JP2020520981A - プロテアーゼのイメージング/検出のための化学発光プローブ - Google Patents
プロテアーゼのイメージング/検出のための化学発光プローブ Download PDFInfo
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- JP2020520981A JP2020520981A JP2019565169A JP2019565169A JP2020520981A JP 2020520981 A JP2020520981 A JP 2020520981A JP 2019565169 A JP2019565169 A JP 2019565169A JP 2019565169 A JP2019565169 A JP 2019565169A JP 2020520981 A JP2020520981 A JP 2020520981A
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Abstract
Description
式中、
R1は、直鎖もしくは分岐鎖(C1〜C18)アルキル、または(C3〜C7)シクロアルキルから選択され;
R2およびR3は、各々独立して、分岐鎖(C3〜C18)アルキルもしくは(C3〜C7)シクロアルキルから選択されるか、またはR2およびR3はこれらが結合している炭素原子と一緒になって縮合環、スピロ環もしくは架橋環もしくは多環式環を形成し;
R4は、式:
の基であり;
R5はHまたは−O−R4基に対してオルト位もしくはパラ位のいずれかで結合したハロゲンであり;
Aは−O−R4基に対してオルト位もしくはパラ位のいずれかで結合した式−CH=CH−Eのπ*アクセプター基であり、Eは−CN、−COOH、−COO(C1〜C18)アルキル、4−ピリジニル、メチルピリジニウム−4−イル、3,3−ジメチル−3H−インドリル、または1,3,3−トリメチル−3H−インドール−1−イウム−2−イルであり;
Pep1は、少なくとも2個のアミノ酸残基からなるプロテアーゼ切断可能ペプチド部分であり、そのカルボン酸基を介して前記アニリン基と結合しており、前記ペプチド部分は保護されていてもよく、そのアミノ基によりPEG含有基と、例えば、アミド結合を介して結合していてもよく;
Lは存在しないか、またはPep1のカルボン酸基もしくはアミノ基のいずれかによりPep1とアミド結合を介して結合したリンカーであり;
Pep2は存在しないか、またはそのアミノ基もしくはカルボン酸基によりアミド結合を介して、もしくはそのチオール基のいずれかによりLと結合した細胞透過性ペプチド部分であり、
但し、LおよびPep2は、両方共に、存在しないか、または存在し、Pep1が保護されているかもしくはPEG含有基と結合している場合、LおよびPep2は存在しない。
ち、上記定義された式Ia/Ibの化合物、または前記化合物を含む医薬組成物に関する。
ん進行に対する重要な寄与因子でもある。多くの研究から、例えば、MMP9は前転移ニッチの形成に重要であり、血管内皮増殖因子のバイオアベイラビリティの調節による腫瘍血管新生において異なる役割を有することが分かった。臨床的に、MMP9のレベル上昇は、広範な範囲のがんタイプにおける腫瘍攻撃性、ステージおよび予後不良と相関する。MMP2に関してデータが公表されている。
(式中、nは1〜227の整数である。)
のPEG含有基と結合していてもよい、化合物を提供する。
(式中、nは1〜227の整数である。)
のPEG含有基と結合している。
ロイシン、アスパラギンまたはグルタミンのカルボン酸基を介して前記アニリン基と結合したアミノ酸配列Val−Cit、Phe−Lys、Gly−Phe−Leu−Gly、Gly−Gly−Pro−Nle、Ala−Ala−AsnまたはHis−Ser−Ser−Lys−Leu−Glnを含むまたはからなるペプチド部分であり;LはPep1のカルボン酸基またはアミノ基のいずれかによりアミド結合を介してPep1と結合したリンカーであり;Pep2はそのチオール基によりLと結合した細胞透過性および可溶性ペプチド部分である、化合物を提供する。特定のかかる実施形態では、Lは、Pep1のアミノ基によりアミド結合を介してPep1と結合した式:
(式中、mは1〜20の整数である。)
のリンカーであり、Lのアルキレン鎖は1つ以上の−O−基が割り込んでいてもよく;Pep2はそのシステイン残基のチオール基によりLと結合した細胞透過性および可溶性ペプチド部分、例えば、配列Cys−Gly−Lys−Arg−Lysのペプチド部分である。
