CN116836161A - Parp1抑制剂 - Google Patents
Parp1抑制剂 Download PDFInfo
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- CN116836161A CN116836161A CN202210305728.XA CN202210305728A CN116836161A CN 116836161 A CN116836161 A CN 116836161A CN 202210305728 A CN202210305728 A CN 202210305728A CN 116836161 A CN116836161 A CN 116836161A
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- Prior art keywords
- compound
- cancer
- pharmaceutically acceptable
- added
- parp1
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Abstract
本发明属于医药化学领域，涉及选择性抑制PARP1的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，化合物及其应用，具体地，本发明提供式Ia所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，以及含有其的药物组合物和这些化合物或组合物用于治疗和/或预防抑制PARP1有益的疾病，例如癌症的应用。
Description
技术领域
本发明属于医药化学领域，具体涉及抑制聚(ADP-核糖)聚合酶1(Poly(ADP-ribose)polymerase 1,PARP1)的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，以及含有其的药物组合物和这些化合物或组合物用于治疗和/或预防抑制PARP1有益的疾病，例如癌症的用途。
背景技术
聚(ADP-核糖)聚合酶(Poly(ADP-ribose)polymerase，PARP)是存在于真核细胞中催化聚ADP核糖化的细胞核酶，它参与的聚ADP核糖化是真核细胞中蛋白质翻译后的重要修饰方式之一。目前已经发现18个PARPs能够以NAD+为底物，催化合成聚(ADP-核糖)(PAR)聚合物。
PARP1是第一个被发现具有催化聚ADP核糖化修饰活性的蛋白，能够以NAD+为底物合成直线状和多枝状的PAR聚合物。PARP1是由1014个氨基酸组成，分为三个主要区域：(1)含有2个锌指基序的DNA结合区域(N端)；(2)由两个核定位信号序列组成且具有capase-3酶切功能的中间区域；以及(3)具有催化功能，以NAD+为底物催化聚腺苷二磷酸核糖合成的区域(C端)。PARP1除了修复DNA损伤之外，还有一系列重要的生理功能，包括在骨髓、血液系统中参与细胞分化。PARP1在细胞核中起到修复单链DNA断裂(SSB)和双链断裂(DSB)的作用，包括同源重组(HR)和非同源末端连接(NHEJ)修复。BRCA1(乳腺癌易感基因1)和BRCA2(乳腺癌易感基因2)是两种关键的抑癌基因，它们在损伤修复、细胞的正常生长方面有重要作用。如果BRCA1/2蛋白中的一种或两种有突变或缺陷，则细胞更加强烈地依赖PARP介导的DNA修复途径。
PARP2与PARP1具有69％的同源性，同样有DNA损伤应激活性，但其DNA绑定结构域和PARP1的不同。Fanes等人研究表明PARP2在红细胞分化和血小板生成中有重要作用(CellDeath Differ 2015；22:1144-1157)，Yelamos等人研究表明在小鼠体内PARP2在维持造血干细胞稳定发挥重要作用(Blood.2013；122,44-54)。PARP2还在脂肪细胞分化、T-cell生成等方面有着一定作用(Oncogene.2010；29(19):2877-2883)。还有研究表明，髓样缺失PARP2会增加骨髓中不成熟髓细胞的数目并增加趋化因子如CCL3的表达，进而增大乳腺癌发生骨转移的几率。此外，对目前已上市的非选择性PARP1/2抑制剂奥拉帕利、尼拉帕利和卢卡帕利的临床不良反应研究表明，它们的副作用有肾毒性、胃肠毒性和血液毒性等，这些可能与对PARP2的抑制剂有关(Lancet Oncology,2019,20(1):15-28)。
结合PARP1/2的生理功能和已上市药物的不良反应，开发新的能降低相关不良反应，特别是改善血液毒性的PARP1型选择性抑制剂将具有很好的临床前景。
