CN115322209B - 作为dna-pk抑制剂的三并环化合物 - Google Patents
作为dna-pk抑制剂的三并环化合物 Download PDFInfo
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- CN115322209B CN115322209B CN202210851965.6A CN202210851965A CN115322209B CN 115322209 B CN115322209 B CN 115322209B CN 202210851965 A CN202210851965 A CN 202210851965A CN 115322209 B CN115322209 B CN 115322209B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
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Abstract
本发明公开了式(I)所示的化合物、其立体异构体、光学异构体、药学上可接受的盐、前药或溶剂合物,可作为DNA‑PK抑制剂,用于治疗或者预防DNA‑PK介导的疾病,与化疗或放疗药物联用可进一步增强其效果,可有效抑制肿瘤生长。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一种作为DNA-PK抑制剂的三并环化合物,及其立体异构体、光学异构体、药学上可接受的盐、前药或溶剂合物。
背景技术
DNA依赖蛋白激酶(DNA-dependent protein kinase,DNA-PK)是细胞DNA损伤反应(DNAdamage response,DDR)过程中重要的组成部分。在肿瘤的治疗中,肿瘤细胞的DNA-PK是重要的药物靶点。DNA-PK是一类丝/苏氨酸蛋白激酶,参与并决定着非同源末端连接DNA损伤修复通路的整个进程。DNA-PK是由催化亚基DNA-PKcs和Ku70/80异二聚体组成的复合物,其中,Ku70/80异二聚体可以识别DNA断裂(DSBs)并募集激酶亚基DNA-PKcs。DNA-PK蛋白是DNA损伤修复的关键组成部分,它负责通过非同源末端连接(NHEJ)识别和修复双链DSBs。由于肿瘤细胞具有较高基础水平的内源复制压力和DNA损伤(癌基因诱导的复制压力)并且在肿瘤细胞中DNA修复机制效率较低,因此肿瘤细胞对DNA-PK的敏感性更高。目前,临床常用的放疗(IR)以及部分化疗药物(如拓扑异构酶抑制剂)的抗肿瘤原理都是引起DNA双键断裂,但是,肿瘤细胞中高表达的DNA-PK可将此类断裂修复从而产生耐药性。因此,寻找一种高选择性的DNA-PK抑制剂,并且与现有的可引起DNA双链断裂的治疗手段联合使用,以进一步提高抗肿瘤效果是非常有必要的。
发明内容
本发明的目的在于提供一种作为DNA-PK抑制剂的三并环化合物,用于治疗和/或预防哺乳动物与DNA-PK相关疾病的药物。
为实现上述目的,本发明采用的技术方案如下:
本发明提供了式(I)所示的化合物、其立体异构体、光学异构体、药学上可接受的盐、前药或溶剂合物,
其中,
Z1选自N、CR2或-C(=O)-;
R2选自H或CH3;
Z2选自N、NH或C;
R1选自取代或未取代的C5-12碳环基或C5-12碳杂环基。
在本发明的一些优选实施方案中,C5-12碳环基或C5-12碳杂环基任选地被一个或多个羟基取代。
在本发明的一些优选实施方案中,化合物的结构通式如式Ia、Ib或Ic所示,
R2选自H或甲基。
在本发明的一些优选实施方案中,化合物选自
上述化合物的制备方法选自如下路线:
氨基乙酸乙酯盐酸盐与R1取代的酮发生还原氨化反应生成中间体2,中间体2和2,4-二氯-5-硝基嘧啶发生亲核取代反应生成中间体3,中间体3在铁粉和醋酸的作用下发生闭环反应生成中间体4,中间体4在五硫化二磷的作用下生成中间体5,中间体5分别与氨基乙二醛二甲酯、R2取代的酰肼(如甲酰肼或乙酰肼)或肼甲酸乙酯反应分别生成中间体6a、6b或6c,中间体6a、6b或6c与W取代的氨基化合物发生偶联反应生成化合物Ia、Ib或Ic。
R2选自H或甲基。
反应条件和试剂为:a.氰基硼氢化钠,二氯甲烷,0℃,2小时;b.碳酸钾,氮氮二甲基甲酰胺,0℃,2小时;c.铁粉,醋酸,90℃,12小时;d.五硫化二磷,三乙胺,乙腈,80℃,4小时;ei.I、三乙胺,乙醇,70℃,2小时;II、冰醋酸,100℃,1小时;eii.环己醇,120℃,12小时;f.碳酸铯,醋酸钯,Xantphos,二氧六环,100℃,2小时。
本发明还提供一种药物组合物,包括上述化合物、其立体异构体、光学异构体、药学上可接受的盐、前药或溶剂合物,和药学上可接受的载体。
在本发明的一些优选实施方案中,药物组合物还包括一种或多种抗癌剂。
在本发明的一些优选实施方案中,抗癌剂为阿霉素或博来霉素。
本发明还提供上述化合物、其立体异构体、光学异构体、药学上可接受的盐、前药或溶剂合物,或上述药物组合物在制备用于治疗或预防与DNA-PK依赖蛋白激酶相关的疾病的药物中的应用。
本发明还提供上述化合物、其立体异构体、光学异构体、药学上可接受的盐、前药或溶剂合物,或上述药物组合物在制备用于使癌细胞对抗癌剂和/或电离辐射敏感的药物中的应用。
与现有技术相比,本发明的有益效果在于:
本发明的化合物及其立体异构体、光学异构体、药学上可接受的盐、前药或溶剂合物具有优良的抑制DNA-PK的活性,与一种或多种抗癌剂联用能增强其对癌细胞的敏感性,可以作为DNA-PK抑制剂,用于制备治疗和/或者预防哺乳动物与DNA-PK相关的疾病的药物。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
本发明包括本发明化合物的所有可能的立体异构体,可以是单一立体异构体,或任何比例的所述立体异构体,例如R或S异构体,或E或Z异构体的任何混合物。利用任何合适的本领域说明的方法,例如,色谱,尤其是手性色谱,可以实现本发明化合物的单一立体异构体的分离,例如,单一对映异构体或单一非对应异构体的分离。
本发明还涉及本文公开的化合物的可用形式,例如,代谢物、水合物、溶剂化物、前药、盐,尤其是药学上可接受的盐,以及共沉淀。
本发明的化合物可以以水合物或溶剂化物形式存在,其中,本发明的化合物含有极性溶剂,尤其是水、甲醇或乙醇,例如,作为化合物的晶格的结构要素。极性溶剂尤其是水的量,可以以化学计量或非化学计量的比例存在。化学计量的溶剂化合物例如水合物的情况下,可以分别是半(部分)、一、一又二分之一、二、三、四、五溶剂化合物或水合物,等等。本发明包括所有这种水合物或溶剂化物。
进一步的,本发明的化合物可以游离形式存在,例如,作为游离碱或游离酸或两性离子,或可以以盐形式存在。所述盐可以是药学通常使用的任何盐,有机或无机加成盐,尤其是任何药学上可接受的有机或无机加成盐。
本发明化合物的药学上可接受的盐可以是,例如,链或环中携带氮原子的本发明化合物的酸加成盐,例如,充分碱性的本发明化合物的酸加成盐,例如,与无机酸形成的酸加成盐,例如,盐酸、氢溴酸、氢碘酸、硫酸、重硫酸、磷酸或硝酸,或与有机酸形成的酸加成盐,例如,甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊酸、二葡糖酸、3-羟基-2-萘酸、烟酸、双羟萘酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、新戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚糖酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
本发明的化合物可以在一个或者多个构成该化合物的原子上包含非天然比例同位素,例如用重氢取代氢形成氘代药物。
