JPWO2019151439A1 - ペプチド系抗腫瘍薬の創製 - Google Patents
ペプチド系抗腫瘍薬の創製 Download PDFInfo
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- JPWO2019151439A1 JPWO2019151439A1 JP2019569581A JP2019569581A JPWO2019151439A1 JP WO2019151439 A1 JPWO2019151439 A1 JP WO2019151439A1 JP 2019569581 A JP2019569581 A JP 2019569581A JP 2019569581 A JP2019569581 A JP 2019569581A JP WO2019151439 A1 JPWO2019151439 A1 JP WO2019151439A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
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- A—HUMAN NECESSITIES
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Abstract
Description
本発明はこれらの知見に基づくものであり、以下の発明を包含する。
[2] R1及びR2は、それぞれ独立して選択することができ同一又は異なって、水素原子、ハロゲン原子、ヒドロキシル基、及び炭素数1〜6のアルキル基からなる群から選択される一又は複数の置換基で置換されていてもよい、キノリル基、イソキノリル基、キナゾリニル基、キノキサリル基、シンノリル基、インドリル基、ベンゾフラニル基、ベンゾチアゾリル基、ベンゾオキサゾリル基、ベンゾチオフェン基、ピラジル基、アントラキノン基、ベンゾフェノン基より選択される基である、[1]の化合物又はその塩。
[3] 以下の式(II):
以下の式(III):
[4] [1]〜[3]のいずれか一項に記載の化合物又はその塩を含む、がんを治療するための医薬組成物。
下記式(6):
[6] 前記式(6)で表わされる化合物が、下記式(3):
PG3はカルボキシル基の保護基を示し、
PG4及びPG5は、同一であっても異なっていてもよく、PG1とは異なるアミノ基の保護基を示す)で表される化合物を、下記式(4):
で表される化合物を製造し、得られた式(5)で表される化合物より製造される、[5]の方法。
[7] 前記式(3)で表わされる化合物が、下記式(1):
PG2はPG1とは異なる、アミノ基の保護基を示し、
PG3はカルボキシル基の保護基を示す)
で表される化合物と、下記式(2):
で表される化合物より製造される、[6]の方法。
[9] がんを治療する方法において使用するための、[1]〜[3]のいずれかの化合物又はその塩。
[10] がんを治療するための医薬の製造における、[1]〜[3]のいずれかの化合物又はその塩の使用。
本明細書は本願の優先権の基礎である日本国特許出願2018−015606号の明細書および/または図面に記載される内容を包含する。
本明細書で引用した全ての刊行物、特許および特許出願をそのまま参考として本明細書にとり入れるものとする。
本発明の化合物は、以下の式(I):
本発明の式(I)で表される化合物は、例えば、下記の製造法又は実施例に示す方法等により製造することができる。ただし、本発明の式(I)で表される化合物の製造法はこれら反応例に限定されるものではない。
本発明の化合物又はその塩は、がんを治療するための医薬組成物(以下、「本発明の医薬組成物」と記載する)における有効成分として利用することができる。
(核磁気共鳴)
核磁気共鳴(以下、1H−NMR)スペクトルは、JEOL JMM−ECS−400、JEOL JNM−ECX−400P、JEOL JNM−ECA−500(日本電子株式会社)を用いて測定した。
室温は、20℃〜25℃程度の範囲を指し、特に記載のない限り非水性反応はアルゴン雰囲気下で行った。
質量分析はSQ Detector2(日本ウォーターズ株式会社)を用いて、ESI(Electron Spray Ionization)法により行った。
反応溶媒として用いた塩化メチレンは五酸化二リンより、N,N−ジメチルホルムアミドは水素化カルシウムより、ベンゼンは金属ナトリウムより蒸留したものを用いた。水は脱イオン水をMillipore Millia−Q(登録商標)Advantage A10(登録商標)超純水製造装置で精製したものを用いた。その他の試薬及び溶媒については特に記載のない限り市販のものを用いた。