(式中、nは17である(例えば、表2の化合物Ib−3aおよび3b−1b)。)
のPEG含有基と結合している;かまたは(iv)Pep1は、それぞれ、シトルリンもしくはグルタミンのカルボン酸基を介して前記アニリン基と結合した配列Val−CitもしくはHis−Ser−Ser−Lys−Leu−Glnのペプチド部分であり;Lは、それぞれ、バリンまたはヒスチジンのαアミノ基によりアミド結合を介してPep1と結合した式:
(式中、mは5の整数である。)
のリンカーであり;Pep2はシステイン残基のチオール基によりLと結合した配列Cys−Gly−Lys−Arg−Lysのペプチド部分である(例えば、表2の化合物Ib−4a、Ib−4b、Ib−5aおよびIb−5b)。
内、腹腔内、筋肉内もしくは皮下投与などの非経口投与、局所投与、経口または腸内投与、または吸入用に製剤することができる。特定の実施形態では、かかる組成物を、静脈内もしくは腹腔内投与用、または皮下投与用に製剤する。
一般方法
無水条件を要する全反応をアルゴン雰囲気下で行った。特に指定されない限り、全反応を室温で行った。化学薬品および溶媒は、A.R.グレードであったか、あるいは標準的方法により精製したかのいずれかである。TLC:シリカゲルプレートMerck 60F254:UV光照射により化合物を可視化した。カラムクロマトグラフィー(FC):シリカゲルMerck 60(粒径0.040〜0.063mm)、括弧内は溶離液。RP−HPLC:C18 5μ、250×4.6mm、括弧内は溶離液。分取RP−HPLC:C18 5μ、250×21mm、括弧内は溶離液。1H−NMRスペクトルを、B
ruker Avanceを用いて400MHzで測定した。13C−NMRスペクトルを、Bruker Avanceを用いて100MHzで測定した。化学シフトを、残溶媒に対してδ目盛のppmで報告した(CDCl3:1H−NMRに関してδ=7.26および13C−NMRに関して77.16、DMSO−d6:1H−NMRに関してδ=2.50および13C−NMRに関して39.52)。質量スペクトルを、Waters
Xevo TQDで測定した。化学発光を、Molecular Devices Spectramax i3xで記録した。円および溶媒を含む全ても一般試薬を、Sigma−Aldrichから購入した。光化学反応のための光照射:LED PAR38ランプ(19W、3000K)。
化合物1b。スキーム3に示されているように、化合物1a(Dubowchik et al.,2002)(300mg、0.58mmol、1当量)をACN 7mLに溶解し、0℃まで冷却した。ヨウ化ナトリウム(264mg、1.76mmol、3当量)を添加し、次いで、TMS−Cl(222μL、1.76mmol、3当量)を直ぐに添加した。反応物を放置して室温まで温めてTLC(MeOH:DCM 10:90)によってモニターした。完了次第、反応混合物をEtOAcで希釈し、飽和Na2S2O3、次いで塩水で洗浄した。有機層を分離し、Na2SO4で乾燥し、ろ過し、減圧下溶媒を蒸発させてオフホワイト固体の化合物1b(245mg、収率67%)を得た。化合物をさらに精製しないで反応させた。MS(ES+):m/z C26H34IN5O5の計算値:623.16;実測値:624.4[M+H」+。
10:90)によりモニターした。完了次第、反応混合物をEtOAcで希釈し、飽和NH4Clで洗浄した。有機層を分離し、塩水で洗浄し、Na2SO4で乾燥し、ろ過して、溶媒を減圧下蒸発させた。粗生成物をさらに精製しないで反応させた。MS(ES+):m/z C44H54ClN5O7の計算値:799.37;実測値:800.5[M+H」+。
5O9の計算値:831.36;実測値:854.5[M+Na」+。1H NMR(400MHz,DMSO) δ 10.07(s,1H),8.10(d,J=7.6Hz,1H),7.60(d,J=8.5Hz,2H),7.54(d,J=7.7Hz,1H),7.44(t,J=8.0Hz,1H),7.41−7.25(m,7H),5.97(s,1H),5.74(s,1H),5.41(s,2H),5.16(q,J=12.0Hz,2H),5.02(s,2H),4.40(dd,J=13.4,7.9Hz,1H),3.95−3.86(m,1H),3.07(s,3H),3.05−2.97(m,1H),2.92(dd,J=13.0,6.1Hz,1H),2.85(s,1H),2.24(d,J=12.8Hz,1H),2.03−1.86(m,2H),1.75−1.49(m,9H),1.37(dd,J=37.8,8.8Hz,3H),1.28−1.12(m,4H),0.86(d,J=6.8Hz,3H),0.82(d,J=6.7Hz,3H)。13C NMR(101MHz,DMSO) δ 171.77,171.17,159.42,156.68,155.07,139.27,137.62,132.84,131.60,128.87,128.29,128.17,125.05,120.70,119.55,116.55,112.02,95.77,70.85,65.92,60.59,53.58,49.75,36.46,33.76,33.48,32.25,31.62,31.31,30.90,30.00,27.31,26.05,25.72,19.74,18.68。
