CN106977584A - 靶向泛素化降解plk1和brd4蛋白的化合物及其应用 - Google Patents
靶向泛素化降解plk1和brd4蛋白的化合物及其应用 Download PDFInfo
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- CN106977584A CN106977584A CN201710260531.8A CN201710260531A CN106977584A CN 106977584 A CN106977584 A CN 106977584A CN 201710260531 A CN201710260531 A CN 201710260531A CN 106977584 A CN106977584 A CN 106977584A
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- C07K5/06008—Dipeptides with the first amino acid being neutral
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- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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Abstract
本发明涉及一种靶向泛素化降解PLK1和BRD4蛋白的化合物及其应用，属于化合物合成领域。本发明选用化合物A结构类似物作为PROTACs中与E3连接酶进行结合的部位，选用连接链将其于同时具有Polo样激酶1(PLK1)和溴结构域蛋白4(BRD4)蛋白酶抑制剂活性的结构相连接构建PROTACs。同时因构建的化合物针对PLK1和BRD4双靶点，相对于单靶点药物可降低其抗肿瘤活性的耐药性。体外PLK1和BRD4蛋白酶抑制活性、体外抗肿瘤活性测试及体外PLK1和BRD4蛋白降解活性表明，该类靶向泛素化降解PLK1和BRD4蛋白的化合物(PROTACs)可将PLK1和BRD4靶向蛋白降解，具有良好的抗肿瘤活性，并表现出优异的PLK1和BRD4抑制作用。本发明制备方法操作简单，条件温和，所得化合物均具有PLK1和BRD4蛋白酶抑制和降解活性，抗肿瘤作用显著。
Description
技术领域
本发明属于化合物合成技术领域，特别是涉及一种靶向泛素化降解PLK1和BRD4蛋白的化合物，及其药学上可接受的盐、水合物和以该化合物为活性成分的药物组合，以及在制备PLK1蛋白和BRD4蛋白抑制剂及其用于治疗和/或预防肿瘤中的应用。
背景技术
泛素-蛋白酶体途径(ubiquitin proteasome pathway，UPP)是细胞内蛋白质降解的主要途径，参与细胞内80％以上蛋白质的降解。UPP由泛素、泛素活化酶E1、泛素结合酶E2、泛素连接酶E3、蛋白酶体及其底物(蛋白质)构成。UPP特异性降解蛋白质的过程分两个阶段：(1)蛋白底物泛素化：泛素分子由APP提供能量，被E1激活转移到E2，然后经E3与特异性蛋白底物结合；(2)蛋白底物降解：被泛素化的蛋白分子能够被蛋白酶体识别，并进入蛋白酶体降解成短链的多肽分子。
蛋白水解靶向嵌合分子(Proteolysis Targeting Chimeras，PROTACs)技术是利用一种双功能小分子将目标蛋白和细胞内的E3拉近，从而导致目标蛋白质的降解。PROTACs包含三部分功能结构：(1)可以与蛋白底物相结合的部分；(2)能够与E3相结合的部分；(3)前两部分的连接链。在细胞内PROTACs可以同时与靶蛋白及E3结合，使本来不能与E3结合的靶蛋白泛素化，进而被蛋白酶体识别并降解。(Angew.Chem.Int.Ed.Engl.,2016,55(6),1966-1973.)
研究证明化合物A类似物可以与VHL蛋白结合，VHL蛋白为E3泛素连接酶复合体Elongin B/C–CUL2–VHL的组成部分。该复合物可利用泛素来标记特定的蛋白，随后水解这些蛋白。(Angew Chem Int Ed Engl.，2016，55(2):807–810.)
