CN110156822A - 一种萘酚-苯硼酸类化合物及其制备方法和用途 - Google Patents
一种萘酚-苯硼酸类化合物及其制备方法和用途 Download PDFInfo
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- CN110156822A CN110156822A CN201910411217.4A CN201910411217A CN110156822A CN 110156822 A CN110156822 A CN 110156822A CN 201910411217 A CN201910411217 A CN 201910411217A CN 110156822 A CN110156822 A CN 110156822A
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- compound
- pharmaceutically acceptable
- chemical compounds
- naphthols
- acceptable salt
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
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Abstract
本发明公开了一种具有抗肿瘤活性的萘酚‑苯硼酸类化合物(I)及其制备方法和用途。该化合物可以被肿瘤内高水平的活性氧簇(ROS)触发激活,释放出具有抗肿瘤活性的邻萘醌类化合物,在细胞水平和动物水平均表现出良好的抗肿瘤作用,且具有良好的安全性,可用于制备抗肿瘤药物。
Description
技术领域
本发明涉及药物化学领域的有机化合物,具体是一种具有抗肿瘤活性的萘酚-苯硼酸类化合物及其制备方法和用途,该化合物在细胞水平和动物水平均表现出良好的抗肿瘤作用。
背景技术
邻萘醌类化合物广泛存在于天然产物中,大多数具有广泛的生物活性,如抗氧化、抗炎、抗菌等。近年来,在抗肿瘤药物筛选过程中,邻萘醌类化合物对肿瘤细胞普遍表现出较强的毒性作用,如丹参酮IIA、沙尔威辛、β-拉帕醌、董尼酮等(Mini-Reviews inMedicinal Chemistry 2005,5,449–467)。研究表明邻萘醌类化合物发挥抗肿瘤活性的机制主要有三方面:一是产生烷基化介质,抑制DNA的合成从而产生细胞毒作用;二是抑制肿瘤细胞内多种关键酶的活性,如丙酮酸激酶、拓扑异构酶等,从而使肿瘤细胞发生凋亡;三是大幅度提升肿瘤细胞中的氧化应激水平,打破肿瘤细胞的氧化还原平衡,从而诱导肿瘤细胞凋亡(Current Cancer Drug Targets,2017,17(2),122-136)。邻萘醌类化合物具有良好的肿瘤抑制活性,但其在临床试验中普遍表现出了对正常组织的毒副作用,这极大限制了该类化合物在临床上的应用。造成该类化合物毒副作用的一个主要原因是由于体内正常组织中存在大量的单电子氧化还原酶(如细胞色素P450还原酶、黄嘌呤氧化酶等),可以还原代谢邻萘醌类化合物,产生半醌自由基及ROS,从而对正常细胞产生毒性(EuropeanJournal of Medicinal Chemistry 2017,129,27–40)。因此,提高邻萘醌类化合物对肿瘤细胞的选择性,降低其毒副作用,具有极大的临床应用价值。
前药策略是实现肿瘤靶向性,降低毒副作用的一种有效策略。高ROS水平是肿瘤细胞微环境的一个重要特征,研究表明诸多肿瘤细胞中ROS水平远高于正常细胞(CancerCell 2006,10,175–176)。因此,设计ROS触发激活的前药可以提高邻萘醌类化合物对肿瘤细胞的选择性,避免其被正常细胞中的单电子氧化还原酶代谢而产生的毒副作用。硼酸或硼酸酯作为肿瘤细胞ROS特异性触发基团,近年来被广泛应用于ROS靶向荧光探针及抗肿瘤前药的设计中(Journal of Medicinal Chemistry 2018,61,3503–3515)。
发明内容
发明目的:本发明目的在于提供一种萘酚-苯硼酸类化合物,该化合物可以被肿瘤内高水平的活性氧簇(ROS)触发激活,释放出具有抗肿瘤活性的邻萘醌类化合物,在细胞水平和动物水平均表现出良好的抗肿瘤作用,且具有良好的安全性,可用于制备抗肿瘤药物。
技术方案:本发明公开了一种萘酚-苯硼酸类化合物及其制备方法和用途。本发明将肿瘤细胞ROS特异性触发的硼酸或硼酸酯结构通过连接链与邻萘醌类化合物“氢醌”上的酚羟基相连,设计并合成了一类ROS触发激活的萘酚-苯硼酸类化合物。
本发明的化合物具有通式I所示的结构:
其中R1a、R1b代表氢或且R1a、R1b不能同时为氢或上述R6a、R6b各自代表相同或不同的氢、C1~C4烷基或R6a、R6b连接形成5~6元含硼杂环;n代表0或1;B代表单键或双键,且当B为双键时R2b、R3b不存在。
化合物(I)或其药学上可接受的盐,其中B代表单键,R2a、R2b、R3a、R3b各自代表相同或不同的氢、C1~C4烷基。
化合物(I)或其药学上可接受的盐,其中B代表双键,R2b、R3b不存在,R2a、R3a各自代表相同或不同的氢、C1~C4烷基。
化合物(I)或其药学上可接受的盐,其中n代表1,R4a、R4b各自代表相同或不同的氢、C1~C4烷基。
化合物(I)或其药学上可接受的盐,其中n代表1,R4a、R4b均代表甲基,B代表单键,R2a、R2b、R3a、R3b均代表氢。