发明内容
本发明的一个目的是提供式Ia所示的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，
本发明的另一个目的是提供包含本发明的式Ia的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药和药学可接受的载体的组合物，以及包含本发明的式Ia的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药和另一种或多种抗肿瘤药物的组合物。
本发明的还一个目的是提供本发明的式Ia的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药或药物组合物在制备治疗和/或预防抑制PAPR1有益的疾病的药物的应用。
针对上述目的，本发明提供以下技术方案：
第一方面，本发明提供式Ia所示的化合物，
或其药学上可接受的盐、异构体、溶剂化物、结晶或前药。
在一些实施方案中，根据本发明的式Ia的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，其中所述式Ia的化合物为游离碱形式。在另一些实施方案中，根据本发明的式Ia的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，其中所述式Ia的化合物为药学上可接受的酸或碱的盐的形式。在一些具体的实施方案中，所述药学上可接受的盐包括乙酸盐、己二酸盐、抗坏血酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、胆碱、柠檬酸盐、环己基氨基磺酸盐、二亚乙基二胺、乙磺酸盐、延胡索酸盐、谷氨酸盐、乙醇酸盐、半硫酸盐、2-羟乙基磺酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基马来酸盐、乳酸盐、苹果酸盐、马来酸盐、甲磺酸盐、葡甲胺、2-萘磺酸盐、硝酸盐、草酸盐、双羟萘酸盐、过硫酸盐、苯乙酸盐、磷酸盐、磷酸氢盐、苦味酸盐、新戊酸盐、丙酸盐、奎尼酸盐、水杨酸盐、硬脂酸盐、琥珀酸盐、氨基磺酸盐、氨基苯磺酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐、对甲苯磺酸盐、三氟乙酸盐及十一烷酸盐等。在另一些具体的实施方案中，所述药学上可接受的盐为盐酸盐、磷酸盐、硫酸盐、氢溴酸盐、柠檬酸盐、马来酸盐、丙二酸盐、扁桃酸盐、琥珀酸盐、富马酸盐、醋酸盐、乳酸盐或硝酸盐。
另一方面，本发明提供一种药物组合物，其包含本发明的式Ia的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药和药学上可接受的载体。
在一些实施方案中，本发明提供药物组合物，其包含本发明的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，还包含其他一种或多种抗肿瘤化疗药物或抗体。
可以将本发明的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药与药学上可接受的载体、稀释剂或赋形剂混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于经口途径，皮内、肌内、腹膜内、静脉内、皮下和鼻内。所述制剂可以通过任何途径施用，例如通过口服，通过输注或推注，通过经上皮或皮肤黏膜(例如口腔黏膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。在一些优选的实施方案中，所述药物制剂是片剂或胶囊剂。
第三方面，本发明提供本发明式Ia所示的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，或包含其的药物组合物在制备治疗和/或预防抑制PARP1有益的疾病的药物中的用途。在一些实施方案中，所述的疾病是癌症。在一些具体的实施方案中，所述癌症是乳腺癌、卵巢癌、胰腺癌、前列腺癌、血液肿瘤、胃肠道肿瘤如胃癌和结肠癌，以及肺癌。在另一些具体的实施方案中，所述癌症为肝癌、肾癌、黑色素瘤、甲状腺肿瘤、胆管癌、恶性淋巴肿瘤、膀胱癌和肉瘤。