发明内容
本发明提供一种靶向泛素化降解PLK1和BRD4蛋白的化合物及其应用，具体为具有化合物A类似物片段的化合物及其制备方法，以及该类化合物作为PLK1和BRD4蛋白抑制和降解剂在预防和/或治疗肿瘤中的应用。
本发明涉及通式Ⅰ所示的化合物、及其药学上可接受的盐、水合物：
其中R1选自H、C1-C6烷基、C3-C6环烷基、任选取代的苯基，其中苯基取代基选自H，卤素，硝基，氨基，C1-C6烷基，C1-C6烷氧基；R2选自H、C1-C6烷氧基，卤素；R3选自H，C1-C6烷基；n为1、2、3、4、5或6。
除非另外指出，本发明所用的术语“卤素”是指氟、氯、溴或碘；C1-C6烷基是指甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、直链或带支链的C5烷基、直链或带支链的C6烷基；C1-C6烷氧基是指甲氧基，乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、直链或带支链的C5烷氧基、直链或带支链的C6烷氧基；C3-C6环烷基是指环丙基，环丁基，环戊基，环己基；任选取代的苯基是指任选被H，卤素，硝基，氨基，C1-C6烷基，C1-C6烷氧基单取代或多取代的苯基。其中烷基优选C1-C6烷基、烷氧基优选甲氧基。
本发明还选自：(2S,4R)-1-((S)-1-(4-(((S)-8-(3-溴苄基)-7-乙基-5-甲基-6-氧-5,6,7,8-四氢喋啶-2-基)氨基)-3-甲氧基苯基)-15-(叔丁基)-1,13-二氧-5,8,11-三噁-2,14-二氮杂十六烷-16-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
(2S,4R)-1-((S)-15-(叔丁基)-1-(4-(((S)-8-环戊基-7-乙基-5-甲基-6-氧-5,6,7,8-四氢蝶啶-2-基)氨基)-3-甲氧基苯基)-1,13-二氧-5,8,11-三噁-2,14-二氮杂十六烷-16-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
(2S,4R)-1-((S)-15-(叔丁基)-1-(4-(((S)-7-乙基-8-异丙基-5-甲基-6-氧-5,6,7,8-四氢喋啶-2-基)氨基)-3-甲氧基苯基)-1,13-二氧-5,8,11-三噁-2,14-二氮杂十六烷-16-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
此外，本发明包括药物组合物，该组合物含有通式Ⅰ化合物或其药学上可接受的盐、水合物和药物上可接受的赋形剂。所述药物上可接受的赋形剂是指任何可用于药物领域的稀释剂、辅助剂和/或载体。本发明的化合物可以与其他活性成分组合使用，只要它们不产生其它不利作用，例如过敏反应。
本发明的药物组合可配置成若干剂型，其中含有药物领域中常用的一些赋形剂，例如，口服制剂(如片剂，胶囊剂，溶液或混悬液)；可注射的制剂(如可注射的溶液或混悬剂，或者是可注射的干燥粉末，在注射前加入注射用水可立即使用)；局部制剂(例如软膏或溶液)。
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、色素、矫味剂等；可注射制剂用的防腐剂、加溶剂、稳定剂等；局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下是不稳定的，可将其配制成肠衣片剂。
通过体外抑酶试验和酶降解试验筛选，我们发现本化合物可抑制并降解PLK1和BRD4蛋白酶活力。因此，本发明化合物可用于与PLK1和BRD4蛋白酶活性异常表达相关的疾病中的应用，如各种癌症。
通过体外活性筛选，我们发现本发明化合物具有抗肿瘤活性，因此本发明化合物可以用于制备治疗和/或预防各种癌症的药物，如乳腺癌，结肠癌，前列腺癌，胰腺癌，非小细胞肺癌，甲状腺乳头状癌，卵巢癌、黑色素瘤、或各种白血病，特别是急性髓性白血病。
本发明化合物可作为唯一的抗癌药物使用，或者与一种或多种其它抗肿瘤药物联合使用。联合治疗通过将各个治疗组分同时，顺序或隔开给药来实现。
本发明选用化合物A结构类似物作为PROTACs中与E3连接酶进行结合的部位，选用连接链将其于同时具有Polo样激酶1(PLK1)和溴结构域蛋白4(BRD4)蛋白酶抑制剂活性的结构相连接构建PROTACs。同时因构建的化合物针对PLK1和BRD4双靶点，相对于单靶点药物可降低其抗肿瘤活性的耐药性。体外PLK1和BRD4蛋白酶抑制活性、体外抗肿瘤活性测试及体外PLK1和BRD4蛋白降解活性表明，该类靶向泛素化降解PLK1和BRD4蛋白的化合物(PROTACs)可将PLK1和BRD4靶向蛋白降解，具有良好的抗肿瘤活性，并表现出优异的PLK1和BRD4抑制作用。