化合物(I)或其药学上可接受的盐,其中R5代表氢,或者单取代或多取代的卤素、氰基、硝基、羟基、氨基、甲氧基、C1~C4烷基。
其中优选为
其他取代基一种优选组合为B为单键,R2a、R2b同时为氢,R3a、R3b同时为氢,n为1,R4a、R4b同时为甲基;
其他取代基一种优选组合为B为双键,R2a同时为甲基,R3a、R3b同时为氢,n为1,R4a、R4b同时为甲基;
本发明部分化合物的代号及化学结构如下:
本发明的化合物可以用下列方法制备:
通式I化合物的制备:
其中n、B、R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R5的定义如前。
化合物II与反应得到目标物I,反应温度为20~80℃,反应时间为2~8h,反应溶剂可选DMF、乙腈、丙酮、四氢呋喃、二氯甲烷等。反应中加入无机碱或有机碱,如氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、三乙胺等。反应中还应加入还原剂,如硼氢化钠、亚硫酸钠、连二亚硫酸钠、钯碳/氢气、锌粉等。
同时I化合物可以采用常见的分离方法进行纯化,如重结晶、柱层析等。
本发明也包括通式I化合物的水合物、立体异构体、溶剂化物和药学上可接受的盐等。它们具有与通式I化合物同样的药理活性。
本发明所述的化合物可以添加药学上可接受的载体制成常见的药用制剂,如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、针剂,可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明所述化合物或其药学上可接受的盐用于制备治疗恶性肿瘤的药物的用途。
上述药物用途中涉及的恶性肿瘤包括但不局限于肺癌、胰腺癌、白血病、乳腺癌、胃癌、肝癌、结肠癌、肾癌、脑胶质瘤等。
有益效果:本发明的萘酚-苯硼酸类化合物的安全性明显优于邻萘醌类化合物。其可以被肿瘤内高水平的活性氧簇(ROS)触发激活,释放出具有抗肿瘤活性的邻萘醌类化合物,具有与邻萘醌类原药相当的抗肿瘤活性,并且在选择性上明显优于邻萘醌类原药。临床所用剂量为0.01mg~1000mg/天,也可根据病情的轻重或剂型的不同进行调整。
具体实施方式
通式I化合物合成路线
2-羟基-3-(3-羟基丙基)萘-1,4-二酮(2a)的制备
将2-羟基萘-1,4-二酮(1.74g,10mmol)溶解于无水DMF(20mL)中,随后加入3-溴丙-1-醇(1.53g,11mmol)、三乙胺(1.52mL,11mmol)和碘化钠(1.50g,10mmol)。将反应液于50℃下搅拌5小时。反应结束后冷却至室温,将反应液倒入冰水中,并以乙酸乙酯萃取,有机相分别用饱和NaHCO3水溶液(30mL)、饱和NaCl溶液(30mL)依次洗涤,无水Na2SO4干燥。以石油醚/乙酸乙酯(20:1)硅胶柱层析纯化,获得黄色固体(766mg,33%)。1H NMR(300MHz,CDCl3)δ8.20(dd,J=5.7,3.9Hz,1H),8.14(dd,J=5.7,3.9Hz,1H),7.79(dd,J=5.7,3.9Hz,2H),6.95(s,1H),2.31(t,J=7.1Hz,2H),1.78(t,J=7.1Hz,2H),1.22(s,6H);m/z(EI-MS):232[M]+。
3,4-二氢-2H-苯并[h]色烯-5,6-二酮(3a)的制备
将2a(1.16g,5mmol)溶解于无水DCM(20mL)中,冰水浴条件下缓慢加入浓硫酸(2.5g,25mmol)于反应液中并于室温下搅拌4小时。反应加水(50mL)淬灭后,以乙酸乙酯萃取,有机相分别用饱和NaHCO3水溶液(30mL)、饱和NaCl溶液(30mL)依次洗涤,无水Na2SO4干燥。以石油醚/乙酸乙酯(20:1)硅胶柱层析纯化,获得红色固体(0.29g,25%)。mp 158-160℃.1H NMR(300MHz,DMSO)δ:8.07(dd,J=1.8Hz,1H),7.82(dd,J=1.8Hz,1H),7.64(dt,J=1.8Hz,1H),7.53(dt,J=1.8Hz,1H),2.58(t,J=6.6Hz,2H),1.86(t,J=6.5Hz,2H),1.47(s,6H);m/z(EI-MS):232[M]+。
实施例1
化合物Ⅰ-1的制备
将3a(0.23g,1mmol),4-溴甲基苯硼酸(0.43g,2mmol)以及连二亚硫酸钠(0.70g,4mmol)溶于N,N-二甲基甲酰胺(10mL)及水(10mL)中,向反应液中加入氢氧化钠(0.40g,10mmol)。反应液于50℃下搅拌3小时。反应结束后冷却至室温,将反应液倒入冰水中,并以乙酸乙酯萃取,有机相分别用饱和NaHCO3水溶液(30mL)、饱和NaCl溶液(30mL)依次洗涤,无水Na2SO4干燥。以石油醚/乙酸乙酯(20:1)硅胶柱层析纯化,获得白色固体(52mg,15%)。1HNMR(300MHz,DMSO)δ:7.60(dd,J=12.5,7.4Hz,2H),7.44(dd,J=9.7,7.6Hz,2H),7.33(d,J=7.7Hz,2H),6.38(d,J=7.7Hz,2H),4.08(d,J=9.1Hz,1H),3.98-3.85(m,3H),2.45-2.31(m,1H),2.04-1.93(m,1H),1.63-1.49(m,2H).ESI-HRMS m/z[M+H]+calculated forC20H20BO5:351.1398,found:351.1340.
