治療剤 Download PDFInfo
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
Description
mは、0または1であり、
A1およびA2は、それぞれ独立して、下記化学式2または下記化学式3:
A3は、下記化学式4または下記化学式5:
で表される基である、
で表される芳香環含有化合物が提供される。
本発明者らによる予備研究から、下記の構造を有する天然物物質(化合物6)が、FIRΔexon2と相互作用すること、さらには癌細胞の増殖抑制作用を有することが判明している。
(細胞の調製)
接着性細胞株であるHeLa細胞(ヒト子宮頸癌由来の細胞)については、化合物処理の前日に、平底96ウェルプレートのウェル(培地100μL)中、37℃/5%CO2の条件下で24時間、化合物処理の時点で40〜80%コンフルエントとなるように培養を行った。
化合物処理の後に37℃にて24時間インキュベーションを行い、CellTiter 96(登録商標)Aqueous One Solution Reagent(Promega社製)を、製造者の指示書に従って各ウェルに添加した。この操作について概説すると、CellTiter 96(登録商標)Aqueous One Solution Reagentを加温し、各ウェルに20μL/ウェルの量で添加し、37℃にてさらに1時間インキュベーションを行った。次いで、10%SDS溶液を各ウェルに添加した(25μL/ウェル)。細胞の生育性については、550 Bio-Radプレートリーダーを用いた波長490nmでの吸光度を測定することにより評価した。すべての試料について2回ずつ実験を行い、吸光度の測定は3回ずつ行った(つまり、6回の測定の平均値を算出して比較した)。なお、すべての実験において、ネガティブコントロール(陰性対照)としてはジメチルスルホキシド(DMSO)を用い、ポジティブコントロール(陽性対照)としては3%過酸化水素水を用いた。
本願発明の実施例に相当する以下の化合物1〜3について、Jurkat細胞を用いたMTSアッセイにより、細胞増殖抑制作用を評価した。なお、評価に用いる化合物試料としては、まずDMSOを溶媒とした10mM溶液を調製しておき、この10mM溶液を各ウェル(培地100μL)に対して1μLずつ(すなわち、100μMの濃度で)添加して、MTSアッセイに供した。吸光度の測定結果を図1に示す。
分子量:440.6
NMRデータ:1H-NMR(400MHz,DMSO-D6) 7.72(s,1H),7.74(s,1H),7.92(s,1H),7.97(dd,J=8.4Hz,1H)
(合成方法)
(4−ブロモ−1,3−フェニレン)ジメタノールの合成
アルゴン雰囲気・氷冷下にて、水素化ホウ素ナトリウム(2.70g,71.4mmol)のテトラヒドロフラン(20ml)溶液に、4−ブロモイソフタル酸(4.98g,20.3mmol)のテトラヒドロフラン(80ml)溶液を加え撹拌した。氷冷したままボロントリフルオリドジエチルエーテル錯体(7.6ml,60.9mmol)を1時間かけて加え、室温に戻し1時間撹拌した。反応溶液に1mol/lの水酸化ナトリウム水溶液(40ml)を加え、酢酸エチルで抽出した。水層を酢酸エチルでさらに2回抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。減圧下で溶媒を留去し、残渣をカラムで精製して、(4−ブロモ−1,3−フェニレン)ジメタノール(3.52g,80%)を白色固体として得た。
(4−ブロモ−1,3−フェニレン)ジメタノール(3.03g,16.2mmol)のテトラヒドロフラン(300ml)溶液に、二酸化マンガン(IV)(22.7g,261mmol)を加え60℃で2時間加熱した。その後セライト濾過を行い、減圧下で濾液から溶媒を除去した。4−ブロモイソフタルアルデヒド(1.69g,49%)が白色固体として得られた。