本发明制备方法操作简单，条件温和，所得化合物均具有PLK1和BRD4蛋白酶抑制和降解活性，抗肿瘤作用显著。
具体实施方式
下文中提供的实施例和制备例进一步阐明和举例说明本化合物及其制备方法，应当理解，下述实施例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线描述了本发明的通式I化合物的制备，所有的原料都是通过这些路线中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终化合物都是通过这些路线中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。这些路线中应用的全部可变因数如下文的定义或如权利要求中的定义。
反应试剂及反应条件:(a)NaBH(OAc)3,Na2CO3(b)K2CO3,丙酮；(c)Zn,NH4Cl(d)NaH,CH3I；(e)MeOH,HCl；(f)HATU,DIPEA。
按照本发明的通式I化合物，合成路线中各取代基如发明内容部分所定义。
化合物(1)的制备
D-2-氨基丁酸甲酯5g，苯甲醛衍生物43mmol加入到二氯甲烷50mL中，冰浴下加入三乙酰氧基硼氢化钠10g，室温反应24h,加饱和碳酸氢钠水溶液50mL,二氯甲烷萃取，合并有机相，无水硫酸镁干燥，过滤蒸干得淡黄色液体化合物(1)。
(R)-甲基2-(3-溴苄氨基)丁酸甲酯(1a)
产率：82％；1H-NMR(CDCl3，400MHz)，δ:0.96(t,3H，CH3),1.56-1.66(m,2H,CH2),3.24-3.28(m,1H,CH),3.56(d,1H,CH),3.68(s,3H,CH3),3.70(d,1H,CH),7.16-7.27(m,2H,ArH),7.34-7.39(m,1H,ArH),7.48(s,1H,ArH)。
(R)-甲基-2-(异丙胺基)丁酸甲酯(1b)
产率：95％；1H-NMR(CDCl3，400MHz)，δ：0.82-0.88(m,9H,CH3×3)，1.51-1.59(m,3H,CH，CH2),2.14-2.17(m,1H,CH),2.25-2.32(m,1H,CH),3.06(t,1H,CH),3.62(s,3H,CH3)。
(R)-甲基2-(环戊胺基)丁酸甲酯(1c)
产率：92％；1H NMR(CDCl3，400MHz),δ:0.87(t,3H,CH3),1.24-1.26(m,2H,CH2),1.46(dd,2H,CH2),1.54-1.83(m,6H,CH2×3),2.92-2.96(m,1H,CH),3.17(t,1H,CH),3.68(s,3H,CH3)。
化合物(2)的制备
化合物(1)(54mmol),K2CO3 7.5g加入到丙酮180mL中，0℃下加入2,4-二氯-5-硝基嘧啶10.5g的丙酮溶液20mL,室温反应24h,过滤，蒸干，硅胶柱层析(乙酸乙酯：石油醚1：20)，得化合物(2)。
(R)-甲基2-(N-(3-溴苄基)-N-(2-氯-5-硝基嘧啶-4-基)氨基)丁酸甲酯(2a)
产率：74％；1H NMR(400MHz,CDCl3)，δ:1.04(t,3H,CH3),2.02-2.08(m,1H,CH),2.20-2.28(m,1H,CH),3.84(s,3H，CH3),4.58(d,1H,CH),4.66-4.78(m,2H,2×CH),7.16-7.27(m,2H,2×ArH),7.34-7.39(m,1H,ArH),7.48(s,1H,ArH),8.68(s,1H,pyrimidine-H)。
(R)-甲基-2-((2-氯-5-硝基嘧啶-4-基)(异丙氨基)丁酸甲酯(2b)
产率：72％；1H NMR(400MHz,CDCl3)，δ:0.68(d,3H,CH3),0.78(d,3H,CH3),0.92(t,3H,CH3),1.88-2.06(m,3H,CH,CH2),2.98-3.05(m,1H,CH),3.13-3.18(m,1H,CH),3.62(s,3H,CH3),4.38(t,1H,CH),8.84(s,1H,pyrimidine-H)。
(R)-甲基-2-((2-氯-5-硝基嘧啶-4-基)(环戊烷基)氨基)丁酸甲酯(2c)
产率，60％；1H NMR(400MHz,CDCl3)，δ:1.04(t,3H，CH3),1.46-1.88(m,6H，CH2×3),2.02-2.09(m,2H，CH2),2.12-2.28(m,1H,CH),2.32-2.48(m,1H,CH),3.45-3.61(m,1H,CH),3.63-3.81(m,4H,CH,CH3),8.65(s,1H,pyrimidine-H)。
化合物(3)的制备
