CN116730969B - 一种β-拉帕醌-氨基酸缀合物及其制备方法和应用 - Google Patents
一种β-拉帕醌-氨基酸缀合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种β‑拉帕醌‑氨基酸缀合物及其制备方法和应用,该化合物的结构式如式(Ⅰ)所示,该类化合物可以通过NQO1酶的诱导的氧化还原循环,是一种有效的NQO1底物;其在保持细胞和动物水平上良好抗肿瘤活性的同时,还具有良好的溶解度以及血液安全性,是一类有效的抗肿瘤药物。
Description
技术领域
本发明涉及一种有机化合物及其制法和应用,具体涉及一种β-拉帕醌-氨基酸缀合物及其制备方法和应用。
背景技术
NQO1全名依赖还原性辅酶I/II:醌氧化还原酶1NAD(P)H:quinineoxidoreductase 1(NQO1,EC1.6.99.2)。在肿瘤细胞中,NQO1酶高度表达,是一种以黄素腺嘌呤二核苷酸(FAD)为辅基的高度表达的双电子氧化还原酶。其是一种黄素蛋白酶,可以在细胞内通过双电子还原的方式,借助辅酶还原性烟酰胺腺嘌呤核二苷酸磷酸NAD(P)H,将醌类化合物还原为氢醌。该过程称为NQO1酶催化醌底物诱导的氧化还原循环。在该过程中,通过辅酶NADPH的介导,产生大量的活性氧。大量外源性活性氧的产生,致使肿瘤细胞中的活性氧超过其所能承受的阈值,从而通过多种下游通路,最终导致肿瘤细胞的凋亡。β-拉帕醌为该循环的代表性化合物。
β-拉帕醌为邻醌类NQO1酶靶向活性氧生成剂,是现如今研究最广泛的邻醌类底物,具有显著的药理活性,已有药物进入到临床II期。然而其显著的缺点,限制了其在临床试验中的发展。如:1)β-拉帕醌选择性较差。其既可以被双电子还原酶还原,又可以被单电子还原酶还原,二者均可产生大量的活性氧,导致肿瘤细胞凋亡。然而,单电子还原酶广泛存在于各种细胞中,这可能会导致正常细胞的凋亡,产生严重的毒副作用。2)β-拉帕醌的水溶性差(43ug/mL),生物利用度低。由于其水溶性差,在临床上需利用大量的羟丙基-β-环糊精进行辅助给药。而大量应用羟丙基-β-环糊精,会导致溶血性贫血,严重限制了β-拉帕醌在临床上的发展。3)β-拉帕醌在体内的稳定性较差。β-拉帕醌本身结构不稳定,在碱性条件下C环容易水解开环,且开环后的代谢物可能对正常细胞具有细胞毒性,因此β-拉帕醌无法顺利到达大、小肠。因此,目前亟待提高β-拉帕醌对于肿瘤细胞的选择性,并降低其毒副作用,提高其稳定性。
发明内容
发明目的:本发明旨在提供一种β-拉帕醌-氨基酸缀合物,该化合物可以通过NQO1酶的诱导的氧化还原循环,是一种有效的NQO1底物,其在保持细胞和动物水平上良好抗肿瘤活性的同时,还具有良好的溶解度以及血液安全性;本发明的第二目的在于提供所述β-拉帕醌-氨基酸缀合物的制备方法;本发明的第二目的在于提供所述β-拉帕醌-氨基酸缀合物的医药用途。
技术方案:本发明所述的β-拉帕醌-氨基酸缀合物,该缀合物为具有式(I)结构的化合物或其药学上可接受的盐:
其中R1代表天然氨基酸或非天然氨基酸侧链。
优选地,所述天然氨基酸为:L-丙氨酸或D-丙氨酸、L-缬氨酸或D-缬氨酸、L-亮氨酸或D-亮氨酸、L-酪氨酸或D-酪氨酸、L-丝氨酸或D-丝氨酸、L-天冬氨酸或D-天冬氨酸、L-天冬酰胺或D-天冬酰胺、L-谷氨酸或D-谷氨酸、L-谷氨酰胺或D-谷氨酰胺、L-苯丙氨酸D-苯丙氨酸、L-色氨酸或D-色氨酸、L-组氨酸或D-组氨酸。
优选地,所述非天然氨基酸为:4-甲氧基-L-苯丙氨酸或4-甲氧基-D-苯丙氨酸、O-乙基-L-酪氨酸或O-乙基-D-酪氨酸、O-苄基-L-酪氨酸或O-苄基-D-酪氨酸、4-苯基-L-苯丙氨酸或4-苯基-D-苯丙氨酸、3-(1-萘基)-L-丙氨酸或3-(1-萘基)-D-丙氨酸、4-(三氟甲基)-L-苯丙氨酸或4-(三氟甲基)-D-苯丙氨酸、L-4-溴苯丙氨酸或D-4-溴苯丙氨酸、3-溴-L-苯基丙氨酸或3-溴-L-苯基丙氨酸。
优选地,所述化合物选自以下任意一种:
优选地,所述药学上可接受的盐为所述化合物与碱形成的盐,所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱,胆碱、二乙醇胺或吗啉。
本发明所述的β-拉帕醌-氨基酸缀合物的制备方法包括:化合物II与不同种氨基酸及其化合物反应得到目标物I,反应式如下:
优选地,反应温度为70-80℃,反应时间为4-12h,反应溶剂可选甲醇、丙酮、四氢呋喃、乙醇、乙腈、二氯甲烷、甲苯、DMF等。反应中还需加入有机碱或无机碱,如三乙胺、N,N-二异丙基乙胺、咪唑、4-二甲氨基吡啶、氢氧化钾、氢氧化钠、碳酸钠、碳酸钾、醋酸钠等。同时化合物I可以采用常见的分离方法进行纯化,如重结晶、柱层析等。
本发明所述药物组合物包含所述的β-拉帕醌-氨基酸缀合物;上述β-拉帕醌-氨基酸缀合物可以添加药学上可接受的载体制成药用制剂。