化合物2b。スキーム5に示されているように、化合物1b(50mg、0.08mmol、1当量)および化合物1c(Green et al.,2017)(34mg、0.09mmol、1.1当量)をDMF 0.5mLに溶解し、K2CO3(24mg、0.18mmol、2.2当量)を添加した。反応をTLC(MeOH:DCM 10:90)によりモニターした。完了次第、反応混合物をEtOAcで希釈し、飽和NH4Clで洗浄した。有機層を分離し、塩水で洗浄し、Na2SO4で乾燥し、ろ過して、溶媒を減圧下蒸発させた。粗生成物をカラムクロマトグラフィーによりシリカゲル(MeOH:DCM 10:90)で精製して黄色がかった固体の化合物2b(29mg、収率41%)を得た。MS(ES+):m/z C48H58ClN5O9の計算値:883.39;実測値:884.8[M+H」+。1H NMR(400MHz,CDCl3) δ 7.83(d,J=16.2Hz,1H),7.53(d,J=8.2Hz,2H),7.35(t,J=8.5Hz,3H),7.30−7.18(m,5H),7.00(d,J=8.0Hz,1H),6.36(d,J=16.2Hz,1H),5.02(q,J=12.3Hz,3H),4.87(d,J=3.1Hz,2H),4.49(dd,J=8.8,4.9Hz,1H),3.96(d,J=6.2Hz,1H),3.71(s,3H),3.25(s,3H),3.22−2.98(m,4H),2.06−1.94(m,3H),1.92−1.80(m,6H),1.80−1.70(m,5H),1.70−1.56(m,5H),1.46(s,3H),0.88(d,J=6
.7Hz,3H),0.84(d,J=6.8Hz,3H)。13C NMR(101MHz,CDCl3) δ 172.55,170.37,167.50,157.00,153.69,139.29,139.04,138.32,138.26,138.20,138.12,136.17,132.78,131.83,129.61,128.51,128.18,127.88,125.15,119.91,119.74,75.82,67.07,60.48,57.26,53.16,51.84,39.13,38.59,36.99,32.94,31.00,29.72,29.29,28.31,25.99,19.17,17.79。
31.79,130.73,130.20,128.87,128.30,128.19,127.39,126.56,121.77,119.39,111.72,95.95,76.26,65.93,60.59,53.60,52.24,49.95,39.83,39.62,39.41,36.39,33.81,33.59,32.36,32.18,31.61,31.38,30.91,30.00,27.31,26.03,25.69,19.73,18.68。
スキーム7に示されているように、化合物1b(40mg、0.064mmol、1当量)および7−ヒドロキシクマリン(12mg、0.07mmol、1.1当量)をDMF 0.5mLに溶解し、K2CO3(20mg、0.141mmol、2.2当量)を添加した。反応をTLC(MeOH:DCM 10:90)によりモニターした。完了次第、反応混合物をEtOAcで希釈し、飽和NH4Clで洗浄した。有機層を分離し、塩水で洗浄し、Na2SO4で乾燥し、ろ過して、溶媒を減圧下蒸発させた。粗生成物をカラムクロマトグラフィーによりシリカゲル(MeOH:DCM 10:90)で精製して黄色がかった固体のZ−Val−Cit−PABA−7HC(29mg、収率71%)を得た。MS(ES+):m/z C35H39N5O8の計算値:657.28;実測値:680.52[M+Na」+。