4−ブロモイソフタルアルデヒド(0.49g,2.3mmol)に、酢酸パラジウム(II)(78mg,0.35mmol)、リン酸三カリウム(0.79g,3.7mmol)、4−t−ブチルスチレン(4.3ml,23.7mmol)、N,N−ジメチルホルムアミド(20ml)を順に加え、140℃で1時間加熱した。反応溶液に水を加え、吸引濾過し、濾液を酢酸エチルで抽出した。水層を酢酸エチルでさらに2回抽出し、有機層を1mol/lの塩酸、飽和食塩水で順に洗浄後、無水硫酸マグネシウムで乾燥させた。減圧下で溶媒を留去し、残渣をカラム(ヘキサン:酢酸エチル=3:1)で精製して、(E)−4−(4−(t−ブチル)スチリル)イソフタルアルデヒド(0.25g,37%)を黄色油状物質として得た。
(E)−4−(4−(t−ブチル)スチリル)イソフタルアルデヒド(0.25g,0.86mmol)に、ロダニン(0.47g,3.5mmol)、酢酸ナトリウム三水和物(6.0g,44mmol)、酢酸(20ml)を加え、100℃で3時間加熱した。その後反応溶液を氷に入れ、氷が解け室温になったら吸引濾過した。残留物を水に溶かし吸引濾過した後、デシケーターで乾燥させた。(5Z,5’Z)−5,5’−((4−((E)−4−(t−ブチル)スチリル)−1,3−フェニレン)ビス(メタニリリデン))ビス(2−チオキソチアゾリジン−4−オン)がオレンジ色固体として得られた。
(5Z,5’Z)−5,5’−((4−((E)−4−(t−ブチル)スチリル)−1,3−フェニレン)ビス(メタニリリデン))ビス(2−チオキソチアゾリジン−4−オン)に、1mol/lの水酸化ナトリウム水溶液(20ml)を加え60℃で10分加熱した。反応溶液に氷を加え、氷が溶けたら酢酸エチルで洗浄した。水層を酢酸エチルでさらに3回洗浄し、水層に2mol/lの塩酸(10ml)を加えて中和した。水層を酢酸エチルで3回抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。減圧下で溶媒を留去して、(E)−3,3’−(4−(4−(t−ブチル)スチリル)−1,3−フェニレン)ビス(2−チオキソプロパノン酸)(0.14g)をオレンジ色固体として得た。
分子量:440.6
NMRデータ:1H-NMR(400MHz,DMSO-D6) 7.38(dd,j=9.1Hz,2H),7.44(dd,j=8.2Hz,2H),7.53(s,1H),7.59(dd,j=8.3Hz,2H),7.73(s,2H),7.92(s,2H)
(合成方法)
(5−ブロモ−1,3−フェニレン)ジメタノールの合成
アルゴン雰囲気・氷冷下にて、水素化ホウ素ナトリウム(2.76g,73.0mmol)のテトラヒドロフラン(20ml)溶液に、5−ブロモイソフタル酸(5g,20.4mmol)のテトラヒドロフラン(80ml)溶液を加え撹拌した。氷冷したままボロントリフルオリドジエチルエーテル錯体(7.6ml,60.9mmol)を1時間かけて加え、室温に戻し1時間撹拌した。反応溶液に0.5mol/lの水酸化ナトリウム水溶液(40ml)を加え、酢酸エチルで抽出した。水層を酢酸エチルでさらに2回抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。減圧下で溶媒を留去し、残渣をカラムで精製して、(5−ブロモ−1,3−フェニレン)ジメタノール(3.60g,81%)を白色固体として得た。
(5−ブロモ−1,3−フェニレン)ジメタノール(3.60g,16.6mmol)のテトラヒドロフラン(250ml)溶液に、二酸化マンガン(IV)(35.5g,408mmol)を加え60℃で4時間加熱した。その後セライト濾過を行い、減圧下で濾液から溶媒を除去した。5−ブロモイソフタルアルデヒド(1.61g,46%)が白色固体として得られた。
5−ブロモイソフタルアルデヒド(0.49g,2.3mmol)に、酢酸パラジウム(II)(82mg,0.37mmol)、リン酸三カリウム(0.78g,3.7mmol)、4−t−ブチルスチレン(4.3ml,23.7mmol)、N,N−ジメチルホルムアミド(20ml)を順に加え、140℃で1時間加熱した。反応溶液に水を加え、吸引濾過し、濾液を酢酸エチルで抽出した。水層を酢酸エチルでさらに2回抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。減圧下で溶媒を留去し、残渣をカラム(ヘキサン:酢酸エチル=3:1)で精製して、(E)−5−(4−(t−ブチル)スチリル)イソフタルアルデヒド(0.37g,55%)を黄色固体として得た。