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。
本发明所述的化合物可以应用于制备治疗肿瘤疾病的药物所述肿瘤疾病为胰腺癌或非小细胞肺癌。
有益效果:与现有技术相比,本发明具有如下显著优点:所述β-拉帕醌-氨基酸缀合物的安全性明显优于β-拉帕醌,在提高药效的同时,该类化合物提高了β-拉帕醌的选择性、稳定性以及水溶性,且有效降低了β-拉帕醌的毒副作用,大大提升了用药安全性,为抗肿瘤治疗提供了良好的应用前景。
具体实施方式
下面结合具体实施例对本发明的技术方案作进一步说明。
中间体化合物II合成路线:
1、2-羟基-3-(3-羟基丙基)萘-1,4-二酮(2)的制备
将2-羟基-萘-1,4-二酮(20g,0.115mol)溶于无水N,N-二甲基甲酰胺(50mL)中,随后加入1-溴-3-甲基-2-丁烯(14.8mL,0.127mol)、三乙胺(17.8mL,0.127mol)和碘化钾(19.1g,0.115mol)。将反应液加热至50℃,搅拌反应6h。TLC监测反应结束后,将反应液冷却至室温,并缓慢加入冰水(300mL)中析出橙黄色固体。抽滤并干燥得橙黄色粗品2(21.7g,77.9%)。mp 139-140℃.1H NMR(300MHz,DMSO-d6)δ:8.05-7.95(m,2H),7.82-7.68(m,2H),5.18-5.08(m,1H),3.15(d,J=6.7Hz,2H),1.70(s,3H),1.61(s,3H);m/z(EI-MS):232[M]+。
2、2,2-二甲基-3,4-二氢-2H-苯并[h]色烯-5,6-二酮(II)的制备
将化合物2(20g,0.083mol)溶于无水二氯甲烷(30mL)中,在冰水浴条件下,缓慢加入浓硫酸(24.4g,0.249mol)于反应液中并于室温下搅拌反应5h。TLC监测反应结束后,将反应液缓慢倒入冰水(80mL)中淬灭后,以乙酸乙酯(40mL×3)萃取,有机相分别用饱和NaHCO3水溶液(50mL×3)、饱和NaCl溶液(20mL×3)依次洗涤,无水Na2SO4干燥,减压浓缩。所得残留物通过硅胶柱层析分离纯化(洗脱剂:石油醚/乙酸乙酯=20:1),得橙红色固体中间体II(14.8g,74.2%)。mp 158-160℃.1H NMR(300MHz,DMSO-d6)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
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-D-丙氨酸(I-1)的制备:
将II(100mg,0.413mmol)、D-丙氨酸(147.2mg,1.652mmol)溶于无水甲醇(15mL)随后加入无水碳酸钾(228.3mg,1.652mmol)。将反应液加热至66℃,搅拌反应8h。TLC监测反应结束后,减压蒸馏除去甲醇,加入水(20mL),以乙酸乙酯(15mL×3)萃取,有机相分别用饱和NH4Cl水溶液(8mL×3)、饱和NaCl溶液(8mL×3)依次洗涤,无水Na2SO4干燥,减压浓缩。所得残留物通过硅胶柱层析分离纯化(洗脱剂:石油醚/乙酸乙酯=7:1),最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-D-丙氨酸(I-1),70.7mg,产率为52.3%,淡黄色固体。mp 256.7-257.2℃;1H NMR(400MHz,chloroform-d)δ8.29(ddd,J=25.4,8.2,3.9Hz,1H),7.59-7.44(m,1H),7.42-7.35(m,1H),7.34-7.28(m,1H),1.45(d,J=7.4Hz,1H),1.40(s,1H),1.36(s,2H),1.31(s,3H),1.28(s,6H);HRMS-ESIm/z[M-H]-calculated for C18H19NO4:312.1241,found:312.1241。
实施例2
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-丙氨酸(I-2)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,用L-丙氨酸(147.2mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-丙氨酸(I-2),86.1mg,产率为63.7%,黄棕色固体。mp285.8-287.2℃;1H NMR(300MHz,chloroform-d)δ8.32(d,J=8.1Hz,1H),8.08(d,J=8.1Hz,1H),7.61-7.55(m,1H),7.48(ddd,J=8.3,6.9,1.4Hz,1H),3.13(s,1H),2.73(s,2H),1.99(t,J=6.7Hz,2H),1.62(s,3H),1.47(s,6H);HRMS-ESI m/z[M-H]-calculatedfor C18H19NO4:312.1241,found:312.1245。