化合物(2)(50mmol),还原锌粉30g，NH4Cl 8.1g加入甲醇200mL中，加热回流24h.过滤蒸干，硅胶柱层析(乙酸乙酯：石油醚1：4)得化合物(3)。
(R)-8-(3-溴苄基)-2-氯-7-乙基-7，8-二氢蝶啶-6(5H)-酮(3a)
产率：72％，1H NMR(400MHz,CDCl3)，δ:0.76(t,3H,CH3),1.76-1.82(m,2H,CH2),4.16-4.19(m,1H,CH),4.48(d,1H,CH),5.14-5.18(m,1H,CH),7.16-7.27(m,2H,ArH),7.34-7.39(m,1H,ArH),7.48(s,1H,ArH),7.69(s,CH，pyrimidine-H),10.86(s,1H,NH)。
(R)-2-氯-7-乙基-8异丙基-7,8-二氢蝶啶-6(5H)-酮(3b)
产率：60％；1H NMR(400MHz,CDCl3)，δ:0.78(t,3H,CH3),0.83(d,3H,CH3),0.92(d,3H,CH3),1.78-1.86(m,2H,CH2),2.03-2.09(m,1H,CH),2.83-2.88(m,1H,CH),3.90-3.96(m,1H,CH),4.16-4.18(m,1H,CH),7.57(s,1H,pyrimidine-H),10.88(s,1H,NH)。
(R)-2-氯-8-环戊基-7-乙基-7,8-二氢蝶啶-6(5H)-酮(3c)
产率：60％；1H NMR(400MHz,CDCl3)，δ：0.92(t,3H,CH3),1.56-1.69(m,2H,CH2),1.78(t,2H,CH2),1.82-2.00(m,5H,CH,CH2×2),2.00-2.16(m,1H,CH),4.20(dd,1H,CH),4.24-4.38(m,1H,CH),7.72(s,1H,pyrimidine-H),10.03(s,1H,NH)。
化合物(4)的制备
化合物(3)(20mmol)，碘甲烷3.4g,加入DMF 50mL，-15℃下加入60％氢化钠1.2g,室温反应3h,加入冰水100mL,乙酸乙酯萃取，蒸干，硅胶柱层析(乙酸乙酯：石油醚1：4)得化合物(4)。
(R)-8-(3-溴苄基)-2-氯-7-乙基-7，8-二氢-5-甲基蝶啶-6(5H)-酮(4a)
产率：72％，1H NMR(400MHz,CDCl3)，δ:0.73(t,3H,CH3),1.78-1.82(m,2H,CH2),3.26(s,3H,CH3),4.28(t,1H,CH),4.46(d,1H,CH),5.18(d,1H,CH),7.16-7.27(m,2H,ArH),7.34-7.39(m,1H,ArH),7.48(s,1H,ArH),7.68(s,1H，pyrimidine-H)。
(R)-2-氯-7-乙基-8-异丙基-5-甲基-二氢-5-甲基蝶啶-6(5H)-酮(4b)
产率：68％,1H NMR(400MHz,CDCl3),δ:0.82(t,3H,CH3),0.86(d,3H,CH3),0.96(d,3H,CH3),1.74-1.80(m,1H,CH),1.86-1.90(m,1H,CH),1.92-2.08(m,1H,CH),2.64(dd,1H,CH),3.32(s,3H,CH3),4.12-4.18(m,2H,CH×2),7.62(s,1H,pyrimidine-H).(R)-2-氯-8-环戊基-7-乙基5-甲基-二氢-5-甲基蝶啶-6(5H)-酮(4c)
产率：70％,1H NMR(400MHz,CDCl3),δ:0.86(t,3H,CH3),1.54-2.00(m,9H,CH,CH2×4),2.00-2.13(m,1H,CH),3.32(s,3H,CH3),4.26(dd,1H,CH),4.26-4.40(m,1H,CH),7.68(s,1H,pyrimidine-H)。
化合物(5)的合成
化合物(4)(7.2mmol),4-氨基-3-甲氧基苯甲酸1.2g,加入甲醇3mL,水12mL和浓盐酸1.5mL，回流48h.减压蒸干溶剂，甲醇和乙醚重结晶得化合物(5)。
4-((R)-8-(3-溴苄基)-7-乙基-5,6,7,8-四氢-5-甲基-6-氧蝶啶-2-基氨基)-3-甲氧基苯甲酸(5a)
产率：82％，1H NMR(400MHz,CDCl3)，δ:0.72(t,3H,CH3),1.78-1.82(m,2H,CH2),3.26(s,3H,CH3),3.92(s,3H,CH3),4.29(t,1H,CH),4.44(d,1H,CH),5.14(d,1H,CH),7.16-7.27(m,2H,ArH),7.34-7.39(m,1H,ArH),7.48(s,1H,ArH),7.58(d,1H，ArH)，7.61(dd,1H，ArH),7.88(s,1H，ArH)，9.86(d,1H，ArH)。