化合物3b。スキーム8に示されているように、化合物3a(Dubowchik et al.,2002)(100mg、0.2mmol、1当量)をACN 7mLに溶解し、0℃まで冷却した。ヨウ化ナトリウム(90mg、0.6mmol、3当量)を添加し、次いで、TMS−Cl(78μL、0.6mmol、3当量)を直ぐに添加した。反応物を放置して室温まで温めてTLC(MeOH:DCM 10:90)によってモニターした。完了次第、反応混合物をEtOAcで希釈し、飽和Na2S2O3、次いで塩水で洗浄した。有機層を分離し、Na2SO4で乾燥し、ろ過し、減圧下溶媒を蒸発させて黄色がかった固体の化合物3b(108mg、収率76%)を得た。MS(ES+):m/z C33H38IN5O5の計算値:711.19;実測値:712.5[M+H」+。1H NMR(400MHz,DMSO) δ 10.10(d,J=7.4Hz,1H),8.13(d,J=7.1Hz,1H),7.87(d,J=7.4Hz,2H),7.73(t,J=7.4Hz,2H),7.59(d,J=8.2Hz,1H),7.52(d,J=8.2Hz,2H),7.46−7.25(m,4H),7.21(s,1H),4.70(s,1H),4.60(s,1H),4.41(s,2H),4.34−4.15(m,4H),3.94−3.89(m,2H),3.00(s,1H),2.94(s,1H),1.97(d,J=6.4Hz,1H),1.67(s,1H),1.59(s,1H),1.50−1.26(m,2H),1.21(s,1H),0.86(d,J=6.8Hz,3H),0.84(d,J=6.7Hz,3H)。13C NMR(101MHz,DMSO) δ 171.84,171.23,159.46,156.65,144.43,144.30,141.23,139.50,132.96,130.06,128.18,127.61,125.90,120.64,120.11,119.64,118.09,66.20,63.11,60.57,57.25,53.64,47.21,46.71,39.83,39.63,39.42,30.97,29.93,29.53,27.29,19.75,18.82。
173.82,171.24,166.96,159.43,153.55,139.87,139.72,138.42,137.91,131.01,130.77,130.11,129.88,129.26,128.19,126.40,120.58,119.41,76.02,59.72,57.06,53.17,52.16,40.04,39.83,39.62,39.41,38.96,38.63,36.98,32.92,31.62,30.46,29.55,28.08,27.26,22.60,19.85,17.61,14.50。
;実測値:790.4[(M+Na)/2」+。
06,60.53,58.62,53.54,53.29,52.27,49.94,40.74,40.54,40.33,40.12,39.91,39.70,39.49,36.46,36.40,33.88,33.78,33.65,32.42,32.23,31.77,31.44,30.94,30.07,29.57,29.21,27.34,26.08,25.79,22.66,19.77,18.70。
化合物4b。スキーム13に示されているように、化合物3d(10mg、0.013mmol、1当量)および化合物4a(Ikeda et al.,2012)をDMF(0.5mL)に溶解し、Et3N数滴を添加した。反応をRP−HPLC(水中ACN
30〜100%、20分)によりモニターした。完了次第、減圧下反応混合物を濃縮した。粗生成物をさらに精製しないでさらに反応させた。粗生成物および数ミリグラムのメチレンブルーをDCM 5mLおよびDMF数滴(溶解性を向上させるため)に溶解した。黄色光を照射しながら、酸素を溶液全体にバブリングした。反応をRP−HPLC(水中ACN 30〜100%、20分)によりモニターした。完了次第、反応混合物を減圧下蒸発させることにより濃縮した。粗生成物を分取RP−HPLC(水中ACN 30〜100%、20分)により精製して白色固体の化合物4b(11mg、収率76%)を得た。MS(ES+):m/z C50H63ClN6O12の計算値:974.42;実測値:975.8[M+H」+。1H NMR(400MHz,DMSO) δ 10.02(s,1H),8.09(d,J=7.5Hz,1H),7.94(d,J=8.4Hz,1H),7.78(t,J=9.4Hz,2H),7.70(d,J=16.2Hz,1H),7.60(d,J=8.5Hz,2H),7.32(d,J=7.2Hz,2H),6.98(s,2H),6.67(d,J=16.2Hz,1H),5.97(s,1H),5.40(s,2H),4.95−4.80(m,2H),4.37(d,J=5.4Hz,1H),4.26−4.10(m,1H),3.71(s,3H),3.35(t,J=7.0Hz,3H),3.10(s,3H),3.06−2.97(m,1H),2.97−2.89(m,1H),2.87(s,1H),2.29−2.02(m,3H),1.99−1.85(m,2H),1.79−1.52(m,9H),1.47(dd,J=14.3,7.9Hz,6H),1.32(d,J=11.3Hz,2H),1.18(dd,J=17.9,10.0Hz,3H),0.84(d,J=6.7Hz,3H),0.80(d,J=6.7Hz,3H)。