实施例2
化合物Ⅰ-2的制备
用6-甲基-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮以及用4-溴甲基苯硼酸二甲酯(2mmol)代替4-溴甲基苯硼酸,已与化合物Ⅰ-1相同的方法合成化合物Ⅰ-2(63mg,16%)。1H NMR(300MHz,DMSO)δ:δ7.78(d,J=7.4Hz,2H),7.54(t,J=7.5Hz,1H),7.45(d,J=7.3Hz,2H),6.80(d,J=7.4Hz,2H),4.08(d,J=9.1Hz,1H),3.98-3.85(m,3H),2.44-2.33(m,4H),2.05-1.92(m,1H),1.60-1.48(m,2H).ESI-HRMS m/z[M+H]+calculatedfor C23H26BO5:393.1368,found:393.1375.
实施例3
化合物Ⅰ-3的制备
用7-碘-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮以及用4-溴甲基苯硼酸频哪醇酯(2mmol)代替4-溴甲基苯硼酸,已与化合物Ⅰ-1相同的方法合成化合物Ⅰ-3(95mg,17%)。1H NMR(300MHz,CDCl3)δ:7.70(d,J=7.6Hz,2H),7.54(t,J=7.5Hz,1H),7.45(d,J=7.3Hz,2H),6.44(d,J=7.6Hz,2H),4.24(d,J=11.2Hz,1H),3.98-3.85(m,3H),2.48-2.38(m,1H),2.04-1.93(m,1H),1.54-1.42(m,2H),1.25(s,12H).ESI-HRMS m/z[M+H]+calculated for C26H29BIO5:559.1147,found:559.1145.
实施例4
化合物Ⅰ-4的制备
用5-羟基-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮以及用2-(4-溴甲基苯基)-1,3,2-二氧杂硼杂环己烷(2mmol)代替4-溴甲基苯硼酸,已与化合物Ⅰ-1相同的方法合成化合物Ⅰ-4(65mg,16%)。1H NMR(300MHz,CDCl3)δ:7.65(s,1H),7.40-7.28(m,2H),7.14(d,J=8.3Hz,2H),6.40(d,J=8.4Hz,2H),4.44(t,J=5.5Hz,4H),4.14(d,J=10.8Hz,1H),3.98-3.85(m,3H),2.53(dt,J=17.6,5.6Hz,1H),2.41-2.34(m,2H),2.18-2.05(m,1H),1.67-1.53(m,2H).ESI-HRMS m/z[M+H]+calculated for C23H24BO6:407.1660,found:407.1664.
实施例5
化合物Ⅰ-5的制备
用8-氟-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮,已与化合物Ⅰ-1相同的方法合成得到化合物Ⅰ-5(129mg,35%)。1H NMR(300MHz,DMSO)δ:7.82(s,2H),7.50(d,J=7.6Hz,2H),7.46-7.41(m,2H),7.38-7.33(m,1H),6.37(d,J=7.6Hz,2H),5.79(s,1H),4.05-3.90(m,2H),3.07(d,J=11.9Hz,1H),2.93(d,J=11.9Hz,1H),2.37-2.27(m,1H),2.00-1.89(m,1H),1.54(t,J=6.0Hz,2H).ESI-HRMS m/z[M+H]+calculated forC20H19BFO5:369.1304,found:369.1308.
实施例6
化合物Ⅰ-6的制备
用6-氯-8-氟-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮以及用4-溴甲基苯硼酸频哪醇酯(2mmol)代替4-溴甲基苯硼酸,已与化合物Ⅰ-1相同的方法合成得到化合物Ⅰ-6(170mg,35%)。1H NMR(300MHz,CDCl3)δ7.75(s,1H),7.48-7.39(m,1H),7.32(d,J=7.2Hz,2H),6.68(d,J=7.7Hz,2H),5.21(s,1H),4.05-3.90(m,2H),3.07(d,J=11.9Hz,1H),2.93(d,J=11.9Hz,1H),2.45-2.31(m,1H),2.04-1.93(m,1H),1.63-1.49(m,2H),1.26(s,12H).ESI-HRMS m/z[M+H]+calculated for C26H28BClFO5:485.1697,found:485.1703.