(R)-4-(8-异丙基-7-乙基-5-甲基-6-氧-5,6,7,8-四氢喋啶-2-氨基)-3-甲氧基苯甲酸(5b)
产率，65％，1H NMR(400MHz,CDCl3),δ:0.82(t,3H,CH3),0.86(d,3H,CH3),0.92(d,3H,CH3),1.72-1.80(m,1H,CH),1.86-1.90(m,1H,CH),1.92-2.06(m,1H,CH),2.64(dd,1H,CH),3.32(s,3H,CH3),4.11-4.18(m,2H,CH×2),7.56(d,1H,ArH),7.62(dd,1H,ArH),7.84(s,1H,ArH),7.89(d,1H,ArH),9.62(s,1H,ArH)。
(R)-4-(8-环戊基-7-乙基-5-甲基-6-氧-5,6,7,8-四氢喋啶-2-氨基)-3-甲氧基苯甲酸(5c)
产率：60％，1H NMR(400MHz,CDCl3)，δ:0.75(t,3H,CH3),1.36-1.58(m,4H,CH2×2),1.66-2.03(m,6H,CH2×3),3.22(s,3H,CH3),3.54(s,1H,CH),3.92(s,3H,CH3),4.12-4.19(m,1H,CH),4.44-4.49(m,1H,CH),7.58(d,1H,ArH),7.61(dd,1H,ArH),7.87(s,1H,ArH),7.94(d,1H,ArH),9.65(s,1H,ArH)。
化合物(6a)的合成路线
叔丁基-4-溴氨基甲酸苄酯(8)的制备
对溴苯乙胺4.0g，NaHCO3 2.0g，加入水20mL，乙酸乙酯20mL,冰浴下加入(Boc)2O5.5g，冰浴反应2h。过滤，干燥得白色固体化合物(8)6g。
1H NMR(400MHz,CD4OD)，δ：1.49(s,9H，CH3×3),4.26(s,2H，CH2),7.15(d,2H，ArH),7.44(d,2H,ArH×2).
(4-(4-甲基噻唑-5-基)苯基)甲胺盐酸盐(9)的制备
化合物(8)4.0g，4-甲基噻唑2.8g,醋酸钯30mg,醋酸钾2.8g加入DMF10mL,N2保护下90℃反应24h。冷却到室温过滤，滤液加水50mL水，室温搅拌4h。过滤，干燥得白色固体3.5g。上述固体溶解到20mL饱和盐酸甲醇溶液中，室温搅拌3h，过滤，干燥得固体化合物(9)2.5g。
1HNMR(400MHz,CD4OD)，δ:2.47(s,3H,CH3),3.85(s,2H,CH2),7.42-7.52(m,4H,ArH×4),8.87(s,1H,Thiazole-H).
(2S,4R)-1-{(S)-2-[(叔丁氧羰)氨基]-3,3-二甲基丁酰基}-4-羟基吡咯烷-2-羧酸(10)的制备
HATU 2.5g，N-Boc-L-叔亮氨酸1.25g,反式-4-羟基-L-脯氨酸甲酯盐酸盐1.0g，DIPEA 2.5g加入到DMF 10mL中。室温反应18h。加入水50mL,乙酸乙酯萃取。有机相先后用饱和氯化铵水溶液，饱和碳酸氢钠水溶液和饱和食盐水清洗，无水硫酸钠干燥，过滤，滤液减压蒸干得油状物1.8g。该油状物加入氢氧化锂2.5g，THF 20mL和水10mL。室温搅拌过夜。将THF蒸干，加入10mL冰水,3N HCI调pH 2-3。过滤，滤饼水洗，干燥得白色固体化合物(10)1.5g。
1H NMR(400MHz,DMSO-d6)，δ：0.94(s,9H,CH3×3)，1.38(s,9H,CH3×3),1.85-1.91(m,1H,CH)，2.08-2.13(m,1H,CH),3.57-3.66(m,2H,CH2),4.16(d,1H,CH),4.25(t,1H,CH),4.32(brs,1H,NH),5.19(brs,1H，OH),6.50(d,1H，COOH).
(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺盐酸盐(11)的制备
HATU 4.0g,化和物(10)3.0g,化合物(9)2.0g,DIPEA 3.0g,加入无水THF 50mL。室温搅拌2h,蒸干加50mL水,搅拌4h，过滤，固体烘干。取上述固体3.0g溶解到10mL饱和HCI甲醇溶液中,室温搅拌3h。过滤，干燥得化合物(11)2.0g。
1H NMR(400MHz,CD4OD):δ0.93(s,9H,CH3×3),2.09-2.14(m,1H),2.49-2.52(m,4H,CH2×2),2.60(s,2H,CH2),3.58-3.62(m,1H,CH),4.07(d,1H,CH),4.33(dd,1H,CH),4.48-4.56(m,3H,CH×3),4.71(t,1H,CH),7.35(dd,4H,ArH×4),8.67(s,1H,Thiazole-H).