实施例3
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-缬氨酸(I-3)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,用L-缬氨酸(193.5mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-缬氨酸(I-3),69.5mg,产率为49.3%,棕色固体。mp201.5-202.2℃;1H NMR(400MHz,chloroform-d)δ8.33(d,J=8.5Hz,1H),8.12(dd,J=8.3,1.2Hz,1H),7.61-7.57(m,1H),7.52-7.48(m,1H),3.47-3.42(m,1H),3.18(t,J=6.7Hz,2H),1.98(d,J=6.7Hz,2H),1.91(q,J=7.3Hz,1H),1.47(s,6H),1.31(s,3H),1.28(s,3H);HRMS-ESI m/z[M-H]-calculated for C20H23NO4:340.1554,found:340.1554。
实施例4
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-亮氨酸(I-4)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,用L-亮氨酸(216.4mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-亮氨酸(I-4),44.9mg,产率为30.6%,淡绿色固体。mp197.7-199.1℃;1H NMR(400MHz,chloroform-d)δ8.39(dt,J=7.8,3.6Hz,1H),8.31(t,J=8.5Hz,1H),7.63-7.56(m,1H),7.52-7.45(m,1H),3.20-3.11(m,1H),3.05(t,J=6.7Hz,1H),2.95-2.86(m,2H),2.33(ddd,J=17.0,13.7,6.9Hz,2H),1.48(d,J=6.0Hz,2H),1.28(s,6H),1.08(t,J=6.9Hz,6H);HRMS-ESI m/z[M-H]-calculated for C21H25NO4:354.1711,found:354.1712。
实施例5
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-D-丝氨酸(I-5)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,用D-丝氨酸(173.6mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-D-丝氨酸(I-5),53.5mg,产率为39.3%,褐色油状液体。1H NMR(400MHz,chloroform-d)δ8.29-8.03(m,1H),7.72-7.60(m,1H),7.59-7.46(m,1H),7.45-7.30(m,1H),3.78-3.58(m,1H),2.95-2.72(m,1H),2.60(t,J=6.6Hz,1H),1.79-1.64(m,2H),1.28(s,6H);HRMS-ESI m/z[M-H]-calculated for C18H19NO5:328.1190,found:328.1190。
实施例6
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-丝氨酸(I-6)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,用L-丝氨酸(173.6mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-丝氨酸(I-6),57.3mg,产率为42.1%,棕色油状液体。1H NMR(400MHz,chloroform-d)δ8.65(dd,J=26.5,7.8Hz,1H),8.21-8.09(m,1H),7.65(dt,J=16.8,8.3Hz,1H),7.57-7.50(m,1H),4.16-4.08(m,1H),3.75(d,J=14.4Hz,1H),3.51(d,J=7.3Hz,1H),2.60(t,J=6.7Hz,1H),1.77-1.67(m,1H),1.52-1.44(m,2H),1.28(s,6H);HRMS-ESI m/z[M-H]-calculated for C18H19NO5:328.1190,found:328.1192.