在一些实施方案中，本发明涉及一种治疗癌症的方法，其包括给予所需患者治疗有效量的式Ia所示的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药，或包含其的药物组合物。在一些具体的实施方案中，所述癌症是乳腺癌、卵巢癌、胰腺癌、前列腺癌、血液肿瘤、胃肠道肿瘤如胃癌和结肠癌，以及肺癌。在另一些具体的实施方案中，所述癌症为肝癌、肾癌、黑色素瘤、甲状腺肿瘤、胆管癌、恶性淋巴肿瘤、膀胱癌和肉瘤。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明的“溶剂合物”在常规意义上是指溶质(如活性化合物、活性化合物的盐)和溶剂(如水)组合形成的复合物。溶剂是指本领域的技术人员所知的或容易确定的溶剂。如果是水，则溶剂合物通常被称作水合物，例如一水合物、二水合物、三水合物等。
本发明的“结晶”是指本发明所述的化合物形成的各种固体形态，包括晶型、无定形。
本发明的“异构体”是指化合物的顺式或反式构型的异构体。因此，本发明包括每种顺式异构体或反式异构体而基本不含其它异构体以及这些异构体的混合物。
本发明的“前药”是指在生物体的生理条件下，由于与酶、胃酸等反应而转化成本发明的化合物的化合物，即通过酶的氧化、还原、水解等转化成本发明的化合物的化合物和/或通过胃酸等的水解反应等转化成本发明的化合物的化合物。
本发明的“药物组合物”是指包含任何一种本文所述的化合物，包括异构体、前药、溶剂合物、药学上可接受的盐或其化学的保护形式，和一种或多种药学上可接受载体的混合物。
本发明的“药学上可接受的载体”是指对有机体不引起明显刺激性和不干扰所给予化合物的生物活性和性质的载体，包含溶剂、稀释剂或其它赋形剂、分散剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。除非任何常规载体介质与本发明化合物不相容。可以作为药学上可接受的载体的一些实例包括，但不限于糖类，如乳糖、葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲基纤维素钠、以及纤维素和乙酸纤维素；麦芽、明胶等。
本发明的“赋形剂”指加入到药用组合物中以进一步促进给予化合物的惰性物质。赋形剂可以包括碳酸钙、磷酸钙、多种糖类和多种类型的淀粉、纤维素衍生物、明胶、植物油、聚乙二醇。
本发明的“在制备用于治疗或预防肿瘤的药物中的应用”是指可以抑制肿瘤的生长、发展和/或转移，主要向所需要的人或动物给治予治疗有效剂量的本发明的化合物以抑制、减慢或逆转受治疗者肿瘤的生长、发展或扩撒。
本发明的化合物中的“氢”、“碳”、“氧”包括其所有同位素。同位素应理解为包括具有相同原子数但具有不同质量数的那些原子。举例来说，氢的同位素包括氕、氚和氘，碳的同位素包括13C和14C，氧的同位素包括16O和18O等。
具体实施方式
下面代表性的实施例是为了更好地说明本发明，而非用于限制本发明的保护范围。以下实施例中使用的材料如无特殊说明均为商购获得。
实施例1:1'-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-1',2',3',6'-四氢-[3,4'-联吡啶]-6-甲酰胺
步骤1:5-丁酰氨基-6-甲基烟酸乙酯的制备
将5-氨基-6-甲基烟酸乙酯(3.6g,20mmol,1.0eq)和三乙胺(3.03g,30mmol,1.5eq)加入到双口瓶中，用氮气进行置换气，通过注射器向反应瓶中加入无水二氯甲烷(40mL)，反应液冷却至0℃。将丁酰氯(2.54g,24mmol,1.2eq)溶于二氯甲烷(5mL)后缓慢滴加到反应溶液中。滴加完毕后，将反应液移至室温反应5h，TLC点板显示反应完全。反应液过滤后，滤液中加水(20mL)，分离的水相用二氯甲烷(20mL)萃取两次，合并的有机相用饱和氯化钠洗涤，无水硫酸钠干燥后，减压浓缩，柱层析分离纯化得到标题化合物。ESI-MS m/z:251.1[M+H]+.
步骤2:5-丁酰氨基-6-甲酰基烟酸乙酯的制备
将5-丁酰氨基-6-甲基烟酸乙酯(3.75g,15mmol,1.0eq)和二氧化硒(2.5g,22.5mmol,1.5eq)加入到二氧六环中(20mL)，反应液置于110℃搅拌16h。TLC点板监测反应完成后，将反应液冷却至室温，反应液抽滤，滤液浓缩后柱层析分离纯化得到标题化合物。ESI-MS m/z:265.1[M+H]+.
步骤3:7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-羧酸乙酯的制备
将5-丁酰氨基-6-甲酰基烟酸乙酯(2.64g,10mmol,1.0eq)溶于无水N,N-二甲基甲酰胺(20mL)中，向该溶液中缓慢加入碳酸铯(6.52g,20mmol,2.0eq)，在70℃下反应3h。TLC点板显示反应完全后，将反应液冷却至室温，抽滤。在滤液中加水(500mL)，并用乙酸乙酯进行萃取(3x100 mL)，饱和食盐水洗涤后，有机相用无水硫酸钠干燥，减压浓缩，柱层析分离得到标题化合物。ESI-MS m/z:247.1[M+H]+.