(2S,4R)-1-((S)-14-叠氮-2-(叔丁基)-4-氧-6,9,12-三噁-3-氮杂十四酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(13)的制备
化合物(11)2.0g化合物(12)11-叠氮基-3,6,9-三氧代十一酸(CAS：172531-37-2)1.2g，加入DMF 20ml，HATU 2.0g,DIPEA 2.0g。室温搅拌4h,加水200mL,乙酸乙酯萃取，有机相减压蒸干，硅胶柱层析(甲醇：二氯甲烷1：10)，得化合物(13)2.4g。
1H-NMR(CDCl3,400MHz)，δ:0.95(s,9H，CH3×3),2.09-2.14(m,1H,CH),2.52(s,3H,CH3),2.58-2.63(m,1H,CH),2.85(s,1H,CH),3.37(t,2H,CH2),3.60(dd,1H,CH),3.64-3.69(m,10H,CH2×5),3.96-4.05(m,2H,CH2),4.12-4.14(m,1H,CH),4.34(dd,1H,CH),4.46(d,1H,CH),4.53-4.59(m,2H,CH2),4.75(t,1H,CH),7.33-7.38(m,4H,ArH×4),8.86(s,1H,Thiazole-H)；
(2S,4R)-1-((S)-14-氨基-2-(叔丁基)-4-氧-6,9,12-三噁-3-氮杂十四酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(6a)的制备
化合物(13)1.0g加入甲醇20mL,10％Pd/C 0.1g,常压下通氢气室温反应6h,过滤，蒸干得化合物(6a)0.9g。
实施例1：(2S,4R)-1-((S)-1-(4-(((S)-8-(3-溴苄基)-7-乙基-5-甲基-6-氧-5,6,7,8-四氢喋啶-2-基)氨基)-3-甲氧基苯基)-15-(叔丁基)-1,13-二氧-5,8,11-三噁-2,14-二氮杂十六烷-16-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(7a)的制备
化合物(6a)0.5g,化合物(5a)0.45g加入10ml of DMF中，然后加入HATU 0.4g,DIPEA 0.4g,室温反应3h。加50mL水，乙酸乙酯萃取，萃取液饱和食盐水清洗，无水硫酸镁干燥，减压蒸干，硅胶柱层析(甲醇：二氯甲烷1:10)得化合物(7a)0.75g。
1H NMR(400MHz,CDCl3)，δ:0.72(t,3H,CH3),0.95(s,9H，CH3×3),1.78-1.82(m,2H,CH2),2.09-2.14(m,1H,CH),2.52(s,3H,CH3),2.58-2.63(m,1H,CH),2.85(s,1H,CH),3.26(s,3H,CH3),3.37(t,2H,CH2),3.60(dd,1H,CH),3.64-3.69(m,10H,CH2×5),3.92(s,3H,CH3),3.96-4.05(m,2H,CH2),4.12-4.14(m,1H,CH),4.29(t,1H,CH),4.34(dd,1H,CH),4.44(d,1H,CH),4.46(d,1H,CH),4.53-4.59(m,2H,CH2),4.75(t,1H,CH),5.14(d,1H,CH),7.16-7.27(m,2H,ArH),7.34-7.39(m,5H,ArH×5),7.48(s,1H,ArH),7.58(d,1H,ArH)，7.61(dd,1H，ArH),7.88(s,1H，ArH)，8.86(s,1H,Thiazole-H),9.86(d,1H，ArH)。
实施例2：(2S,4R)-1-((S)-15-(叔丁基)-1-(4-(((S)-8-环戊基-7-乙基-5-甲基-6-氧-5,6,7,8-四氢蝶啶-2-基)氨基)-3-甲氧基苯基)-1,13-二氧-5,8,11-三噁-2,14-二氮杂十六烷-16-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(7b)的制备
化合物(6a)0.5g,化合物(5b)0.35g加入10ml of DMF中，然后加入HATU 0.4g,DIPEA 0.4g,室温反应3h。加50mL水，乙酸乙酯萃取，萃取液饱和食盐水清洗，无水硫酸镁干燥，减压蒸干，硅胶柱层析(甲醇：二氯甲烷1:10)得化合物(7b)0.6g。