实施例7
化合物Ⅰ-7的制备
用4-溴-2-甲基丁-2-醇(11mmol)代替3-溴丙-1-醇,已与化合物Ⅰ-1相同的方法合成得到化合物Ⅰ-7(121mg,32%)。1H NMR(300MHz,DMSO)δ:7.82(s,2H),7.63(d,J=7.7Hz,1H),7.50(d,J=7.6Hz,2H),7.46-7.41(m,2H),7.38-7.33(m,1H),6.37(d,J=7.6Hz,2H),5.79(s,1H),3.07(d,J=11.9Hz,1H),2.93(d,J=11.9Hz,1H),2.37-2.27(m,1H),2.00-1.89(m,1H),1.54(t,J=6.0Hz,2H),1.27(s,3H),0.86(s,3H).ESI-HRMS m/z[M+H]+calculated for C22H24BO5:379.1711,found:379.1715.
实施例8
化合物Ⅰ-8的制备
用3-溴-2,2-二甲基丙-1-醇(11mmol)代替3-溴丙-1-醇以及用2-(4-溴甲基苯基)-1,3,2-二氧杂硼杂环己烷(2mmol)代替4-溴甲基苯硼酸,已与化合物Ⅰ-1相同的方法合成得到化合物Ⅰ-8(142mg,34%)。1H NMR(300MHz,DMSO)δ:7.67-7.60(m,2H),7.51-7.42(m,3H),7.34(td,J=7.6,1.4Hz,1H),6.59(d,J=8.0Hz,2H),4.14(t,J=5.5Hz,4H),4.01(s,1H),3.10(d,J=11.9Hz,1H),2.98-2.89(m,3H),2.54(dt,J=17.3,5.6Hz,1H),2.21-2.10(m,1H),2.08-1.97(m,2H),1.36(s,3H),1.10(s,3H).ESI-HRMS m/z[M+H]+calculated forC25H28BO5:419.2024,found:419.2030.
实施例9
化合物Ⅰ-9的制备
用3-溴-3-甲基丁-1-醇(11mmol)代替3-溴丙-1-醇以及用4-溴甲基苯硼酸频哪醇酯(2mmol)代替4-溴甲基苯硼酸,已与化合物Ⅰ-1相同的方法合成得到化合物Ⅰ-9(161mg,35%)。1H NMR(300MHz,CDCl3)δ:7.68-7.64(m,2H),7.53-7.45(m,3H),7.35(td,J=7.6,1.4Hz,1H),6.60(d,J=8.0Hz,2H),3.92(t,J=6.8Hz,2H),3.11(s,1H),1.62(t,J=6.6Hz,2H),1.35(s,3H),1.32(s,12H),1.00(s,3H).ESI-HRMS m/z[M+H]+calculated forC28H34BO5:461.2494,found:461.2502.
实施例10
化合物Ⅰ-10的制备
用4-溴-2-甲基丁-2-醇(11mmol)代替3-溴丙-1-醇以及用2-(4-溴甲基苯基)-1,3,2-二氧杂硼杂环己烷(2mmol)代替4-溴甲基苯硼酸,已与化合物Ⅰ-1相同的方法合成得到化合物Ⅰ-10(150mg,36%)。1H NMR(300MHz,CDCl3)δ:7.67-7.60(m,2H),7.51-7.42(m,3H),7.34(td,J=7.6,1.4Hz,1H),6.59(d,J=8.0Hz,2H),4.14(t,J=5.5Hz,4H),4.01(s,1H),3.10(s,2H),2.54(dt,J=17.3,5.6Hz,1H),2.21-2.10(m,1H),2.08-1.97(m,2H),1.65-1.57(m,2H),1.36(s,3H),1.07(s,3H).ESI-HRMS m/z[M+H]+calculated for C25H28BO5:419.2024,found:419.2027.
实施例11
化合物Ⅰ-11的制备
用4-溴-2-甲基丁-2-醇(11mmol)代替3-溴丙-1-醇以及用4-溴甲基苯硼酸频哪醇酯(2mmol)代替4-溴甲基苯硼酸,已与化合物Ⅰ-1相同的方法合成得到化合物Ⅰ-11(179mg,39%)。1H NMR(300MHz,CDCl3)δ:7.68-7.64(m,2H),7.53-7.45(m,3H),7.35(td,J=7.6,1.4Hz,1H),6.60(d,J=8.0Hz,2H),4.01(s,1H),3.11(s,1H),2.54(dt,J=17.3,5.6Hz,1H),2.10(dt,J=17.4,7.6Hz,1H),1.62(t,J=6.6Hz,2H),1.39(s,3H),1.32(s,12H),1.00(s,3H).ESI-HRMS m/z[M+H]+calculated for C28H34BO5:461.2494,found:461.2506.