Analytical thin layer chromatography(TLC)は、Merck silica gel 60 F254を用いた。シリカゲルカラムクロマトグラフィーには充填剤としてWakogel 60N(63〜212μm)、フラッシュシリカゲルカラムクロマトグラフィーには充填剤としてKanto Chemical Silica Gel 60N(spherical,neutral,40〜50μm)、ハイフラッシュシリカゲルカラムクロマトグラフィーには充填剤としてCHROMATOREX PSQ60Bをそれぞれ用いた。重金属除去用SHシリカゲルは、Fuji Silysia Chemical LTD.Scavenger SH Silicaを用いた。
(化合物1の合成)
D−Ser(10.0g,95.2mmol)を出発物質とし、公知の手法(Kohn,H.et al.J.Med.Chem.2011,54,4815.Kunz,H.;Friedrich−Bochnitschek,S.J.Org.Chem.1989,54,751.)と同様の条件によって、下記化合物1(19.5g,69.8mmol,73%,2工程)を無色油状物質として得た。
Boc−L−Val−OH(15.0g,69.0mmol)を出発物質とし、公知の手法(Nagasawa,H.et al.上掲)と同様の条件によって、下記化合物2(15.1g,65.3mmol,95%)を淡黄色油状物質として得た。
化合物1(5.78g,20.7mmol)及び化合物2(4.79g,20.7mmol)より公知の手法(Nagasawa,H.et al.上掲)と同様の条件によって、下記化合物3(6.48g,13.2mmol,64%)を無色油状物質として得た。
(R)−チアゾリジンカルボン酸(50.0g,375mmol)を出発物質とし、公知の手法(US20140187546)と同様の条件によって、下記化合物4(24.6g,52.5mmol,28%,3工程)を白色泡状物質として得た。
化合物4(25.4g,54.2mmol)及び炭酸カリウム(16.4g,119mmol)のジメチルホルムアミド(180mL)懸濁液に、ヨウ化メチル(7.41mL,119mmol)を氷冷下にて加え、1.5時間撹拌した。さらに、ヨウ化メチル(0.74mL,11.9mmol)を加え、1.5時間撹拌した。反応液を酢酸エチルで希釈し、水、飽和チオ硫酸ナトリウム水溶液、及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をベンゼン(42mL)に溶解し、トリスジメチルアミノホスフィン(11.8mL,65.0mmol)を加え、室温で24時間撹拌した。反応液を減圧下溶媒を留去し、得られた残渣をフラッシュシリカゲルカラムクロマトグラフィー(φ6.5×25cm、ヘキサン/酢酸エチル:11/3→11/7)にて精製することで、下記化合物5(22.7g,48.8mmol,90%,2工程)を淡黄色油状物質として得た。
化合物5(23.9g,51.4mmol)のテトラヒドロフラン(150mL)、メタノール(50mL)、及び水(50mL)の混合溶媒に、水酸化リチウム水和物(4.74g,113mmol)の水(100mL)溶液を氷冷下にて加え、1時間撹拌した。水酸化リチウム水和物(474mg,11.3mmol)の水(10mL)溶液を氷冷下にて加え、30分撹拌した。反応液を減圧下溶媒を留去することでおよそ150mLに濃縮して得られた残渣に、1M塩酸水溶液を加え、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去することで、下記化合物6(22.4g,51.3mmol,定量的収率)を白色泡状物質として得た。
化合物3(25.4g,69.0mmol)に4M塩化水素/ジオキサン溶液(100mL,400mmol)を加え、室温で1時間撹拌した。減圧下溶媒を留去して得られた残渣に、ジオキサンを加えて減圧下溶媒を留去することで白色固体を得た。この白色固体、化合物6(16.0g,34.5mmol)、及びHOAt(12.2g,89.7mmol)の塩化メチレン(130mL)懸濁液にジイソプロピルエチルアミン(17.0mL,100mmol)、及びEDCI(17.2g,89.7mmol)を氷冷下にて加え、室温で19時間撹拌した。反応液を酢酸エチルで希釈し、1M塩酸水溶液、飽和重曹水、及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をフラッシュシリカゲルカラムクロマトグラフィー(φ6.5×15cm、ヘキサン/酢酸エチル:5/3→5/6)にて精製することで、下記化合物7(30.6g,25.8mmol,74%,2工程)を白色泡状物質として得た。