实施例7
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-天门冬氨酸(I-7)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,用L-天门冬氨酸(219.9mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-天门冬氨酸(I-7),51.2mg,产率为34.7%,淡黄色固体。mp 200.0-201.2℃;1H NMR(400MHz,chloroform-d)δ8.38-8.26(m,2H),7.63-7.59(m,1H),7.50(s,1H),4.18(d,J=24.1Hz,2H),3.51(s,1H),1.99(s,2H),1.38(s,2H),1.28(s,6H);HRMS-ESI m/z[M-H]-calculated for C19H19NO6:356.1140,found:356.1139。
实施例8
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-天冬酰胺(I-8)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,用L-天冬酰胺(218.3mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-天冬酰胺(I-8),54.6mg,产率为37.1%,黄色固体。mp169.2-171.7℃;1H NMR(300MHz,chloroform-d)δ8.38-8.33(m,1H),8.12(d,J=7.9Hz,1H),7.84-7.69(m,1H),7.68-7.49(m,3H),4.07(s,1H),3.14(t,J=6.6Hz,1H),3.06(t,J=6.6Hz,1H),2.15(d,J=8.7Hz,1H),2.01(t,J=6.7Hz,2H),1.88(t,J=7.5Hz,1H),1.50(d,J=3.4Hz,6H);HRMS-ESI m/z[M-H]-calculated for C19H20N2O5:355.1299,found:355.1302。
实施例9
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-谷氨酸(I-9)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,用L-谷氨酸(243mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-谷氨酸(I-9),69.5mg,产率为47.2%,棕色固体。mp169.9-170.5℃;1H NMR(400MHz,chloroform-d)δ7.70-7.66(m,1H),7.60-7.57(m,1H),7.51-7.48(m,1H),7.38(t,J=2.3Hz,1H),3.51(s,1H),3.36(t,J=7.7Hz,2H),2.60(t,J=6.6Hz,2H),1.48(s,2H),1.36(s,1H),1.31(s,1H),1.28(s,6H);HRMS-ESI m/z[M-H]-calculatedfor C20H21NO6:370.1296,found:370.1292。
实施例10
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-谷氨酰胺(I-10)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,用L-谷氨酰胺(241.4mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-谷氨酰胺(I-10),50.3mg,产率为32.9%,淡黄色固体。mp 164.2-165.7℃;1H NMR(400MHz,chloroform-d)δ8.32(q,J=7.4Hz,1H),7.67(d,J=8.2Hz,1H),7.61-7.56(m,1H),7.50(d,J=8.0Hz,1H),4.32(q,J=7.0Hz,1H),2.63-2.51(m,2H),2.34(q,J=14.0,10.8Hz,2H),2.00-1.96(m,2H),1.35(s,1H),1.31(s,1H),1.28(s,6H);HRMS-ESI m/z[M-H]-calculated for C20H22N2O5:369.1456,found:369.1459。
实施例11
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-D-苯丙氨酸(I-11)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,D-苯丙氨酸(272.9mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-D-苯丙氨酸(I-11),101.7mg,产率为61.1%,棕黄色固体。mp 175.4-177.0℃;1H NMR(400MHz,chloroform-d)δ8.75(ddd,J=8.4,1.3,0.7Hz,1H),8.20(ddd,J=8.4,1.4,0.7Hz,1H),8.12(dd,J=8.2,1.6Hz,2H),7.76-7.69(m,1H),7.54(d,J=0.8Hz,1H),7.52-7.49(m,2H),7.44-7.41(m,1H),6.14(s,1H),2.95(td,J=6.7,1.7Hz,2H),2.06(dd,J=13.0,6.3Hz,1H),2.00(t,J=6.8Hz,2H),1.92-1.81(m,1H),1.52(s,3H),1.49(s,3H);HRMS-ESI m/z[M-H]-calculated for C24H23NO4:388.1554,found:388.1553。