步骤4:3-乙基-7-(羟甲基)-1,5-萘啶-2(1H)-酮的制备
将7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-羧酸乙酯(0.5g,2mmol,1.0eq)加入到双口瓶中，加入无水四氢呋喃(15mL)。反应液冷却至0℃，将氢化铝锂(304mg,8mmol,4.0eq)缓慢加入到反应液中，然后室温搅拌3小时。TLC点板显示反应完全，缓慢加入饱和氯化铵(30mL)淬灭反应，加入二氯甲烷/乙醇(5:1，100mL)萃取3次，合并的有机相用无水硫酸钠干燥，抽滤，滤液浓缩，得到标题化合物。ESI-MS m/z:205.1[M+H]+.
步骤5:7-(氯甲基)-3-乙基-1,5-萘啶-2(1H)-酮的制备
将3-乙基-7-(羟甲基)-1,5-萘啶-2(1H)-酮(200mg,0.98mmol)加入到二氯甲烷中(5mL)，加入N,N-二甲基甲酰胺(4.3mg，0.1mmol，0.1eq)，0℃下滴加氯化亚砜(0.4mL，6mmol,6.0eq)。滴加完毕后，反应混合物室温搅拌5h，LC-MS监测反应完毕后，减压浓缩反应液得到标题化合物。ESI-MS m/z:223.2[M+H]+.
步骤6:1'-(叔丁基)6-甲基3',6'-二氢-[3,4'-联吡啶]-1',6(2'H)-二羧酸酯的制备
将5-溴吡啶-2-羧酸甲酯(2.0g,9.3mmol,1.0eq)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(3.45g,11.2mmol,1.2eq)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(1.36g，1.86mmol,0.2eq)和碳酸钾(2.57g,18.6mmol,2.0eq)加入到1,4-二氧六环(20mL)和水(0.3mL)的混合溶剂中。反应体系置换氮气后，102℃加热回流反应3h。LC-MS跟踪监测反应完毕，反应液减压浓缩。柱层析分离得到标题化合物。ESI-MS m/z:319.2[M+H]+.
步骤7:1',2',3',6'-四氢-[3,4'-联吡啶]-6-羧酸甲酯盐酸盐的制备
取1'-(叔丁基)6-甲基3',6'-二氢-[3,4'-联吡啶]-1',6(2'H)-二羧酸酯(300mg，0.94mmol，1.0eq)于反应瓶中，加入无水甲醇溶解，冰浴至0℃后，加入盐酸-二氧六环溶液(4M,2.35mL,9.4mmol,10.0eq)，移至室温搅拌反应4h。LC-MS跟踪监测反应，反应完毕。反应液减压浓缩，得到标题化合物。ESI-MS m/z:219.1[M+H]+.
步骤8:1'-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-1',2',3',6'-四氢-[3,4'-联吡啶]-6-羧酸甲酯的制备
将7-(氯甲基)-3-乙基-1,5-萘啶-2(1H)-酮(200mg,0.9mmol,1.0eq)，1',2',3',6'-四氢-[3,4'-联吡啶]-6-羧酸甲酯盐酸盐(235mg,1.08mmol,1.2eq)，N,N-二异丙基乙胺(0.78mL,4.5mmol,5.0eq)，碘化钾(30mg,0.18mmol,0.2eq)加入到乙腈(5mL)中，并80℃加热搅拌反应3h。LC-MS跟踪监测反应完毕，将反应混合物减压浓缩后，加入二氯甲烷稀释。加入饱和氯化铵水溶液(20mL)，用二氯甲烷(3x50mL)萃取，合并的有机相用无水硫酸钠干燥，浓缩，柱层析分离得到标题化合物。ESI-MS m/z:405.2[M+H]+.