实施例12
化合物Ⅰ-12的制备
用4-溴-2-甲基丁-2-醇(11mmol)代替3-溴丙-1-醇,已与化合物Ⅰ-1相同的方法合成得到化合物Ⅰ-12(78mg,17%)。1H NMR(300MHz,DMSO)δ:7.63(d,J=7.7Hz,1H),7.50(d,J=7.6Hz,2H),7.46-7.41(m,2H),7.38-7.33(m,1H),6.37(d,J=7.6Hz,2H),5.79(s,1H),4.03(d,J=11.9Hz,1H),3.93(d,J=11.9Hz,1H),2.37-2.27(m,1H),2.00-1.89(m,1H),1.55-1.45(m,2H),1.37(s,3H),1.32(s,12H),0.90(s,3H).ESI-HRMS m/z[M+H]+calculated for C28H34BO5:461.2494,found:461.2501.
实施例13
化合物Ⅰ-13的制备
用3-溴-2-甲基丁-1-醇(11mmol)代替3-溴丙-1-醇以及用2-(4-溴甲基苯基)-1,3,2-二氧杂硼杂环己烷(2mmol)代替4-溴甲基苯硼酸,已与化合物Ⅰ-1相同的方法合成得到化合物Ⅰ-13(79mg,19%)。1H NMR(300MHz,CDCl3)δ:7.63(d,J=7.7Hz,1H),7.50(d,J=7.6Hz,2H),7.46-7.41(m,2H),7.38-7.33(m,1H),6.37(d,J=7.6Hz,2H),4.44(t,J=5.5Hz,4H),4.14(d,J=10.8Hz,1H),3.98-3.85(m,3H),2.53(d,J=5.6Hz,1H),1.56(d,J=5.8Hz,1H),1.25(s,3H),1.10(s,3H).ESI-HRMS m/z[M+H]+calculated for C25H28BO5:419.2024,found:419.2030.
实施例14
化合物Ⅰ-14的制备
用3-溴-3-甲基丁-2-醇(11mmol)代替3-溴丙-1-醇以及用4-溴甲基苯硼酸频哪醇酯(2mmol)代替4-溴甲基苯硼酸,已与化合物Ⅰ-1相同的方法合成化合物Ⅰ-14(69mg,15%)。1H NMR(300MHz,CDCl3)δ:7.70(d,J=7.6Hz,2H),7.62-7.53(m,2H),7.43-7.26(m,2H),6.44(d,J=7.6Hz,2H),4.70(q,J=6.9Hz,1H),4.24(d,J=11.2Hz,1H),3.93(d,J=11.0Hz,1H),1.52(d,J=6.0Hz,3H),1.45(s,3H),1.27(s,3H),1.15(s,12H).ESI-HRMS m/z[M+H]+calculated for C28H34BO5:461.2494,found:461.2498.
实施例15
化合物Ⅰ-15的制备
用2-溴乙-1-醇(11mmol)代替3-溴-3-甲基丁-2-醇以及用6-氨基-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮,已与化合物Ⅰ-14相同的方法合成化合物Ⅰ-15(73mg,17%)。1H NMR(300MHz,CDCl3)δ:7.71(s,1H),7.63-7.54(m,2H),7.43-7.26(m,2H),6.44(d,J=7.6Hz,2H),4.24(d,J=11.0Hz,1H),4.05-3.95(m,3H),2.54(d,J=6.5Hz,1H),2.00-1.89(m,1H),1.20(s,12H).ESI-HRMS m/z[M+H]+calculated for C25H29BNO5:434.2133,found:434.2137.
实施例16
化合物Ⅰ-16的制备
用2-溴-2-甲基丙-1-醇(11mmol)代替3-溴-3-甲基丁-2-醇以及用5-羟基-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮,已与化合物Ⅰ-14相同的方法合成化合物Ⅰ-16(171mg,37%)。1H NMR(300MHz,CDCl3)δ:7.72(s,1H),7.65-7.55(m,2H),7.43-7.26(m,2H),6.45(d,J=7.6Hz,2H),4.70(s,2H),3.09(d,J=11.2Hz,1H),2.92(d,J=11.2Hz,1H),1.25(s,3H),1.17(s,12H),0.91(s,3H).ESI-HRMS m/z[M+H]+calculated for C28H34BO5:463.2286,found:463.2294.
实施例17
化合物Ⅰ-17的制备
用1-溴-2-甲基丙-2-醇(11mmol)代替3-溴-3-甲基丁-2-醇以及用7-甲基-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮,已与化合物Ⅰ-14相同的方法合成化合物Ⅰ-17(175mg,38%)。1H NMR(300MHz,CDCl3)δ:7.70(s,1H),7.65-7.55(m,2H),7.43-7.26(m,2H),6.45(d,J=7.6Hz,2H),3.09(d,J=11.2Hz,1H),2.92(d,J=11.2Hz,1H),2.54(d,J=6.5Hz,1H),2.25(s,3H),2.00-1.89(m,1H),1.28(s,3H),1.19(s,12H),0.92(s,3H).ESI-HRMS m/z[M+H]+calculated for C28H34BO5:461.2494,found:461.2498.