13C NMR(101MHz,DMSO) δ 172.80,171.61,171.22,166.74,159.43,154.25,139.89,137.90,134.99,130.19,127.40,121.79,119.37,111.72,95.96,76.27,58.07,53.63,52.24,49.96,39.83,39.62,39.42,37.54,36.39,35.45,33.58,32.18,31.38,30.93,29.82,28.30,27.36,26.31,26.02,25.69,25.44,19.78,18.72。
30〜100%、20分)によりモニターした。完了次第、反応混合物を減圧下蒸発させることにより濃縮した。粗生成物を分取RP−HPLC(水中ACN 30〜100%、20分)により精製して白色固体のプローブ4(8mg、収率68%)を得た。MS(ES+):m/z C73H109ClN16O18Sの計算値:1566.26;実測値:784.1[(M+H)/2」+。1H NMR(400MHz,DMSO) δ 10.06(s,1H),8.88−8.74(m,1H),8.36(s,2H),8.23−8.06(m,4H),7.93(t,J=12.1Hz,1H),7.85−7.74(m,9H),7.71(d,J=16.2Hz,1H),7.60(t,J=7.5Hz,2H),7.33(d,J=8.4Hz,3H),6.70−6.65(m,1H),6.05(s,1H),4.93−4.83(m,2H),4.46−4.02(m,13H),3.85(s,2H),3.71(s,3H),3.33(dd,J=14.4,7.3Hz,2H),3.24−2.90(m,8H),2.87(s,1H),2.71(dd,J=13.8,9.6Hz,4H),2.52(d,J=3.0Hz,1H),2.28−2.04(m,2H),2.01−1.86(m,1H),1.76−1.40(m,28H),1.37−1.26(m,6H),1.23−1.11(m,3H),0.85(d,J=6.7Hz,3H),0.81(d,J=6.8H
z,3H)。13C NMR(101MHz,DMSO) δ 177.35,175.41,173.84,172.76,171.95,171.85,171.23,168.35,167.82,166.74,159.53,159.12,158.80,157.34,154.24,139.88,137.89,134.85,131.77,130.72,130.19,128.87,127.39,126.57,121.77,119.37,118.78,115.83,111.71,95.95,76.26,57.99,53.63,52.67,52.55,52.24,49.95,42.52,40.02,39.81,39.61,39.40,39.21,39.09,38.71,36.39,35.45,33.81,33.59,32.19,31.60,31.38,30.99,30.88,29.84,27.35,27.11,26.36,26.02,25.69,25.45,22.85,22.76,19.78,18.70。
活性緩衝液は:リン酸緩衝液0.1M、55mM NaCl、1mM EDTA、5mMグルタチオンを含有した。全分光分析測定を3回反復して行った。検出限界算出のためのブランク測定を10回反復した。検出限界(LOD)をこのように算出した:
LOD=Meanblank+3×SD
式中のSDは標準偏差。
化学発光画像を、EMCCDカメラ(浜松ホトニクスC9100−13)を取り付けたオリンパスLV200倒立顕微鏡を用いて得た。RAW264.7アベルソンマウス白血病ウイルス誘発腫瘍細胞、CT26CL25結腸がん細胞およびNIH3T3マウス線維芽(コントロール)細胞を、37℃、24時間、35mmガラス底ペトリ皿上で増殖させた。細胞培養培地を、5μMのプローブMR3−128またはMR3−131を含むMolecular Probes(登録商標)生細胞イメージング溶液へ変更した。37℃で更に20分間、細胞をインキュベートした。化学発光の可視化のため、画像を露光時間20分で記録した。