化合物7(21.1g,17.8mmol)の塩化メチレン(20mL)溶液に4M塩化水素/ジオキサン溶液(50mL)を加え、室温で1時間撹拌した。減圧下溶媒を留去して得られた残渣に、ジオキサンを加えて減圧下溶媒を留去することで白色固体を得た。この白色固体、Boc−Ala−OH(10.1g,53.4mmol)、HOAt(9.69g,71.2mmol)のジメチルホルムアミド(23mL)、及び塩化メチレン(117mL)の懸濁液に、炭酸水素ナトリウム(7.78g,92.6mmol)を室温で、及びEDCI(13.6g,71.2mmol)を氷冷下にて加え、室温で14時間撹拌した。反応液を酢酸エチルで希釈し、1M塩酸水溶液、飽和重曹水、及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をフラッシュシリカゲルカラムクロマトグラフィー(φ4×15cm、ヘキサン/酢酸エチル:3/1→1/1)にて精製することで、下記化合物8(16.5g,12.5mmol,70%,2工程)を白色泡状物質として得た。
化合物8(22.3g,16.8mmol)のテトラヒドロフラン(110mL)溶液にモルホリン(5.12mL,58.8mmol)、及びテトラキストリフェニルホスフィンパラジウム(38.9mg,33.6μmol)を氷冷下にて加え、4時間撹拌した。反応液を酢酸エチルで希釈し、1M塩酸水溶液、及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣を上部に重金属除去用SHシリカゲルを含むシリカゲルカラムクロマトグラフィー(φ4×2cm、クロロホルム/メタノール/酢酸:100/0/0→98/0/2→95/3/2)にて粗精製することで淡黄色泡状化合物を得た。この残渣に4M塩化水素/ジオキサン溶液(100mL)を加え、室温で1時間撹拌した。減圧下溶媒を留去して得られた残渣にジオキサンを加えて溶媒置換を行った後、ジエチルエーテルで洗浄することで、下記化合物9(17.9g,16.0mmol,95%,2工程)を得た。
化合物9(2.69g,2.40mmol)のジメチルホルムアミド(1.2L)溶液に、ジフェニルホスホリルアジド(5.16mL,24.0mmol)、及びN−メチルモルホリン(3.69mL,33.6mmol)を氷冷下にて加え、室温で72時間撹拌した。反応液を、減圧下溶媒を留去することでおよそ(10mL)に濃縮した。この残渣を酢酸エチル/混合溶媒で希釈し、水、1M塩酸水溶液、飽和重曹水、及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(φ3×15cm、クロロホルム/メタノール:100/0→99.5/0.5→99/1→98.5/1.5→98/2)にて精製することで、下記化合物10(676mg,0.669mmol,28%)を白色固体として得た。
化合物10(70.0mg,69.2μmol)、及びメチルフェニルスルフィド(324μL,2.77mmol)にトリフルオロ酢酸(6.9mL)を加え、40℃で15時間撹拌した。反応液を減圧下濃縮して得られた残渣をジエチルエーテルで洗浄することで淡黄色の固体を得た。この固体を、キノキサリン−2−カルボン酸(48.2mg,0.277mmol)、HOAt(47.1mg,0.346mmol)、ジイソプロピルエチルアミン(70.6μL,0.415mmol)、及びEDCI(66.3mg,0.346mmol)のジメチルホルムアミド(1mL)の懸濁液に氷冷下にて加え、室温で5時間撹拌した。反応液を酢酸エチルで希釈し、水、1M塩酸水溶液、飽和重曹水、及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をフラッシュシリカゲルカラムクロマトグラフィー(φ1×15cm,クロロホルム/メタノール:100/0→99/1→98/2→97/3)にて精製することで、下記化合物11(30.0mg,28.4μmol,41%,2工程)を無色固体として得た。