实施例18
化合物Ⅰ-18的制备
将化合物Ⅰ-12(0.46g,1mmol)溶于四氯化碳(10mL)中,向反应液中加入DDQ(23mg,1mmol)。反应液于77℃下搅拌24小时。反应结束后冷却至室温,减压蒸馏除去溶剂,乙酸乙酯溶解,有机相分别用饱和NaHCO3水溶液(30mL)、饱和NaCl溶液(30mL)依次洗涤,无水Na2SO4干燥。以石油醚/乙酸乙酯(20:1)硅胶柱层析纯化,获得白色固体(207mg,45%)。1HNMR(300MHz,CDCl3)δ:7.70(d,J=7.6Hz,2H),7.62-7.53(m,2H),7.43-7.26(m,2H),6.44(d,J=7.6Hz,2H),6.21(d,J=11.1Hz,1H),5.04(d,J=11.0Hz,1H),4.24(d,J=11.2Hz,1H),3.93(d,J=11.0Hz,1H),1.27-1.12(m,15H),0.77(s,3H).ESI-HRMS m/z[M+H]+calculated for C28H32BO5:459.2337,found:459.2342.
实施例19
化合物Ⅰ-19的制备
用6-氰基-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮,已与化合物Ⅰ-18相同的方法合成化合物Ⅰ-19(82mg,18%)。1H NMR(300MHz,CDCl3)δ:7.71(d,J=7.6Hz,2H),7.63-7.53(m,1H),7.43-7.26(m,2H),6.44(d,J=7.6Hz,2H),6.21(d,J=11.1Hz,1H),5.04(d,J=11.0Hz,1H),4.24(d,J=11.2Hz,1H),4.05-3.90(m,3H),1.27(s,12H).ESI-HRMS m/z[M+H]+calculated for C27H27BNO5:456.1977,found:456.1983.
实施例20
化合物Ⅰ-20的制备
用7-羟基-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮,已与化合物Ⅰ-18相同的方法合成化合物Ⅰ-20(156mg,34%)。1H NMR(300MHz,CDCl3)δ:7.71(d,J=7.6Hz,2H),7.63-7.53(m,1H),7.43-7.26(m,2H),6.44(d,J=7.6Hz,2H),5.04(d,J=11.0Hz,1H),3.94(s,2H),3.10(d,J=11.2Hz,1H),2.94(d,J=11.2Hz,1H),2.10(s,3H),1.27(s,12H).ESI-HRMS m/z[M+H]+calculated for C27H30BO6:461.2130,found:461.2135.
实施例21
化合物Ⅰ-21的制备
用6-硝基-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮,已与化合物Ⅰ-18相同的方法合成化合物Ⅰ-21(75mg,15%)。1H NMR(300MHz,CDCl3)δ:7.71(d,J=7.6Hz,2H),7.63-7.53(m,1H),7.43-7.26(m,2H),4.24(d,J=11.2Hz,1H),4.05-3.90(m,3H),2.10(s,3H),2.03(s,3H),1.27(s,12H).ESI-HRMS m/z[M+H]+calculated for C28H31BO7:504.2188,found:504.2194.
实施例22
化合物Ⅰ-22的制备
用5-氯-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮,已与化合物Ⅰ-18相同的方法合成化合物Ⅰ-22(75mg,15%)。1H NMR(300MHz,CDCl3)δ:7.71(d,J=7.6Hz,2H),7.63-7.53(m,1H),7.43-7.26(m,2H),6.44(d,J=7.6Hz,2H),6.08(d,J=11.0Hz,1H),3.10(d,J=11.2Hz,1H),2.94(d,J=11.2Hz,1H),2.10(s,3H),1.30-1.22(m,15H),0.90(s,3H).ESI-HRMS m/z[M+H]+calculated for C29H33BClO5:507.2104,found:507.2109.
实施例23
化合物Ⅰ-23的制备
用2-溴乙-1-醇(11mmol)代替3-溴-3-甲基丁-2-醇,已与化合物Ⅰ-18相同的方法合成化合物Ⅰ-23(62mg,15%)。1HNMR(300MHz,CDCl3)δ:8.09(d,J=7.8Hz,1H),7.69-7.62(m,2H),7.47(d,J=9.0Hz,1H),7.43-7.26(m,3H),6.74(d,J=7.6Hz,1H),6.44(d,J=7.6Hz,2H),5.21(s,1H),4.20(d,J=11.2Hz,1H),3.97(d,J=11.0Hz,1H),1.27(s,12H).ESI-HRMS m/z[M+H]+calculated for C25H26BO5:417.1868,found:417.1873.