在本发明的背景下,术语“治疗”包括抑制、延迟、检查、缓解、减弱、限制、减少、压制、抵制或治愈疾病(术语“疾病”包括但不限于病状、病症、损失或健康问题),或者这种状态和/或这种状态的症状的发展、进程或进展、术语“疗法”在本文理解为与术语“治疗”同义。
术语“防止”、“预防”或“阻止”在本发明的背景下是同义使用的,并且是指避免或减少感染、经历、患有或具有疾病的风险或者这种和/或这种状态的症状的发展或进展。治疗或预防疾病可以是部分或完全的。
本发明化合物合成方法中所用起始原料和试剂均可商业购买或通过文献报道的方法合成。
具体实施方式
以下结合具体实施例对本发明作进一步的详细说明,以使本领域的技术人员更加清楚地理解本发明。所举实例只用于解释本发明,并非用于限定本发明的范围。基于本发明中的具体实施例,本领域普通技术人员在没有做出创造性劳动的情况下,所获得的其他所有实施例,都属于本发明的保护范围。在本发明实施例中,若无特殊说明,所有原料组分均为本领域技术人员熟知的市售产品;在本发明实施例中,若未具体指明,所用的技术手段均为本领域技术人员所熟知的常规手段。本发明反应的进程可采用本领域中的常规监测方法(例如TLC(薄层色谱)、LCMS(液质联用)或NMR(核磁共振))进行监测,一般以反应底物消失时为反应终点。
在下列具体实施例中,对制备化合物检测鉴定的液相条件为:岛津LCMS2020,G1322A脱气机,G1312二元高压泵,G1329A自动进样器,G1316A柱温箱,G4212B二极管阵列检测器。色谱柱为XbridgeC18(50mm×4.6mm,5.0μm),以去离子水为流动相A,以含0.1%的三氟乙酸的乙腈为流动相B,按下表进行梯度洗脱:
时间(min) | 流动相A(%) | 流动相B(%) |
0.01 | 95 | 5 |
1.50 | 95 | 5 |
3.00 | 5 | 95 |
3.50 | 5 | 95 |
4 | 95 | 5 |
5 | 95 | 5 |
流速为1.5mL/min,柱温为40℃,检测波长为254nm。
实施例1
化合物1:氮-(7-甲基-[1,2,4]三氮唑[1,5-a]吡啶-6-基)-5-(四氢吡喃-4-基)-5,6-二氢咪唑[1,2-f]蝶啶-3-胺
步骤一:向反应瓶中加入四氢吡喃酮(中间体1,5g,49.94mmol)、二氯甲烷(60mL)、冰乙酸(3mL)和甘氨酸乙酯盐酸盐(10.46g,74.91mmol),搅拌降温至0℃,分次加入氰基硼氢化钠(6.28g,99.88mmol),加毕,保存0℃反应2小时,TLC点板监控原料完全反应后,用饱和碳酸氢钠溶液调节反应液PH=7,分液,用二氯甲烷萃取三次(30mL*3),合并有机相,饱和食盐水洗一次,减压浓缩得黄色油状中间体2(8.69g,收率92.93%)。LCMS:(MS-ESI,m/z):[M+H]+=188.2。
步骤二:向反应瓶中加入2,4-二氯-5-硝基嘧啶(5g,25.78mmol)和氮氮二甲基甲酰胺(50mL)搅拌降温至0℃,加入中间体2(8.69g,46.40mmol)、碳酸钾(7.13g,51.55mmol),搅拌反应30分钟,TLC点板监控,原料反应完全后停止反应,加入100mL水淬灭反应,分液,乙酸乙酯萃取3次(30mL*3),合并乙酸乙酯相,减压浓缩,用柱层析硅胶过柱,用乙酸乙酯:石油醚体系洗脱(PE:EA=5:1),得黄绿色粉末状固体中间体3(2.1g,收率23.63%)。LCMS:(MS-ESI,m/z):[M+H]+=345.3。
步骤三:室温下,向反应瓶中加入中间体3(2.10g,6.09mmol)、醋酸(42ml)搅拌溶解,加入铁粉(1.02g,18.27mmol),升至90℃反应2小时,TLC监控,原料反应完全后,降温至25℃,浓缩除去醋酸,随后向浓缩液中加入100mL水,乙酸乙酯萃取3次(30mL*3),合并乙酸乙酯相,减压浓缩,用甲醇(5mL)打浆的得白色粉末状固体中间体4(1.22g,收率74.55%)。LCMS:(MS-ESI,m/z):[M+H]+=269.2。