(E)−5−(4−(t−ブチル)スチリル)イソフタルアルデヒド(0.37g,1.3mmol)に、ロダニン(1.02g,7.7mmol)、酢酸ナトリウム三水和物(6.0g,44mmol)、酢酸(20ml)を加え、100℃で2時間加熱した。その後反応溶液を氷に入れ、氷が解け室温になったら吸引濾過した。残留物を水に溶かし吸引濾過した後、デシケーターで乾燥させた。(5Z,5’Z)−5,5’−((5−((E)−4−(t−ブチル)スチリル)−1,3−フェニレン)ビス(メタニリリデン))ビス(2−チオキソチアゾリジン−4−オン)がオレンジ色固体として得られた。
(5Z,5’Z)−5,5’−((5−((E)−4−(t−ブチル)スチリル)−1,3−フェニレン)ビス(メタニリリデン))ビス(2−チオキソチアゾリジン−4−オン)に、1mol/lの水酸化ナトリウム水溶液(20ml)を加え60℃で10分加熱した。反応溶液に氷を加え、氷が溶けたら酢酸エチルで洗浄した。水層を酢酸エチルでさらに3回洗浄し、水層に2mol/lの塩酸(15ml)を加えて中和した。水層を酢酸エチルで3回抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。減圧下で溶媒を留去して、(E)−3,3’−(5−(4−(t−ブチル)スチリル)−1,3−フェニレン)ビス(2−チオキソプロパノン酸)を山吹色固体として得た。
上述したJurkat細胞を用いたMTSアッセイにおいて最も優れた細胞増殖抑制作用を示した化合物3について、癌細胞の増殖抑制作用におけるIC50を測定した。
SPF45のC末端側のアミノ酸配列(第372〜384番目のアミノ酸)を表す。
〔配列番号2〕
野生型FIRのC末端側のアミノ酸配列(第505〜517番目のアミノ酸)を表す。
〔配列番号3〕
Cyclin E(T380)のC末端側のアミノ酸配列を表す。
〔配列番号4〕
Cyclin E(T62)のC末端側のアミノ酸配列を表す。
〔配列番号5〕
MYC(T58)のC末端側のアミノ酸配列を表す。
〔配列番号6〕
JUN(T239)のC末端側のアミノ酸配列を表す。
〔配列番号7〕
SREBP1(T456*)のC末端側のアミノ酸配列を表す。
〔配列番号8〕
SV40 large T antigen(T701)のC末端側のアミノ酸配列を表す。
〔配列番号9〕
Notch1(T2512*)のC末端側のアミノ酸配列を表す。
〔配列番号10〕
Presenilin1(T116)のC末端側のアミノ酸配列を表す。
Claims (13)
- 下記化学式1:
mは、0または1であり、
A1およびA2は、それぞれ独立して、下記化学式2または下記化学式3:
A3は、下記化学式4または下記化学式5:
で表される基である、
で表される芳香環含有化合物。 - A1が前記化学式2で表される基である、請求項1に記載の芳香環含有化合物。
- A1が前記化学式3で表される基である、請求項1に記載の芳香環含有化合物。
- mが1である、請求項1〜3のいずれか1項に記載の芳香環含有化合物。
- A2が前記化学式2で表される基である、請求項4に記載の芳香環含有化合物。
- A3が前記化学式4で表される基である、請求項1〜5のいずれか1項に記載の芳香環含有化合物。
- Rが置換または非置換のアリール基である、請求項6に記載の芳香環含有化合物。
- Rがp−置換フェニル基である、請求項7に記載の芳香環含有化合物。
- 前記p−置換フェニル基のパラ位における置換基が、フッ素原子またはtert−ブチル基である、請求項8に記載の芳香環含有化合物。
- A3が前記化学式5で表される基である、請求項1〜5のいずれか1項に記載の芳香環含有化合物。
- 下記化合物1〜5のいずれかである、芳香環含有化合物:
- 請求項1〜11のいずれか1項に記載の芳香環含有化合物の1種または2種以上を有効成分として含有する、癌の予防剤および/または治療剤。
- 前記癌が白血病である、請求項12に記載の予防剤および/または治療剤。
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