この試験では、プローブ1、2、3および4として本明細書で同定された4つのプローブを実験項に記載されているように合成した。プローブ1はカテプシンB不安定保護基を有する従来のシャープアダマンチリデン・ジオキセタン系であり、一方、プローブ2は長いπ系および電子求引基を付加して構築した。このドナーアクセプタ対デザインは、生理的条件下発光団の発光を増大させて、酵素活性を用いた一段階アッセイ、および生細胞イメージングのための良好な発光団の役割をすることを可能とする。水中溶解性および細胞に侵入するプローブの可能性を向上させるために、本発明者らはプローブ3および4も合成した。プローブ3では、N−カルボキシベンジル(Cbz)付加物を中程度の長さのPEGに置き換えた。PEGは、水可溶性であり、結合分子の薬物速度論的特性を改良し、FDA承認されているので、生体に適用可能な系の構築物において広く利用されている。
プローブ5(PSAプローブ)の合成
化合物5a。スキーム15に示されているように、Fmoc−グルタミン(Fmoc−Gln)(380mg、1.03mmol、1当量)およびp−アミノベンジルアルコール(133mg、1.08mmol、1.05当量)をTHF(7mL)に溶解し、EEDQ(266.3mg、1.08、1.05当量)を添加した。16時間後、混合物を30℃で蒸発乾固させて、残渣をエーテル(15mL)でトリチュレートした。得られたオフホワイト固体生成物をろ過によって集め、エーテルで洗浄し、真空乾燥した(467mg、96%)。
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Claims (26)
- 式IaまたはIbの化合物であって、
式中、
R1は、直鎖もしくは分岐鎖(C1〜C18)アルキル、または(C3〜C7)シクロアルキルから選択され;
R2およびR3は、各々独立して、分岐鎖(C3〜C18)アルキルもしくは(C3〜C7)シクロアルキルから選択されるか、またはR2およびR3はこれらが結合している炭素原子と一緒になって縮合環、スピロ環もしくは架橋環もしくは多環式環を形成し;
R4は、式:
の基であり;
R5はHまたは−O−R4基に対してオルト位もしくはパラ位のいずれかで結合したハロゲンであり;
Aは−O−R4基に対してオルト位もしくはパラ位のいずれかで結合した式−CH=CH−Eのπ*アクセプター基であり、Eは−CN、−COOH、−COO(C1〜C18)アルキル、4−ピリジニル、メチルピリジニウム−4−イル、3,3−ジメチル−3H−インドリル、または1,3,3−トリメチル−3H−インドール−1−イウム−2−イルであり;
Pep1は、少なくとも2個のアミノ酸残基からなるプロテアーゼ切断可能ペプチド部分であり、そのカルボン酸基を介して前記アニリン基と結合しており、前記ペプチド部分は保護されていてもよく、そのアミノ基によりポリエチレングリコール(PEG)含有基と結合していてもよく;
Lは存在しないか、またはPep1のカルボン酸基もしくはアミノ基のいずれかによりPep1とアミド結合を介して結合したリンカーであり;
Pep2は存在しないか、またはそのアミノ基もしくはカルボン酸基によりアミド結合を介して、もしくはそのチオール基のいずれかによりLと結合した細胞透過性ペプチド部分であり、
但し、LおよびPep2は、両方共に、存在しないか、または存在し、Pep1が保護されているかもしくはPEG含有基と結合している場合、LおよびPep2は存在しない、化合物。 - R1は、直鎖または分岐鎖(C1〜C8)アルキルである、請求項1に記載の化合物。
- R2およびR3はこれらが結合している炭素原子と一緒になって縮合環、スピロ環もしくは架橋環もしくは多環式環を形成する、請求項1に記載の化合物。
- R2およびR3はこれらが結合している炭素原子と一緒になってアダマンチルを形成する、請求項3に記載の化合物。
- R5は、−O−R4基に対してオルト位もしくはパラ位のいずれかで結合したハロゲンである、請求項1に記載の化合物。
- Aは−O−R4基に対してオルト位に結合した−CH=CH−Eであり、Eは−CN、−COOH、−COO(C1〜C8)アルキル、4−ピリジニル、メチルピリジニウム−4−イル、3,3−ジメチル−3H−インドリル、または1,3,3−トリメチル−3H−インドール−1−イウム−2−イルである、請求項1に記載の化合物。
- Eは、−CN、−COOH、または−COO(C1〜C4)アルキルである、請求項6に記載の化合物。
- R1は、直鎖または分岐鎖(C1〜C8)アルキルであり;
R2およびR3はこれらが結合している炭素原子と一緒になって縮合環、スピロ環もしくは架橋環もしくは多環式環を形成し;