步骤9:1'-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-1',2',3',6'-四氢-[3,4'-联吡啶]-6-甲酰胺的制备
将1'-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-1',2',3',6'-四氢-[3,4'-联吡啶]-6-羧酸甲酯(120mg，0.30mmol)加入到氨-甲醇溶液(7M,3mL)中，置于封管中50℃搅拌，12h后，LC-MS跟踪监测反应，反应完毕。反应液浓缩，得到标题化合物。ESI-MSm/z:390.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.70(s,1H),8.42(s,1H),8.05(s,1H),7.99(s,2H),7.76(s,1H),7.66(s,1H),7.60(s,1H),6.42(s,1H),3.73(s,2H),3.16(s,2H)，2.75-2.63(m,4H),2.33(s,2H),1.18(t,J＝4.0Hz,3H).
实施例2:1'-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-1',2',3',6'-四氢-[3,4'-联吡啶]-6-甲酰胺盐酸盐
步骤1:1'-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-1',2',3',6'-四氢-[3,4'-联吡啶]-6-甲酰胺盐酸盐的制备
将1'-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-1',2',3',6'-四氢-[3,4'-联吡啶]-6-甲酰胺(117mg,0.30mmol,1.0eq)加入甲醇(2mL)中，随后加入盐酸-二氧六环溶液(4M,75μL,0.30mmol,1.0eq)，搅拌1h，LC-MS检测反应完全。旋干溶剂，加水溶解，二氯甲烷萃取，冻干水相，得到标题化合物。ESI-MS m/z:390.2[M+H]+.
实验例1:PARP1/2酶抑制活性
1.实验材料
化合物准备：使用以上实施例2制备的本发明式Ia化合物盐酸盐，对于PARP1酶活实验，用DMSO配制成2.5mM后，依次4倍稀释至625μM、156.25μM、39.06μM、9.766μM、2.441μM、0.610μM、0.153μM、0.038μM、0.010μM。对于PARP2酶活实验，本发明式Ia化合物盐酸盐用DMSO配制30mM储备液，依次稀释3倍至10mM、3.3mM、1.1mM、0.367mM、0.122mM、0.041mM、0.0136mM、0.0045mM。
试剂：PARP1，购自于BPS公司，Cat.No.80501；PARP2，购自于BPS公司，Cat.No.80502)，Histone购自于Active Motif公司，Cat.No.811167；Activited DNA，购自于Genscript公司，Cat.No.L05182-01&02&03；anti-rabbit IgG，HRP-linked Antibody购自于CST公司，Cat.No.7074P2；anti-Poly/Mono-ADP Ribose(E6F6A)Rabbit mAb购自于CST，Cat.No.83732S；SuperSignal ELISA Femto Substrate购自于THERMO PIERCE公司，Cat.No.37074；Strep-HRP，购自于Thermo Pierce，Cat.No.21127)。
2.实验方法
2.1.在384孔板中加入组蛋白Histone溶液，每孔25μL，4℃孵育过夜。
2.2.制备PBST缓冲液、封闭液和检测液；
2.3.用PBST缓冲液清洗包被有组蛋白的384孔板3次。加入50μL封闭液，室温封闭1h。然后用PBST缓冲液清洗3次。
2.4.对于PARP1酶活实验，在一个96孔板中制备1000×的化合物，然后转移1μL到新的96孔板中进行稀释。1000rpm，离心1min。之后每孔转移5μL化合物或DMSO到384孔板中。对于PARP2酶活实验，在一个96孔板中制备2000×的化合物，然后转移50nL到新的96孔板中并加入39.95μL检测液。1000rpm，离心1min。之后每孔转移5μL化合物或DMSO到384孔板中。
2.5.提前将PARP1/PARP2和DNA混合后25℃下孵育10min。每孔加入10μLPARP1/PARP2&DNA，PARP1酶活实验最小对照板中加入10μL DNA，PARP2酶活实验最小对照板中加入10μL检测液。室温条件下孵育10min。然后加入2.5×NAD+，每孔10μL，25℃孵育60min。然后用PBST缓冲液清洗3次。