实施例12
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-苯丙氨酸(I-12)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,L-苯丙氨酸(272.9mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-苯丙氨酸(I-12),123.6mg,产率为74.2%,黄色固体。mp 173.1-174.2℃;1H NMR(400MHz,chloroform-d)δ8.71-8.64(m,1H),8.43-8.26(m,2H),7.71(ddt,J=7.7,6.6,1.5Hz,1H),7.65-7.57(m,2H),7.49(ddd,J=8.3,6.9,1.3Hz,1H),7.46-7.42(m,1H),7.39-7.35(m,1H),4.38(s,1H),3.17(t,J=6.7Hz,1H),3.01(t,J=6.7Hz,1H),2.05(q,J=6.3Hz,1H),1.96(t,J=6.7Hz,1H),1.65(s,2H),1.53(s,3H),1.47(s,3H);HRMS-ESI m/z[M-H]-calculated for C24H23NO4:388.1554,found:388.1554。
实施例13
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-酪氨酸(I-13)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,L-酪氨酸(224.5mg,1.239mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-酪氨酸(I-13),76.2mg,产率为47.4%,黄色固体。mp212.7-213.4℃;1H NMR(400MHz,chloroform-d)δ8.21(d,J=8.6Hz,1H),8.08(s,1H),7.60-7.47(m,2H),7.39(t,J=7.8Hz,1H),7.34(d,J=8.5Hz,1H),7.02(s,1H),6.80(d,J=8.6Hz,1H),5.74(s,1H),2.83(dt,J=13.1,6.9Hz,2H),1.89(t,J=8.3Hz,2H),1.42(d,J=2.5Hz,2H),1.28(s,6H);HRMS-ESI m/z[M-H]-calculated for C24H23NO5:404.1503,found:404.1498。
实施例14
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-色氨酸(I-14)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,L-色氨酸(337.4mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-色氨酸(I-14),54.5mg,产率为29.8%,棕褐色固体。mp 198.2-199.9℃;1H NMR(300MHz,chloroform-d)δ8.68(s,1H),8.40(d,J=8.3Hz,1H),8.29(d,J=8.4Hz,1H),8.24-8.19(m,1H),7.94(d,J=3.0Hz,1H),7.81(d,J=7.8Hz,1H),7.58(d,J=7.6Hz,1H),7.43-7.37(m,2H),7.20(dd,J=4.3,1.5Hz,1H),4.53-4.52(m,1H),3.52(s,1H),3.43(s,1H),3.00(t,J=6.7Hz,2H),1.95(t,J=6.7Hz,2H),1.46(s,6H);HRMS-ESI m/z[M-H]-calculated for C26H24N2O4:427.1663,found:427.1661。
实施例15
N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-组氨酸(I-15)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,L-组氨酸(256.3mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物N-[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]-L-组氨酸(I-15),51.2mg,产率为32.7%,黄色固体。mp197.2-198.6℃;1H NMR(400MHz,chloroform-d)δ8.30(d,J=8.5Hz,1H),7.70(s,1H),7.68-7.58(m,2H),7.50(d,J=7.9Hz,1H),7.40(s,1H),3.91(s,1H),3.10-3.02(m,2H),1.97(s,2H),1.52(d,J=5.6Hz,2H),1.49-1.45(s,6H);HRMS-ESI m/z[M-H]-calculated forC21H21N3O4:378.1459,found:378.1456。
实施例16
(2S)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}-3-(4-甲氧基苯基)丙酸(I-16)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,4-甲氧基-L-苯丙氨酸(334mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物(2S)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}-3-(4-甲氧基苯基)丙酸(I-16),74.1mg,产率为42.8%,棕黄色固体。mp 179.9-180.4℃;1H NMR(400MHz,chloroform-d)δ8.22-8.19(m,1H),7.82(d,J=8.4Hz,1H),7.36-7.30(m,2H),7.13(d,J=8.6Hz,2H),6.87-6.85(m,2H),5.10(d,J=6.9Hz,1H),3.80(s,3H),3.32(d,J=8.4Hz,1H),3.19(d,J=7.9Hz,1H),2.80(t,J=6.7Hz,2H),1.91(s,2H),1.33(s,3H),1.28(s,3H);HRMS-ESI m/z[M-H]-calculated for C25H25NO5:418.1660,found:418.1668。