R5は、−O−R4基に対してオルト位に結合したハロゲンであり;
Aは、−O−R4基に対してオルト位に結合した−CH=CH−Eであり、Eは、−CN、−COOH、−COO(C1〜C8)アルキル、4−ピリジニル、メチルピリジニウム−4−イル、3,3−ジメチル−3H−インドリル、または1,3,3−トリメチル−3H−インドール−1−イウム−2−イルである、
請求項1に記載の化合物。 - R1はメチルであり;R2およびR3はこれらが結合している炭素原子と一緒になってアダマンチルを形成し;R5は−O−R4基に対してオルト位に結合したハロゲンであり;Eは−CN、−COOH、−COO(C1〜C4)アルキルである、請求項8に記載の化合物。
- Eは、−CN、−COOH、−COOCH3、または−COOC(CH3)3である、請求項9に記載の化合物。
- Pep1は、アミノ酸配列Val−Cit、Phe−Lys、Gly−Phe−Leu−Gly、Gly−Gly−Pro−Nle、Ala−Ala−AsnまたはHis−Ser−Ser−Lys−Leu−Glnを含むまたはからなるペプチド部分であり、前記アミノ酸配列は(i)それぞれ、シトルリン、リジン、グリシン、ノルロイシン、アスパラギンまたはグルタミンのカルボン酸基を介して前記アニリン基と結合し;(ii)そのアミノ基において保護されていてもよく、アミド結合を介して前記アミノ基によりPEG含有基と結合していてもよい、請求項1〜10のいずれか一項に記載の化合物。
- Pep1は、それぞれ、シトルリン、リジン、グリシン、ノルロイシン、アスパラギンまたはグルタミンのカルボン酸基を介して前記アニリン基と結合された配列Val−Ci
t、Phe−Lys、Gly−Phe−Leu−Gly、Gly−Gly−Pro−Nle、Ala−Ala−AsnまたはHis−Ser−Ser−Lys−Leu−Glnのペプチド部分であり、それぞれ、バリン、フェニルアラニン、グリシン、グリシン、アラニンまたはヒスチジンのαアミノ基においてアミノ保護基により保護されている、請求項11に記載の化合物。 - Pep1は、それぞれ、シトルリン、リジン、グリシン、ノルロイシン、アスパラギンまたはグルタミンのカルボン酸基を介して前記アニリン基と結合したアミノ酸配列Val−Cit、Phe−Lys、Gly−Phe−Leu−Gly、Gly−Gly−Pro−Nle、Ala−Ala−AsnまたはHis−Ser−Ser−Lys−Leu−Glnを含むまたはからなるペプチド部分であり;LはPep1のカルボン酸基またはアミノ基のいずれかによりアミド結合を介してPep1と結合したリンカーであり;Pep2はそのチオール基によりLと結合したペプチド部分である、請求項1〜10のいずれか一項に記載の化合物。
- R1はメチルであり;R2およびR3はこれらが結合している炭素原子と一緒になってアダマンチルを形成し;R5は−O−R4基に対してオルト位に結合したClであり;Aは−O−R4基に対してオルト位に結合した−CH=CH−Eであり;Eは−COOCH3または−CNであり;
(i)Pep1は、シトルリンのカルボン酸基を介して前記アニリン基と結合した配列Val−Citのペプチド部分であり、バリンのアミノ基においてカルボキシベンジルに
より保護されており;
(ii)Pep1は、グルタミンのカルボン酸基を介して前記アニリン基と結合した配列His−Ser−Ser−Lys−Leu−Glnのペプチド部分であり、ヒスチジンのαアミノ基においてN-モルホリンカルボニルにより保護されており;
(iii)Pep1は、シトルリンのカルボン酸基を介して前記アニリン基と結合した配列Val−Citのペプチド部分であり、バリンのアミノ基を介して式:
(式中、nは17である。)
のPEG含有基と結合しているか;または
(iv)Pep1は、それぞれ、シトルリンもしくはグルタミンのカルボン酸基を介して前記アニリン基と結合した配列Val−CitもしくはHis−Ser−Ser−Lys−Leu−Glnのペプチド部分であり;Lは、それぞれ、バリンもしくはヒスチジンのαアミノ基によりアミド結合を介してPep1と結合した式:
(式中、mは5の整数である。)
のリンカーであり、Pep2は前記システイン残基のチオール基によりLと結合した配列Cys−Gly−Lys−Arg−Lysのペプチド部分である、
請求項1に記載の化合物。 - 表2の化合物Ib−1a、Ib−1b、Ib−2a、Ib−2b、Ib−3a、Ib−3b、Ib−4a、Ib−4b、Ib−5a、またはIb−5bから選択される、請求項17に記載の化合物。
- 請求項1〜18に記載の化合物および担体を含む組成物。