步骤四:室温下,向反应瓶中加入三乙胺(20mL)和乙腈(30ml)搅拌溶解,分批次加入五硫化二磷(1.51g,6.81mmol),待五硫化二磷完全溶解后,加入中间体4(1.22g,4.54mmol),氮气保护下,升至80℃继续反应5小时,TLC监控,原料反应完全后,降温至25℃,加入硅胶拌样浓缩,用柱层析硅胶过柱,用乙酸乙酯:石油醚体系洗脱(PE:EA=10:1),得亮黄色粉末状中间体5(1.1g,收率85.08%)。LCMS:(MS-ESI,m/z):[M+H]+=285.1。
步骤五:室温下,向反应瓶中加入中间体5(100mg,351.17μmol)和乙醇(5ml)搅拌溶解,随后加入氨基乙二醛二甲酯(73.84mg,702.34μmol)以及0.5mL三乙胺,升至70℃继续反应2小时,TLC监控,原料反应完全后,降温至25℃,减压浓缩反应液。随后,用醋酸(5ml)溶解浓缩反应液,升至100℃反应2小时,TLC监控,原料反应完全后,降温至25℃,加入硅胶拌样浓缩,用柱层析硅胶过柱,用二氯甲烷:甲醇体系洗脱(DCM:MeOH=30:1),得黄色固体中间体6(43mg,收率41.97%)。LCMS:(MS-ESI,m/z):[M+H]+=292.2。
步骤六:向反应瓶中加入中间体6(43mg,147.39μmol)、7-甲基-[1,2,4]三氮唑[1,5-a]吡啶-6-胺(26.21mg,176.87μmol)、醋酸钯(3.31mg,14.74μmol)、碳酸铯(96.05mg,294.78μmol)、Xantphos(8.53mg,14.74μmol)和二氧六环(5ml),抽真空氮气置换3次,在氮气保护下,搅拌升温至100℃反应2小时,TLC监控,原料反应完全后,降温至25℃,用柱层析硅胶过柱,用二氯甲烷:甲醇体系洗脱(DCM:MeOH=10:1)得白色固体化合物1(30.3mg,收率51%)。LCMS:(MS-ESI,m/z):[M+H]+=404.2 1H NMR:(400MHz,DMSO-d6,ppm):δ9.17(s,1H),8.63(s,1H),8.39(s,2H),7.86(s,1H),7.71(s,1H),7.11(s,1H),4.67(d,J=16.2Hz,3H),3.92(d,J=10.0Hz,2H),3.28(s,2H),2.42(s,3H),1.89(d,J=9.1Hz,2H),1.60(d,J=11.9Hz,2H)。
实施例2
化合物2:5-(8-氧杂双环[3.2.1]辛烷-3-基)-氮-(7-甲基-[1,2,4]三氮唑[1,5-a]吡啶-6-基)-5,6-二氢咪唑[1,2-f]蝶啶-3-胺
化合物2(23mg,收率45.1%)。LCMS:(MS-ESI,m/z):[M+H]+=430.3 1H NMR:(400MHz,DMSO-d6,ppm):δ9.18(s,1H),8.63(s,1H),8.40(s,2H),7.88(s,1H),7.75(s,1H),7.12(s,1H),4.66–4.61(m,1H),4.51(s,2H),3.89(dd,J=11.4,3.8Hz,2H),3.31(s,2H),2.37(s,3H),1.95(m,2H),1.78(dt,J=12.1,7.8Hz,2H),1.63(m,2H)。
实施例3
化合物3:4-(3-((7-甲基-[1,2,4]三氮唑[1,5-a]吡啶-6-基)氨基)咪唑[1,2-f]蝶啶-5(6氢)-基)环己烷-1-醇
化合物3(17mg,收率52.1%)。LCMS:(MS-ESI,m/z):[M+H]+=418.3 1H NMR:(400MHz,DMSO-d6,ppm):δ9.15(s,1H),8.38(s,1H),8.31(s,2H),7.87(s,1H),7.70(s,1H),7.05(s,1H),4.56(ddd,J=12.0,8.2,3.8Hz,1H),4.04(s,2H),3.12(m,2H),2.42(s,3H),1.76(m,4H),1.53(m,4H)。