化合物10(30.0mg,29.7μmol)、及びメチルフェニルスルフィド(139μL,1.19mmol)にトリフルオロ酢酸(3.0mL)を加え、40℃で15時間撹拌した。反応液を減圧下濃縮して得られた残渣をジエチルエーテルで洗浄することで淡黄色の固体を得た。この固体を、3−ヒドロキシキノリン−2−カルボン酸(16.9mg,89.1μmol)、HOAt(12.1mg,89.1μmol)、炭酸水素ナトリウム(20.0mg,238μmol)、及びEDCI(17.1mg,89.1μmol)のジメチルホルムアミド(0.3mL)懸濁液に氷冷下にて加え、室温で5時間撹拌した。反応液を酢酸エチルで希釈し、水、1M塩酸水溶液、飽和重曹水、及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をフラッシュシリカゲルカラムクロマトグラフィー(φ1×15cm,クロロホルム/メタノール:100/0→99/1→98/2→97/3)にて精製することで、下記化合物12(9.6mg,8.8μmol,30%,2工程)を無色固体として得た。
(1)実験方法
(細胞株及びその培養)
細胞は、大腸がん細胞株であるSW620細胞株(ATCC)、膵臓がん細胞株であるMIA PaCa−2細胞株(ATCC)及びSuit2細胞株(ヒューマンサイエンス資源バンク)を用いた。
96穴プレートに1.0×104個/ウェルとなるように分注した被験細胞を24時間培養した後、上記化合物11又は化合物12を終濃度1ng/mL、10ng/mL、100ng/mL、又は1000ng/mLとなるように培養液に添加してインキュベーションを開始し、24時間、48時間、72時間、96時間後にプレートを回収した(各n=5)。
1.TUNEL法
4ウェルガラスチャンバースライドに5.0×104個/ウェルとなるように分注したSW620細胞株を24時間培養した後、上記化合物12を終濃度10ng/mLとなるように培養液に添加してインキュベーションを開始し、48時間後にスライドを回収した。
TUNEL(TdT−mediateddUTPnickendlabeling)法を利用する市販の細胞死検出キット(In Situ Cell Death Detection Kit and TMR red(Roche Diagnostic))を製造元のプロトコルに従って使用し、TUNEL染色された細胞(すなわち、細胞死を起こした細胞)を検出・カウントした。対照群には化合物を添加せず、エキノマイシン投与群には、エキノマイシンの終濃度が10ng/mLとなるように添加して、同様に操作した。
対照群、エキノマイシン投与群、及び化合物12投与群はそれぞれn=4にて実施した。
6穴プレートに2.0×105個/ウェルとなるように分注したSW620細胞株を24時間培養した後、上記化合物12を終濃度10ng/mLとなるように培養液に添加してインキュベーションを開始し、48時間後にプレートを回収した。
市販のタンパク回収キット(mammalian cell extraction kit(BioVision))を製造元のプロトコルに従って使用してタンパク質を回収し、cleaved caspase−3に対する特異抗体(Cell Signaling)を用いたウエスタン・ブロッティング法により活性化型カスパーゼ−3を定量した。内在性コントロールにはアクチンを用いた。対照群には化合物を添加せず、エキノマイシン投与群には、エキノマイシンの終濃度が10ng/mLとなるように添加して、同様に操作した。
対照群、エキノマイシン投与群、及び化合物12投与群はそれぞれn=4にて実施した。
BALB/cヌードマウスに抗アシアロGM1(ウサギ)(和光純薬工業株式会社)を腹腔内投与し、室温にて2時間飼育した。2×106個の被験細胞を、BALB/cヌードマウスの背部皮下に注射して移植した。SW620細胞株を移植したマウスには移植の翌日から、MIA PaCa−2細胞株を移植したマウスには移植の一週間後から、化合物11又は化合物12を一匹あたり50ng又は500ng、あるいは40ng又は400ngの用量で毎日腹腔内に投与し、各移植部位における腫瘍塊の成長を観察した。対照群には化合物を投与せず、エキノマイシン投与群には、エキノマイシンを一匹あたり40ng又は400ngの用量で毎日腹腔内に投与した。
対照群、エキノマイシン投与群、化合物11投与群、及び化合物12投与群は、それぞれn=5にて実施した。