- 請求項17または18に記載の化合物を含む、請求項19に記載の組成物。
- 診断またはイメージングにおいてインビボで使用するための、請求項19または20に記載の組成物。
- 診断またはイメージングにおいてインビボで使用するための、請求項1〜18のいずれか一項に記載の化合物。
- サンプル中のプロテアーゼの存在の決定方法、またはそのレベルの測定方法であって、前記方法は:
(i)Pep1が前記プロテアーゼにより切断可能な基である、請求項1〜18のいずれか一項に記載の化合物と、または前記化合物を含む組成物と、前記サンプルとを接触させて、これにより前記化合物を、前記サンプル中に存在する場合に前記プロテアーゼにより発光性化学種に加水分解すること、および
(ii)前記発光性化学種の化学発光を検出すること、
を含む、方法。 - 前記サンプルは生体サンプルである、請求項23に記載の方法。
- 前記生体サンプルは体液、体液系溶液、または組織生検サンプルである、請求項24に記載の方法。
- 前記プロテアーゼは、カテプシンA、B、C、D、E、F、G、H、K、L1、L2、O、S、WおよびZなどのカテプシン、レグマイン、前立腺特異抗原(PSA)、またはメタロプロテアーゼである、請求項23〜25のいずれか一項に記載の方法。
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WO2021165959A1 (en) * | 2020-02-19 | 2021-08-26 | Ramot At Tel-Aviv University Ltd. | Chemiluminescence probes for tuberculosis |
CN117769549A (zh) * | 2021-08-11 | 2024-03-26 | 南洋理工大学 | 用于检测和成像的超亮化学发光探针 |
CN114315791B (zh) * | 2021-12-22 | 2023-12-08 | 东南大学 | 用于实现手术导航和微小转移瘤成像的小分子化学发光探针及其制备方法和用途 |
CN114380786B (zh) * | 2021-12-23 | 2023-03-24 | 苏州大学 | 基于氨基肽酶激活型化学发光探针及其在恶性肿瘤的活体检测与手术导航方面的应用 |
CN114716407A (zh) * | 2022-03-16 | 2022-07-08 | 大连理工大学 | 一种检测泛酰巯基乙胺酶活性的化学发光探针、制备方法及其生物应用 |
CN115819416A (zh) * | 2022-11-29 | 2023-03-21 | 遵义医科大学 | 一种用于检测和区分的多模态化学发光分子及其应用 |
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US20100278745A1 (en) * | 2006-12-21 | 2010-11-04 | Norbert Lange | Compounds for fluorescence imaging |
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JP2021525273A (ja) * | 2018-05-25 | 2021-09-24 | ネミス テクノロジーズ アクチェンゲゼルシャフト | ジオキセタン化合物及び微生物検出のためのそれらの使用 |
JP7462574B2 (ja) | 2018-05-25 | 2024-04-05 | ネミス テクノロジーズ アクチェンゲゼルシャフト | ジオキセタン化合物及び微生物検出のためのそれらの使用 |
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EP3630742A1 (en) | 2020-04-08 |
ES2963606T3 (es) | 2024-04-01 |
WO2018216012A1 (en) | 2018-11-29 |
EP3630742C0 (en) | 2023-08-16 |
US20200277647A1 (en) | 2020-09-03 |
PL3630742T3 (pl) | 2024-04-08 |
CN110944985B (zh) | 2022-12-13 |
EP3630742B1 (en) | 2023-08-16 |
EP3630742A4 (en) | 2021-03-03 |
CN110944985A (zh) | 2020-03-31 |
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