实施例17
(2S)-3-(4-乙氧基苯基)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}丙酸(I-17)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,O-乙基-L-酪氨酸(345.7mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物(2S)-3-(4-乙氧基苯基)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}丙酸(I-17),83.8mg,产率为49.2%,深黄色固体。mp 207.9-208.7℃;1H NMR(400MHz,chloroform-d)δ8.17(d,J=7.9Hz,1H),8.09(s,1H),7.67(s,1H),7.56(d,J=3.6Hz,1H),7.48(s,1H),7.39-7.37(m,1H),7.17-7.13(m,1H),7.07(d,J=7.9Hz,1H),5.47(s,1H),4.25(dd,J=11.5,5.6Hz,2H),3.12-3.05(m,1H),2.38(t,J=7.6Hz,1H),1.47-1.45(m,4H),1.36(s,3H),1.31(s,6H);HRMS-ESI m/z[M-H]-calculated for C26H27NO5:432.1816,found:432.1819。
实施例18
(2S)-3-[4-(苄基氧基)苯基]-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}丙酸(I-18)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,O-苄基-L-酪氨酸(448.2mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物(2S)-3-[4-(苄基氧基)苯基]-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}丙酸(I-18),98mg,产率为47.9%,棕褐色固体。mp 114.2-114.8℃;1H NMR(400MHz,chloroform-d)δ8.02(d,J=8.9Hz,1H),7.45(d,J=7.8Hz,3H),7.39(dd,J=15.2,7.4Hz,5H),7.21-7.11(m,2H),7.04-6.99(m,2H),5.13(d,J=15.0Hz,2H),4.37(d,J=7.1Hz,1H),3.51(s,1H),3.04(s,1H),1.43-1.38(m,4H),1.28(s,6H);HRMS-ESI m/z[M-H]-calculated forC31H29NO5:494.1973,found:494.1978。
实施例19
(2S)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}-3-[4-(三氟甲基)苯基]丙酸(I-19)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,4-(三氟甲基)-L-苯丙氨酸(385.2mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物(2S)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}-3-[4-(三氟甲基)苯基]丙酸(I-19),94.8mg,产率为50.2%,棕黄色固体。HRMS-ESI m/z[M-H]-calculated forC25H22F3NO4:457.1501,found:457.1534。
实施例20
(2S)-3-(4-溴苯基)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}丙酸(I-20)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,L-4-溴苯丙氨酸(403.2mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物(2S)-3-(4-溴苯基)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}丙酸(I-21),89.4mg,产率为46.2%,棕色固体。HRMS-ESI m/z[M-H]-calculated for C24H22BrNO4:467.0732,found:467.0734。
实施例21
(2S)-3-(3-溴苯基)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}丙酸(I-21)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,3-溴-L-苯基丙氨酸(403.2mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物(2S)-3-(3-溴苯基)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}丙酸(I-21),84.5mg,产率为43.7%,棕色固体。HRMS-ESI m/z[M-H]-calculated for C24H22BrNO4:467.0732,found:467.0736。