实施例24
化合物Ⅰ-24的制备
用7-甲氧基-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮,已与化合物Ⅰ-18相同的方法合成化合物Ⅰ-24(412mg,32%)。1HNMR(300MHz,CDCl3)δ:8.10(d,J=7.8Hz,1H),7.72-7.66(m,2H),7.47(d,J=9.0Hz,1H),7.40-7.24(m,2H),6.74(d,J=7.6Hz,1H),6.45(d,J=7.6Hz,2H),5.21(s,1H),3.93(s,3H),3.08(d,J=11.2Hz,1H),2.97(d,J=11.0Hz,1H),3.21(s,3H),1.26(s,12H).ESI-HRMS m/z[M+H]+calculated for C27H30BO6:461.2130,found:461.2136.
实施例25
化合物Ⅰ-25的制备
用8-氟-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮,已与化合物Ⅰ-18相同的方法合成化合物Ⅰ-25(54mg,12%)。1HNMR(300MHz,CDCl3)δ:8.13(d,J=7.8Hz,1H),7.70-7.62(m,1H),7.45(d,J=9.0Hz,1H),7.43-7.25(m,3H),6.44(d,J=7.6Hz,2H),5.21(s,1H),4.20(d,J=11.2Hz,1H),3.97(d,J=11.0Hz,1H),3.21(s,3H),1.27(s,12H).ESI-HRMS m/z[M+H]+calculated for C26H27BFO5:449.1930,found:449.1934.
实施例26
化合物Ⅰ-26的制备
用6-溴-2-羟基萘-1,4-二酮(10mmol)代替2-羟基萘-1,4-二酮,已与化合物Ⅰ-18相同的方法合成化合物Ⅰ-25(188mg,36%)。1HNMR(300MHz,CDCl3)δ:8.09(d,J=7.8Hz,1H),7.73-7.65(m,1H),7.47(d,J=9.0Hz,1H),7.40-7.24(m,2H),6.45(d,J=7.6Hz,2H),5.21(s,1H),3.93(s,3H),3.08(d,J=11.2Hz,1H),2.97(d,J=11.0Hz,1H),3.21(s,3H),3.02(s,3H),1.26(s,12H).ESI-HRMS m/z[M+H]+calculated for C27H29BO5:523.1286,found:523.1290.
测试实施例1
以下是本发明部分化合物的药理学实验及结果:
(1)化合物被H2O2激活释放情况测定
在1.5mL微量离心管中,加入目标前药(1mM),内标溶液(1mM,双氯芬酸),适量PBS缓冲溶液稀释,保证最终总体积为1mL。将离心管置于恒温混匀仪中,加入H2O2(5mM,5equiv)后于37℃下开始混匀,以此时为基准开始计时,并在1h以及2h后取样。采用岛津液质联用仪LC-MS在254nm波长下检测前药的浓度变化。每次测试都需要重复三次以上。
表1本发明部分化合物一定时间内含量的变化
从上述结果可以看出,本发明的化合物可以在H2O2刺激下,快速、定量释放出邻醌类化合物。
此外,本发明研究还发现,实施例中的化合物在测试缓冲溶液、血浆中共孵育24小时,均表现出极高的稳定性,并不能释放出邻醌化合物,提示化合物具有不在血液、正常组织中释放,而选择性在高ROS水平的肿瘤组织中释放的潜在优势,从而具备选择性。
所述萘酚-苯硼酸类化合物可以选择性的被肿瘤细胞内高水平的ROS氧化断裂,使得连接链通过1,6-消除及自氧化释放出邻萘醌类原药,从而发挥选择性抗肿瘤作用。萘酚-苯硼酸衍生物被肿瘤细胞高ROS触发激活释放机制如下所示:
(2)化合物对肿瘤细胞的毒性的测定
实验方法:采用MTT比色法,培养时间为48~72小时。在肿瘤细胞培养基中加入用非细胞毒性浓度的H2O2(50μM-100μM)来刺激肿瘤细胞,模拟肿瘤细胞在肿瘤组织中的高氧化应激及高ROS水平状态。随后加入不同浓度的待测化合物,测定化合物对多种肿瘤细胞中的抗增殖活性。在96孔板中分别以3.0×103/孔接种,每一个化合物与非细胞毒性浓度的H2O2孵育后,设置六个浓度梯度,每一浓度设三个复孔。用酶标仪,在波长570nm处测定光密度值(OD)。以溶剂对照处理的肿瘤细胞为对照组,用Grapad Prism 6软件计算IC50。