实施例4
化合物4:氮-(7-甲基喹喔啉-6-基)-5-(四氢吡喃-4-基)-5,6-二氢咪唑[1,2-f]蝶啶-3-氨基
化合物4(23mg,收率42.6%)。LCMS:(MS-ESI,m/z):[M+H]+=415.3 1H NMR:(400MHz,DMSO-d6,ppm):δ9.19(s,1H),8.76(s,1H),8.68(s,2H),8.34(d,J=14.1Hz,2H),7.85(d,J=13.5Hz,2H),4.76(t,J=10.1Hz,1H),4.10(s,2H),3.92(dd,J=9.3,2.2Hz,2H),3.47(s,2H),2.54(s,3H),1.82(dd,J=11.9,3.8Hz,2H),1.63(dd,J=13.1,1.6Hz,2H)。
实施例5
化合物5:氮-(7-甲基喹啉-6-基)-5-(四氢吡喃-4-基)-5,6-二氢咪唑[1,2-f]蝶啶-3-氨基
化合物5(33mg,收率54.2%)。LCMS:(MS-ESI,m/z):[M+H]+=414.2 1H NMR:(400MHz,DMSO-d6,ppm):δ9.08(s,1H),8.71(dd,J=4.3,1.6Hz,1H),8.24(d,J=3.6Hz,2H),8.15(d,J=7.5Hz,1H),7.82(s,2H),7.77(s,1H),7.40(dd,J=8.1,4.1Hz,1H),4.64(ddd,J=12.0,8.2,4.0Hz,1H),4.06(s,2H),3.89(dd,J=11.0,4.0Hz,2H),3.22–3.10(m,5H),2.47(s,3H),1.77(tt,J=12.3,6.1Hz,2H),1.56(d,J=10.0Hz,2H)。
实施例6
化合物6:氮-(7-甲基-[1,2,4]三氮唑[1,5-a]吡啶-6-基)-5-(四氢吡喃-4-基)-4,5-二氢-[1,2,4]三氮唑[4,3-f]蝶啶-7-胺
室温下,向反应瓶中加入中间体5(100mg,351.17μmol)和环己醇(5ml)搅拌溶解,随后加入甲酰肼(42.18mg,702.34μmol),升至120℃继续反应12小时,TLC监控,原料反应完全后,降温至25℃,减压浓缩反应液。随后,加入硅胶拌样浓缩,用柱层析硅胶过柱,二氯甲烷:甲醇体系洗脱(DCM:MeOH=30:1),得黄色固体中间体6b(61mg,收率59.34%)。LCMS:(MS-ESI,m/z):[M+H]+=293.1。
其余步骤同实施例1,制得化合物6(19mg,收率40.2%)。LCMS:(MS-ESI,m/z):[M+H]+=405.2 1H NMR:(400MHz,DMSO-d6,ppm):δ9.18(s,1H),8.72(s,1H),8.61(s,1H),8.42(s,2H),7.88(s,1H),4.71(d,J=16.2Hz,3H),3.95(d,J=10.0Hz,2H),3.29(s,2H),2.42(s,3H),1.87(d,J=9.2Hz,2H),1.62(d,J=12.0Hz,2H)。
实施例7
化合物7:1-甲基-7氮-(7-甲基-[1,2,4]三氮唑[1,5-a]吡啶-6-基)-5-(四氢吡喃-4-基)-4,5-二氢-[1,2,4]三氮唑[4,3-f]蝶啶-7-胺
室温下,向反应瓶中加入中间体5(100mg,351.17μmol)和环己醇(5ml)搅拌溶解,随后加入乙酰肼(52.03mg,702.34μmol),升至120℃继续反应12小时,TLC监控,原料反应完全后,降温至25℃,减压浓缩反应液。随后,加入硅胶拌样浓缩,用柱层析硅胶过柱,二氯甲烷:甲醇体系洗脱(DCM:MeOH=30:1),得黄色固体中间体6bi(39mg,收率36.2%)。LCMS:(MS-ESI,m/z):[M+H]+=306.2。