2.7.对PARP1酶活实验，每孔加入20μL anti-Poly/Mono-ADP Ribose RabbitmAb，室温孵育1.5小时，然后用PBST缓冲液清洗3次。加入稀释后的anti-rabbit IgG,HRP-linked Antibody(终止液1:2000进行稀释)，每孔20μL，室温孵育1h后，用PBST缓冲液清洗3次。对PARP2酶活实验，每孔加入25μL Stre-HRP，室温孵育1h后，用PBS缓冲液清洗3次。
2.8.每孔加入25μL Femto-ECLSubstrate A和Femto-ECLSubstrate B(1:1)的混合液之后，检测化学发光信号。利用公式：inh％＝(Max-Signal)/(Max-Min)×100，将数据拟合后得到IC50值，实验结果见表1。
表1
以上实验结果表明，本发明的化合物对PARP1酶抑制活性强，同时对PARP2酶抑制弱，具有非常好的PARP1选择性。
实验例2:PARP1/2DNA Trapping
1.实验材料
化合物准备：使用以上实施例2制备的本发明式Ia化合物盐酸盐，对于PARP1 DNATrapping，用DMSO配制成10μM后，依次4倍稀释至2500nM、625nM、156.25nM、39.06nM、9.766nM、2.441nM、0.610nM、0.153nM、0.038nM。对于PARP2 DNA Trapping，本发明式Ia化合物盐酸盐用DMSO配制成100μM后，依次4倍稀释至25μM、6.25μM、1562.5nM、390.625nM、24.414nM、6.104nM、1.526nM、0.381nM、0.095nM。
试剂：PARP1，购自于BPS公司，Cat.No.80501；PARP2，购自于BPS公司，Cat.No.80502；NAD购自于Sigma公司，Cat.No.10127965001；Activited DSB DNA probe-1，购自于Generay公司；PARP2 probe 2，购自于Generay公司；Mab anti GST-Tb cryptate，购自于cisbio公司，Cat.No.61GSTTLA；DMSO购自于Sigma，Cat.No.D8418。
2.实验方法
2.1.制备分析缓冲液：10mM磷酸钾(pH 7.9)、50mM NaCl、1mM EDTA、0.05％Brij-35、1mM DTT；
2.2.用分析缓冲液制备4×的PARP1和Mab anti GST-Tb cryptate混合液以及PARP2和Mab anti GST-Tb cryptate混合液；并将其分别加入到384孔板中，每孔4μL；
2.3.用分析缓冲液制备4×的DSB DNA probe1和PARP2 probe2，并将其分别加入到384孔板中，每孔4μL；
2.4.然后加入制备好的化合物溶液，每孔4μL，室温孵育；
2.5.用分析缓冲液制备4×的NAD溶液，每孔4uL，室温孵育10min；
2.6.检测化学发光信号。利用公式：％inhibition＝(Signal cmpd-Signal Ave_PC)/(Signal Ave_VC-Signal Ave_PC)×100，将数据拟合后得到IC50值，实验结果见表2。
表2
以上实验结果表明，本发明的化合物对PARP1抑制强，同时对PARP2没有抑制作用，具有非常好的PARP1选择性。
实验例3:对人结直肠癌细胞DLD-1(wt)增殖抑制
1.实验材料
受试化合物：使用以上实施例2制备的本发明式Ia化合物盐酸盐，用DMSO配制成20mM，然后依次3倍稀释为6666.6μM、2222.2μM、740.74μM、246.9μM、82.3μM、27.43μM、9.14μM、3.05μM。
人结直肠癌细胞DLD-1(wild type,wt)购于武汉普诺赛生命科技有限公司。
试剂：RPMI-1640，购自于美国Invitrogen公司；FBS，购自于美国Invitrogen公司；青链霉素，购自于美国Invitrogen公司；EDTA，购自于美国Invitrogen公司；Luminescent Cell Viability Assay Kit，购自于美国Progema公司；Backseal膜，购自于美国Perkin Elmer公司。
2.实验方法
2.1细胞培养：
细胞复苏：将细胞置于37度水浴中溶解，然后转移到15mL已预热的培养基中，1000rpm离心5分钟，弃去培养基。用15mL新鲜培养基重悬细胞，转移至培养皿中，置37℃，5％CO2、95％潮湿空气的CO2培养箱中培养，24小时后细胞更换新鲜培养基。