表2本发明部分化合物对肿瘤细胞A549、Mia PaCa-2、PANC-1、MV4-11以及对正常细胞L02、HUVEC的抑制作用(IC50:μM):
A549:人肺癌细胞;Mia PaCa-2、PANC-1:人胰腺癌细胞;MV4-11:人白血病细胞;L02:人正常肝细胞;HUVEC:人脐静脉内皮细胞
由表2可见,本发明的化合物具有较强的抗肿瘤细胞增殖的活性,其活性与β-拉帕醌相当;同时该类化合物对正常细胞均无杀伤作用,安全性明显优于邻醌类化合物阳性药物β-拉帕醌。
此外,本发明代表性化合物对乳腺癌细胞(MCF-7)、胃癌(HGC-27)、肝癌(HepG2)、结肠癌(HCT116)、肾癌(A498)、脑胶质瘤(U251)等均具有良好的抗肿瘤细胞增殖活性,说明本发明化合物具有广谱的抗肿瘤作用,对这些肿瘤具有治疗潜力。
表3本发明部分化合物对其他多种肿瘤细胞株生长抑制作用(IC50:μM):
(2)体内抗肿瘤活性研究
实验方法:收集生长旺盛期人肺癌细胞,在无菌条件下制备成细胞悬液,接种于裸小鼠腋下。裸小鼠移植瘤用游标卡尺测量移植瘤直径,待肿瘤生长至一定大小后将动物分组,每组5只。使用测量瘤径的方法,动态观察被试物抗肿瘤的效应。空白对照给予生理盐水;化合物组:尾静脉注射,隔天一次,持续21天。21天后处死荷瘤裸鼠,并分离瘤块称重。所得数据进行统计学处理(t检验),计算相对肿瘤增值率。同时,对最终剥离的瘤块拍照保存图片。
表4本发明代表性化合物的A549移植瘤的相对肿瘤增值率
由表2可见,本发明的代表性化合物Ⅰ-1、Ⅰ-5对裸鼠A549移植瘤具有较好的抑制作用,与β-拉帕醌具有相当的抑制活性。
(3)体内安全性研究
实验方法:进行小鼠急性毒性实验。通过测试Ⅰ-1、Ⅰ-5和β-拉帕醌的半数致死量来评估化合物的体内安全性。实验中所用小鼠为ICR小鼠,每组10只,雌雄各半。空白对照给予生理盐水;给药组当天给药后4小时内,每小时观察动物临床体征及死亡情况,连续观察14天。
表5本发明代表性化合物对正常ICR小鼠的半数致死量(LD50)数据
组别 | 半数致死量(mg/kg) |
Ⅰ-7 | 3500.0 |
Ⅰ-12 | 3200.0 |
I-14 | 3700.0 |
I-25 | 3300.0 |
β-拉帕醌 | 160.0 |
由表5可见,本发明的代表性化合物Ⅰ-1、Ⅰ-5具有明显优于β-拉帕醌的安全性,毒副作用显著小于β-拉帕醌。
由此可见,本发明的萘酚-苯硼酸衍生物具有与邻萘醌类原药相当的抗肿瘤活性,并且在选择性上明显优于邻萘醌类原药,可用于制备抗肿瘤药物。
Claims (10)
1.一种萘酚-苯硼酸类化合物或其药学上可接受的盐,其特征在于该化合物的结构如通式(Ⅰ)所示:
其中R1a、R1b代表氢或且R1a、R1b不能同时为氢或上述R6a、R6b各自代表相同或不同的氢、C1~C4烷基或R6a、R6b连接形成5~6元含硼杂环;n代表0或1;B代表单键或双键,且当B为双键时R2b、R3b不存在。
2.根据权利要求1所述的萘酚-苯硼酸类化合物或其药学上可接受的盐,其特征在于B代表单键,R2a、R2b、R3a、R3b各自代表相同或不同的氢、C1~C4烷基。
3.根据权利要求1所述的萘酚-苯硼酸类化合物或其药学上可接受的盐,其特征在于B代表双键,R2b、R3b不存在,R2a、R3a各自代表相同或不同的氢、C1~C4烷基。
4.根据权利要求1所述的萘酚-苯硼酸类化合物或其药学上可接受的盐,其特征在于n代表1,R4a、R4b各自代表相同或不同的氢、C1~C4烷基。
5.根据权利要求1所述的萘酚-苯硼酸类化合物或其药学上可接受的盐,其特征在于n代表1,R4a、R4b均代表甲基,B代表单键,R2a、R2b、R3a、R3b均代表氢。
6.根据权利要求1所述的萘酚-苯硼酸类化合物或其药学上可接受的盐,其特征在于R5代表氢,或者单取代或多取代的卤素、氰基、硝基、羟基、氨基、甲氧基、C1~C4烷基。
7.一种权利要求1所述的通式(Ⅰ)化合物的制备方法,其特征在于包括下列步骤:
控制反应原料配比可以分别得到仅R1a单取代化合物以及仅R1b单取代化合物。
8.一种药物组合物,其特征在于含有权利要求1~6任一项所述的萘酚-苯硼酸类化合物或其药学上可接受的盐及药学上可接受的载体。
9.如权利要求1所述的化合物或其药学上可接受的盐在制备治疗恶性肿瘤的药物的用途。
10.根据权利要求9所述的用途,其特征在于所述恶性肿瘤为肺癌、胰腺癌、白血病、乳腺癌、胃癌、肝癌、结肠癌、肾癌、脑胶质瘤。
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