1H NMR(400MHz,CDCl3),δ:0.75(t,3H,CH3),0.95(s,9H，CH3×3),1.59-1.36(m,4H,CH2×2),1.67-2.03(m,6H,CH2×3),2.09-2.14(m,1H,CH),2.52(s,3H,CH3),2.58-2.63(m,1H,CH),2.85(s,1H,CH),3.22(s,3H,CH3),3.37(t,2H,CH2),3.54(s,1H,CH),3.60(dd,1H,CH),3.64-3.69(m,10H,CH2×5),3.91(s,3H,CH3),3.96-4.05(m,2H,CH2),4.12-4.14(m,1H,CH),4.19(m,1H,CH),4.34(dd,1H,CH),4.46-4.49(m,2H,CH×2),4.53-4.59(m,2H,CH2),4.75(t,1H,CH),7.33-7.38(m,4H,ArH×4),7.58(d,1H,ArH),7.61(dd,1H,ArH),7.87(s,1H,ArH),7.94(d,1H,ArH),8.86(s,1H,Thiazole-H),9.65(s,1H,ArH)。
实施例3：(2S,4R)-1-((S)-15-(叔丁基)-1-(4-(((S)-7-乙基-8-异丙基-5-甲基-6-氧-5,6,7,8-四氢喋啶-2-基)氨基)-3-甲氧基苯基)-1,13-二氧-5,8,11-三噁-2,14-二氮杂十六烷-16-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(7c)的制备
化合物(6a)0.5g,化合物(5c)0.35g加入10ml of DMF中，然后加入HATU 0.4g,DIPEA 0.4g,室温反应3h。加50mL水，乙酸乙酯萃取，萃取液饱和食盐水清洗，无水硫酸镁干燥，减压蒸干，硅胶柱层析(甲醇：二氯甲烷1:10)得化合物(7c)0.6g。
1H NMR(400MHz,CDCl3),δ:0.81(t,3H,CH3),0.85(d,3H,CH3),0.93(d,3H,CH3),0.95(s,9H，CH3×3),1.73-1.80(m,1H,CH),1.85-1.90(m,1H,CH),1.91-2.07(m,1H,CH),2.09-2.14(m,1H,CH),2.52(s,3H,CH3),2.58-2.65(m,2H,CH×2),2.85(s,1H,CH),3.31(s,3H,CH3),3.37(t,2H,CH2),3.60(dd,1H,CH),3.64-3.69(m,10H,CH2×5),3.96-4.05(m,2H,CH2),4.12-4.18(m,3H,CH×3),4.34(dd,1H,CH),4.46(d,1H,CH),4.53-4.59(m,2H,CH2),4.75(t,1H,CH),7.33-7.38(m,4H,ArH×4),7.56(d,1H,ArH),7.62(dd,1H,ArH),7.84(s,1H,ArH),7.89(d,1H,ArH),8.86(s,1H,Thiazole-H),9.62(s,1H,ArH)。
实施例4：PLK1蛋白抑制活性测定
用ELSIA方法测定化合物对PLK1蛋白的抑制活性，96孔微板孔中依次加入PLK1纯化蛋白，2.5μL DMSO稀释的不同浓度抑制剂，150mM底物、10mM ATP、90μL反应缓冲液，，同时设立空白和本底对照组，室温孵育30min。洗板，加入100μL PPT-07,室温孵育30min。洗板，每孔中加入100μL抗兔的辣根连接的二抗，室温下孵育30min。洗板，每孔中加入100uL显色剂，室温下孵育15min。每孔加入100uL反应终止液，以激发光450nm，测定各孔荧光计数，计算抑制率IC50。
实施例5：BRD4蛋白抑制活性测定方法
采用时间分辨荧光(TR-FRET)法通过BRD4bromodomain 1 TR-FRET Assay Kit(Cayman Chemical，USA)测定化合物对BRD4蛋白的抑制活性。将10uL DMSO溶解的不同浓度的抑制剂加入384微孔板中中，加入5uL含10nM BRD4的蛋白反应缓冲液。室温孵育15分钟。随后每孔加入5uL Ac-H4肽和TR-FRET检测试剂[Anti-6His-XL665和Streptavidin-Eu]混合液，黑暗中室温孵育1h。测量在330-350nm下激发后在620nm和665nm处的荧光发射。将在665nm和622nm处的发射的比率作为所形成的BRD4/Ac-H4复合物的量的指示，计算化合物对BRD4蛋白的抑制活性IC50。
| 化合物编号 | PLK1IC50(nM) | BRD4IC50(nM) |