细胞传代：细胞生长至约80-90％融合，吸弃原有完全培养基，加入1mL的PBS将残余培养基洗净后吸弃，加入1mL胰蛋白酶消化液，镜下观察细胞伪足回缩变圆但细胞还未成片脱落，此时吸弃胰酶并用2mL完全培养基终止消化，轻轻吹打并收集细胞悬液，1000rpm，离心5min。去除上清，取分散均匀的细胞计数，调整合适的细胞浓度接种于培养皿中，置于37℃、5％CO2、95％潮湿空气的CO2培养箱中培养。
2.2实验步骤：
DLD-1细胞在培养皿中长至1×105-1×106个细胞/mL后，使用新鲜培养基(RPMI1640+10％FBS+1％青链霉素)重悬，并计数。将重悬的细胞调整细胞浓度至1×104个细胞/mL，每孔加入25μL(250个细胞/well)，并加入完全培养基75μL。每种浓度两复孔。24h后，在原有旧培养基(100μL)基础上，加入100μL稀释有不同浓度(2×)药物的培养基。药物处理7d后吸弃孔内培养基，尽量吸干，加入150μL已加入CTG的完全培养基(CTG:培养基＝1:1)，室温孵育10min后，检测化学发光信号，震荡，Read进样检测条件为500ms。药物处理7d后向待测孔加入100μLLuminescent Cell Viability Assay buffer。轻轻摇匀。10分钟后，在Assay板底部贴上Backseal膜，置于Envison上读取荧光读数，并计算细胞存活率(cell survive(％))，计算公式为cell survive(％)＝(Com-Min)/(Max-Min)，其中Max为溶媒对照组的读数，Min为无细胞对照组的读数，Com为化合物处理组的读数，数据经Graphpad Prism 6处理，拟合得IC50，实验结果见表3。
表3
从以上实验可以看出，本发明的化合物对野生型人结直肠癌细胞没有表现出抑制活性。
实验例4:对人结直肠癌细胞DLD-1(BRCA2-/-)增殖抑制
1.实验材料
受试化合物准备：使用以上实施例2制备的本发明式Ia化合物盐酸盐，用DMSO配制成10mM储备液后，依次4倍稀释至2500μM、625μM、156.25μM、39.06μM、9.766μM、2.441μM、0.610μM、0.153μM、0.038μM。
人结直肠癌细胞DLD-1(BRCA2-/-)购于ATCC。
试剂：CelltiterGlo assay kit(CTG)，购自Promega，Cat.No.G7573；384孔板，购自PerkinElmer，Cat.No.6007680。
实验步骤：细胞培养传代遵循ATCC的说明。将配好的化合物溶液吸取40nL到384孔板中，同时每孔加入6×102个细胞(悬液体积为40μL)，孵育7天，7天后每孔加入20μLCelltiterGlo assay kit试剂并读取化学发光值。％inhibition＝(Signal cmpd-SignalAve_PC)/(Signal Ave_VC-Signal Ave_PC)×100，将数据拟合后得到IC50值，实验结果见表4。
表4
从以上实验结果可以看出，本发明的化合物对BRCA2-/-人结直肠癌细胞具有显著的抑制活性。
尽管以上已经对本发明作了详细描述，但是本领域技术人员理解，在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述，而应归属于权利要求书。
Claims (7)
1.式Ia的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药：
2.一种药物组合物，其包含权利要求1所述的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药和药学上可接受的载体。
3.权利要求1所述的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药或权利要求2所述的药物组合物在制备治疗和/或预防肿瘤药物中的应用。
4.根据权利要求3所述的应用，其中所述肿瘤选自乳腺癌、卵巢癌、胰腺癌、前列腺癌、血液肿瘤、胃肠道肿瘤和肺癌。
5.权利要求1所述的化合物或其药学上可接受的盐、异构体、溶剂化物、结晶或前药或权利要求2所述的药物组合物在制备治疗和/或预防抑制PAPR1有益的疾病的药物中的应用。
6.根据权利要求5所述的应用，其中所述疾病为癌症。
7.根据权利要求6所述的应用，其中所述癌症选自乳腺癌、卵巢癌、胰腺癌、前列腺癌、血液肿瘤、胃肠道肿瘤和肺癌。
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