其余步骤同实施例1,制得化合物7(21mg,收率48.2%)。LCMS:(MS-ESI,m/z):[M+H]+=419.3 1H NMR:(400MHz,DMSO-d6,ppm):δ9.17(s,1H),8.62(s,1H),8.41(s,2H),7.88(s,1H),4.66(d,J=15.9Hz,3H),3.94(d,J=9.72Hz,2H),3.31(s,2H),2.44(s,3H),2.12(s,3H),1.88(d,J=9.3Hz,2H),1.62(d,J=11.5Hz,2H)。
实施例8
化合物8:5-(8-氧杂双环[3.2.1]辛烷-3-基)-氮-(7-甲基-[1,2,4]三氮唑[1,5-a]吡啶-6-基)-5,6-二氢-[1,2,4]三氮唑[4,3-f]蝶啶-7-胺
化合物8(12mg,收率38.2%)。LCMS:(MS-ESI,m/z):[M+H]+=431.2 1H NMR:(400MHz,DMSO-d6,ppm):δ9.17(s,1H),8.72(s,1H),8.62(s,1H),8.44(s,2H),7.89(s,1H),4.70–4.62(m,1H),4.52(s,2H),3.92(d,J=10.0Hz,2H),3.29(s,2H),2.44(s,3H),1.96(m,2H),1.91(d,J=12.0Hz,2H),1.64(m,2H)。
实施例9
化合物9:7-((7-甲基-[1,2,4]三氮唑[1,5-a]吡啶-6-基)-5-(四氢吡喃-4-基)-4,5-二氢-[1,2,4]三氮唑[4,3-f]蝶啶-1(2氢)-酮
室温下,向反应瓶中加入中间体5(100mg,351.17μmol)和环己醇(5ml)搅拌溶解,随后加入肼基乙酸乙酯(73.12mg,702.34μmol),升至120℃继续反应12小时,TLC监控,原料反应完全后,降温至25℃,减压浓缩反应液。随后,加入硅胶拌样浓缩,用柱层析硅胶过柱,二氯甲烷:甲醇体系洗脱(DCM:MeOH=20:1),得黄色固体中间体6c(46mg,收率42.43%)。LCMS:(MS-ESI,m/z):[M+H]+=309.1。
其余步骤同实施例1,制得化合物9(38mg,收率55.4%)。LCMS:(MS-ESI,m/z):[M+H]+=421.2 1H NMR:(400MHz,DMSO-d6,ppm):δ9.18(s,1H),8.62(s,1H),8.45(s,2H),7.90(s,1H),4.50(d,J=16.1Hz,3H),3.79(d,J=10.0Hz,2H),3.33(s,2H),2.51(s,3H),1.79(d,J=9.0Hz,2H),1.59(d,J=12.0Hz,2H)。
实施例10
化合物10:5-(8-氧杂双环[3.2.1]辛烷-3-基)-7-((7-甲基-[1,2,4]三氮唑[1,5-a]吡啶-6-基)氨基)-4,5-二氢-[1,2,4]三氮唑[4,3-f]蝶啶-1(2氢)-酮
化合物10(21mg,收率49.3%)。LCMS:(MS-ESI,m/z):[M+H]+=447.21H NMR:(400MHz,DMSO-d6,ppm):δ9.17(s,1H),8.69(s,1H),8.44(s,2H),7.96(s,1H),4.71–4.61(m,1H),4.51(s,2H),4.01(d,J=10.0Hz,2H),3.31(s,2H),2.45(s,3H),1.97(m,2H),1.88(d,J=12.0Hz,2H),1.65(m,2H)。
测试例1体外酶学检测
本发明化合物对DNA-PK酶活性抑制作用的测定,检测方法如下:
将DNA-依赖性蛋白激酶、DNA-依赖性蛋白激酶肽底物(10mg/mL)、ATP(包含在ADP-Glo Kinase Assay试剂盒中)在冰上融化。取1μl/孔待测化合物(化合物1-10和阳性对照AZD7648)工作液加入到微孔板中,阳性对照加入1μl/孔1X assay buffer含有5%DMSO,空白对照加入1μl/孔1X缓冲液(assay buffer);DNA-依赖性蛋白激酶完全溶解后,用1X缓冲液将酶稀释到2.5unit/μl后,取2μl/孔酶溶液加入到微孔板中,空白对照孔加入2μl/孔1X缓冲液,微孔板1000转离心1分钟。
使用1X缓冲液对DNA-依赖性蛋白激酶肽底物(10mg/mL)进行稀释并加入ATP,使ATP的浓度为125μM,DNA-依赖性蛋白激酶肽底物浓度为0.5μg/μl,底物与ATP的混合溶液置于冰上备用;取2μl/孔底物与ATP的混合溶液到微孔板中,微孔板1000转离心1分钟,此时DNA-依赖性蛋白激酶肽底物浓度为0.2μg/μl,ATP浓度为50μM,DMSO浓度为1%;微孔板封膜,置于25℃孵育60min;结束孵育后,取5μl/孔ADP-GloTM试剂加入到微孔板中,微孔板1000转离心1分钟,微孔板封膜后置于25℃,孵育40分钟;结束孵育后,取10μl/孔KinaseDetection加入到微孔板中,微孔板1000转离心1分钟,微孔板封膜后,置于25℃,孵育30分钟;结束孵育后,使用Nivo进行Luminescence检测,读取发光值(RLU)。酶活率计算:酶活%=(RLU(样品)-RLU(空白))/(RLU(1%DMSO)-RLU(空白)))×100%。实验结果如表1所示。
表1 DNA-PK激酶活性测定结果
化合物 | IC50(nM) |
实施例1 | 1.1 |
实施例2 | 0.5 |
实施例3 | 2.3 |
实施例4 | 11.2 |
实施例5 | 6.5 |
实施例6 | 0.9 |
实施例7 | 1.4 |
实施例8 | 0.4 |
实施例9 | 6.2 |
实施例10 | 2.9 |
AZD7648 | 0.9 |
结论:本发明化合物对DNA-PK激酶活性具有很好的抑制作用。
测试例2 MTT细胞毒测试
应用MTT检测法测定化合物1-10对Jurkat细胞(人T淋巴细胞瘤细胞)增长的抑制作用。实验步骤如下:
Jurkat细胞以6000细胞/孔接种于96孔板中,150μL/孔,37℃培养24h。按照浓度设置进行实施例1-10化合物配置,化合物1-10用无血清培养基梯度稀释,加药量为50μL/孔。药物处理72h后,每孔加入10μl MTT溶液,37℃孵育4h。仔细吸去上清,每孔加入150μlDMSO,轻轻振荡以使甲臜溶解。1h内在检测波长570nm处用酶标仪测定OD值。采用GraphpadPrism软件进行分析计算。抑制率=(100-OD样品/OD溶媒)×100%,其中OD样品为添加各浓度受试物后检测到的吸光度值,OD溶媒为溶媒组(添加溶媒,不加受试物)检测到的吸光度值。阳性对照物为阿斯利康公司的DNA-PK抑制剂,代号为AZD7648。化合物1-10对Jurkat细胞的细胞毒测试结果如表2所示。
表2 MTT细胞毒活性测试结果
化合物 | IC50(μM) |
实施例1 | 9.4 |
实施例2 | 5.5 |
实施例3 | 7.3 |
实施例4 | 15.2 |
实施例5 | 9.3 |
实施例6 | 5.9 |
实施例7 | 7.6 |
实施例8 | 3.4 |
实施例9 | 16.9 |
实施例10 | 22.9 |
AZD7648 | 7.9 |
结论:本发明化合物对Jurkat细胞具有很好的抑制活性。
测试例3化合物1-10与阿霉素联用细胞毒测试
阿霉素作为化疗药可使细胞产生DNA双链断裂,DNA-PK抑制剂可抑制细胞对双链断裂的修复,因此阿霉素与DNA-PK抑制剂联用可增强DNA-PK抑制剂的细胞毒杀伤效果。本实施例应用MTT检测法,测定化合物1-10联合阿霉素对Jurkat细胞(人T淋巴细胞瘤细胞)增长的抑制作用。
实验步骤如下:
Jurkat细胞以6000细胞/孔接种于96孔板中,150μL/孔,37℃培养24h。每孔加入50nM阿霉素溶液,同时按照浓度设置进行实施例1-10化合物配置,实施例1-10化合物用无血清培养基梯度稀释,加药量为50μL/孔。药物处理72h后,每孔加入10μl MTT溶液,37℃孵育4h。仔细吸去上清,每孔加入150μl DMSO,轻轻振荡以使甲臜溶解。1h内在检测波长570nm处用酶标仪测定OD值。采用Graphpad Prism软件进行分析计算。抑制率=(100-OD样品/OD溶媒)×100%,其中OD样品为添加各浓度受试物后检测到的吸光度值,OD溶媒为溶媒组(添加溶媒,不加受试物)检测到的吸光度值。阳性对照物为阿斯利康公司的DNA-PK抑制剂,代号为AZD7648。化合物1-10联合阿霉素对Jurkat细胞的细胞毒测试结果如表3所示。
表3化合物1-10与阿霉素联用细胞毒测试
化合物 | IC50(μM) |
实施例1 | 4.4 |
实施例2 | 2.1 |
实施例3 | 4.3 |
实施例4 | 10.2 |
实施例5 | 6.4 |
实施例6 | 3.9 |
实施例7 | 5.6 |
实施例8 | 1.4 |
实施例9 | 12.9 |
实施例10 | 18.8 |
AZD7648 | 2.3 |
结论:本发明化合物与阿霉素联用能增强其对Jurkat细胞的抑制效果。
测试例4化合物1-10与博来霉素联用细胞毒测试
博来霉素具有和放疗类似的药理作用,本实施例应用MTT检测法,测定化合物1-10联合博来霉素对Jurkat细胞(人T淋巴细胞瘤细胞)增长的抑制作用。实验步骤如下:
Jurkat细胞以6000细胞/孔接种于96孔板中,150μL/孔,37℃培养24h。每孔加入50nM博来霉素溶液,同时按照浓度设置进行化合物1-10配置,化合物1-10用无血清培养基梯度稀释,加药量为50μL/孔。药物处理72h后,每孔加入10μl MTT溶液,37℃孵育4h。仔细吸去上清,每孔加入150μlDMSO,轻轻振荡以使甲臜溶解。1h内在检测波长570nm处用酶标仪测定OD值。采用Graphpad Prism软件进行分析计算。抑制率=(100-OD样品/OD溶媒)×100%,其中OD样品为添加各浓度受试物后检测到的吸光度值,OD溶媒为溶媒组(添加溶媒,不加受试物)检测到的吸光度值。阳性对照物为阿斯利康公司的DNA-PK抑制剂,代号为AZD7648。化合物1-10联合阿霉素对Jurkat细胞的细胞毒测试结果如表4所示。
表4化合物1-10与博来霉素联用细胞毒测试
化合物 | IC50(nM) |
实施例1 | 5.6 |
实施例2 | 3.9 |
实施例3 | 4.9 |
实施例4 | 11.3 |
实施例5 | 8.4 |
实施例6 | 5.9 |
实施例7 | 6.7 |
实施例8 | 2.4 |
实施例9 | 11.9 |
实施例10 | 17.8 |
AZD7648 | 3.2 |
结论:本发明化合物与博来霉素联用能增强其对Jurkat细胞的抑制效果。
以上结果表明,相较于阳性对照AZD7648,本发明化合物具有相当甚至更好的抑制DNA-PK激酶活性,同时本发明化合物和阿霉素以及博来霉素联用能增强其对Jurkat细胞的杀伤作用。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (6)
3.一种药物组合物,其特征在于,包括权利要求1~2任一项所述的化合物和药学上可接受的载体。
4.根据权利要求3所述的药物组合物,其特征在于,还包括一种或多种抗癌剂。
5.根据权利要求4所述的药物组合物,其特征在于,所述抗癌剂为阿霉素或博来霉素。
6.权利要求1~2任一项所述的化合物或权利要求3~5任一项所述的药物组合物在制备用于治疗或预防与DNA-PK依赖蛋白激酶相关的疾病的药物中的应用。
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