BALB/cヌードマウスに抗アシアロGM1(ウサギ)(和光純薬工業株式会社)を腹腔内投与し、室温にて2時間飼育した。2×106個のMIA PaCa−2細胞株を、BALB/cヌードマウスの背部皮下に注射して移植した。移植の翌日から、化合物11又は化合物12を一匹あたり500ngの用量で毎日腹腔内に投与し、毎日体重を計測した(各n=5)。対照群には化合物を投与せず、エキノマイシン投与群には、エキノマイシンを一匹あたり400ngの用量で毎日腹腔内に投与し、屠殺日に体重を計測した(各n=5)。
(SRBアッセイ)
SRBアッセイの結果を、図1−1〜図1−3に示す。
化合物12については、100ng/mL以上の添加により、いずれの細胞株においても、対照における吸光度との間に有意な差が認められ、当該化合物ががん細胞の増殖を抑制する活性を有することが確認された(図1−1〜図1−3)。また、低濃度(10ng/mL)における当該活性は、エキノマイシンよりも高いものであることが、MIA PaCa−2細胞株及びSW620細胞株において確認された。
腫瘍細胞移植動物モデルアッセイ1−移植した腫瘍サイズの評価の結果を、図2−1〜図2−2に示す。
化合物11については、500ngの投与により、移植した腫瘍サイズの縮小が認められた(図2−1)。この活性は、400ngのエキノマイシンを投与した場合に匹敵することが確認された。
TUNEL法による、細胞死を起こした細胞数の測定結果を図3に示す。
化合物12の投与により誘導された細胞死を起こした細胞の数は、対照群やエキノマイシン投与群のそれと比べて有意に高いことが確認された(*:p<0.05(vs対照、スチューデントのt検定))。
また、ウエスタン・ブロッティング法による活性化型カスパーゼ−3の定量結果を図4に示す。
化合物12投与群における活性化型カスパーゼ−3の量は*1107±273であり、対照群(100±45)及びエキノマイシン投与群(*362±176)の値と比べて高いことが確認された(*:p<0.05(vs対照、スチューデントのt検定))。化合物12投与群及びエキノマイシン投与群における各数値は、対照群の数値に対する相対値にて示す。
これらの結果は、化合物12がエキノマイシンと比べて、腫瘍に対する高い細胞死誘導活性、すなわち抗がん活性を有することを示す。
各群における投与28日目の体重を図5に示す。化合物11及び化合物12のいずれの投与群についても、対照群及びエキノマイシン投与群と同様に、大きな体重減少は認められなかった。この結果は、本発明の化合物の毒性が低いことを示す。
Claims (7)
- R1及びR2は、それぞれ独立して選択することができ同一又は異なって、水素原子、ハロゲン原子、ヒドロキシル基、及び炭素数1〜6のアルキル基からなる群から選択される一又は複数の置換基で置換されていてもよい、キノリル基、イソキノリル基、キナゾリニル基、キノキサリル基、シンノリル基、インドリル基、ベンゾフラニル基、ベンゾチアゾリル基、ベンゾオキサゾリル基、ベンゾチオフェン基、ピラジル基、アントラキノン基、ベンゾフェノン基より選択される基である、請求項1に記載の化合物又はその塩。
- 請求項1〜3のいずれか一項に記載の化合物又はその塩を含む、がんを治療するための医薬組成物。
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HATTORI KOZO, ET AL.: "Solution-Phase Synthesis and Biological Evaluation of Triostin A and its Analogues", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 14, no. 6, JPN6019005676, 2016, pages 2090 - 2111, XP055630686, ISSN: 0004931689, DOI: 10.1039/C5OB02505B * |
KIM YUN BONG, ET AL.: "Synthesis and biological activity of new quinoxaline antibiotics of echinomycin analogues", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, JPN6019005673, 2004, pages 541 - 544, XP055630644, ISSN: 0004931688, DOI: 10.1016/j.bmcl.2003.09.086 * |
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