| 7a | 40.6 | 10.8 |
| 7b | 20.4 | 42.6 |
| 7c | 12.2 | 207.6 |
实施例6：MTT法测定肿瘤细胞增殖抑制活性方法的建立以及化合物活性测定
将处于细胞对数生长期的要进行实验的肿瘤细胞(HepG2、A549、HeLa、MV4-11)按一定的细胞量接种于培养板内，培育24h,加入不同浓度抑制剂，细胞在37℃、5％CO2条件下继续培养48小时，每孔加入20uL MTT溶液继续培养4小时，用DMSO溶解结晶，用酶联免疫检测仪在570nm波长处测定其OD值计算IC50。
实施例7：Western-blot测定PLK1和BRD4蛋白降解方法
将药物干预过的Hela或MV4-11细胞收集，用预冷的PBS洗涤2次，PMSF与RIPA裂解液以1：100的比例混合，冰上裂解细胞20min，4℃，12000r/min×20min离心，取上清，即细胞总蛋白，用BCA法定量检测蛋白量，用5×蛋白上样缓冲液稀释蛋白后100℃变性5min。蛋白在SDS－PAGE电泳分离，转膜，封闭2h，一抗4℃孵育过夜。TBST洗膜，二抗1:1000孵育2h，化学发光后X胶片显影，用Image J软件分析每个条带的灰度值，计算蛋白降解50％时抑制剂浓度DC50。
| 化合物编号 | HeLa PLK1DC50(nM) | MV4-11BRD4DC50(nM) |
| 7a | 66.4 | 18.6 |
| 7b | 14.8 | 24.2 |
| 7c | 17.8 | 256.8 |
Claims (10)
1.一种靶向泛素化降解PLK1和BRD4蛋白的化合物，其特征在于，如通式Ⅰ所示的化合物、及其药学上可接受的盐、水合物：
其中R1选自H、C1-C6烷基、C3-C6环烷基、任选取代的苯基，其中苯基取代基选自H，卤素，硝基，氨基，C1-C6烷基，C1-C6烷氧基；R2选自H、C1-C6烷氧基，卤素；R3选自H，C1-C6烷基；n为1、2、3、4、5或6。
2.根据权利要求1所述的靶向泛素化降解PLK1和BRD4蛋白的化合物，其特征在于所述的化合物、及其药学上可接受的盐、水合物，选自：
(2S,4R)-1-((S)-1-(4-(((S)-8-(3-溴苄基)-7-乙基-5-甲基-6-氧-5,6,7,8-四氢喋啶-2-基)氨基)-3-甲氧基苯基)-15-(叔丁基)-1,13-二氧-5,8,11-三噁-2,14-二氮杂十六烷-16-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
(2S,4R)-1-((S)-15-(叔丁基)-1-(4-(((S)-8-环戊基-7-乙基-5-甲基-6-氧-5,6,7,8-四氢蝶啶-2-基)氨基)-3-甲氧基苯基)-1,13-二氧-5,8,11-三噁-2,14-二氮杂十六烷-16-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
(2S,4R)-1-((S)-15-(叔丁基)-1-(4-(((S)-7-乙基-8-异丙基-5-甲基-6-氧-5,6,7,8-四氢喋啶-2-基)氨基)-3-甲氧基苯基)-1,13-二氧-5,8,11-三噁-2,14-二氮杂十六烷-16-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
3.一种药物组合，其特征在于：包含权利要求1-2中任意一项的化合物、及其药学上可接受的盐、水合物以及药学上可接受的赋形剂。
4.如权利要求1-2中任意一项的化合物、及其药学上可接受的盐、水合物在制备与PLK1蛋白和BRD4蛋白活性异常表达相关的疾病药物中的应用。
5.如权利要求3所述药物组合在制备与PLK1蛋白和BRD4蛋白活性异常表达相关的疾病药物中的应用。
6.如权利要求1-2中任意一项的化合物、及其药学上可接受的盐、水合物在制备抗肿瘤药物中的应用。
7.如权利要求3所述药物组合在制备抗肿瘤药物中的应用。
8.如权利要求1-2中任意一项的化合物、及其药学上可接受的盐、水合物在制备用于治疗和/或预防乳腺癌，结肠癌，前列腺癌，胰腺癌，非小细胞肺癌，甲状腺乳头状癌，卵巢癌、黑色素瘤或各种白血病的药物中的应用。
9.如权利要求3所述药物组合在制备用于治疗和/或预防乳腺癌，结肠癌，前列腺癌，胰腺癌，非小细胞肺癌，甲状腺乳头状癌，卵巢癌、黑色素瘤或各种白血病的药物中的应用。
10.根据权利要求8或9所述的应用，其特征在于，其中白血病是指急性髓性白血病。
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