实施例22
(2S)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}-3-(萘-1-基)丙酸(I-22)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,3-(1-萘基)-L-丙氨酸(355.6mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物(2S)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}-3-(萘-1-基)丙酸(I-22),88.9mg,产率为49.1%,棕色固体。mp 169.6-171.0℃;1H NMR(400MHz,chloroform-d)δ8.19(d,J=8.0Hz,1H),7.88-7.80(m,3H),7.75(d,J=7.7Hz,1H),7.50(s,2H),7.36(d,J=7.8Hz,3H),7.17(d,J=7.4Hz,1H),5.15-5.07(m,1H),3.75(t,J=7.0Hz,1H),3.60-3.55(m,1H),2.41-2.31(m,2H),1.44(d,J=10.0Hz,2H),1.30(s,6H);HRMS-ESI m/z[M-H]-calculated forC28H25NO4:438.1771,found:438.1773。
实施例23
(2S)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}-3-(4-苯基苯基)丙酸(I-23)的制备:
制备方法同实施例1,中间体II(100mg,0.413mmol)原料不变,L-4,4'-联苯丙氨酸(398.6mg,1.652mmol)代替D-丙氨酸。最终获得目标化合物(2S)-2-{[(9Z)-3,3-二甲基-10-氧亚基-1,2,3,4,9,10-六氢菲-9-亚基]氨基}-3-(4-苯基苯基)丙酸(I-23),107.9mg,产率为61.3%,黄色固体。mp 189.3-190.2℃;1H NMR(400MHz,chloroform-d)δ8.40(d,J=8.1Hz,1H),8.34(d,J=8.3Hz,1H),8.29(d,J=8.5Hz,1H),7.59(q,J=5.9,4.4Hz,2H),7.55-7.47(m,2H),7.41(dd,J=16.8,8.8Hz,3H),7.23(d,J=8.4Hz,1H),6.80(d,J=8.5Hz,1H),6.73(d,J=8.5Hz,1H),4.31(s,1H),3.02(t,J=6.7Hz,1H),2.79-2.74(m,1H),1.97(t,J=6.6Hz,2H),1.51(d,J=4.3Hz,2H),1.28(s,6H);HRMS-ESI m/z[M-H]-calculated for C30H27NO4:464.1867,found:464.1869。
实施例24
本发明部分化合物的药理学实验及结果:
1.本发明化合物的NQO1还原活化活性评价
实验方法:采取分光光度法评价化合物的NQO1还原活性。测试选用器材为96孔板透明板,测试终体积为200μL,由192μL PBS缓冲液,2μL NQO1蛋白,2μL化合物以及4μLNADPH组成。将所测试化合物经缓冲液PBS依次稀释到20μM后,进行检测。每孔依次加入192μL PBS缓冲液,2μL NQO1蛋白,2μL化合物,在37℃下孵育5min后,加入4μL NADPH,加后立即开始检测340nm下的吸光度变化。该实验中阴性对照为2μL PBS缓冲溶液,阳性对照为同浓度β-拉帕醌。缓冲溶液配置方法为:0.2M Na2HPO4,0.2M NaH2PO4,0.9% NaCl。还原速率记为μmol NADPH/min/μmol NQO1。
表1实施例化合物被NQO1酶还原活化的速率
由表1可知,本发明的β-拉帕醌-氨基酸缀合物具有良好的NQO1酶还原速率。大部分实施例化合物的活性优于β-拉帕醌。实施例化合物中,实施例I-12化合物的NQO1酶还原速率最优。
2.本发明化合物对于肿瘤细胞的毒性测定
实验方法:采用MTT比色法,培养时间为72h。将不同种细胞接种至96孔板中,待其贴壁后,加入被稀释成6个浓度的待测化合物,每一种浓度设置三个复孔。在37℃下孵育72h,随后加入20μL 5mg/mL的MTT溶液,待孵育结束后检测其在570nm下的吸光度,以检测化合物在多种细胞中的抗增殖活性。测试结果使用Graphpad Prism 8进行分析。阳性对照为β-拉帕醌和吉西他滨。
表2部分化合物对肿瘤细胞Mia PaCa-2以及对正常细胞L02的抑制作用(IC50:μM)
Mia PaCa-2:人胰腺癌细胞;L02:人正常肝细胞。
由表2可知,本系列部分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;同时本系列化合物对正常细胞均无杀伤作用,说明该系列化合物安全性高于β-拉帕醌与GEM。
表3本发明部分化合物对其他细胞株的抑制作用(IC50:μM)
AsPC-1、CFPAC-1、PANC-1:人胰腺癌细胞。
由表2、3可知,本发明代表性化合物对胰腺癌细胞(AsPC-1、CFPAC-1、PANC-1和MiaPaCa-2细胞)均具有良好的抗肿瘤细胞增殖活性且安全性明显优于β-拉帕醌与吉西他滨,其中,I-12的抗肿瘤细胞增殖活性与安全性最为优秀。
3.本发明化合物溶解度评价
实验方法:在中性溶液中通过Avdeef-Bucher电位滴定法在Gemini Profiler仪器(pION)上测定化合物水溶解度。本发明化合物在基本条件下用磷酸盐缓冲溶液处理,25℃震动8h,目测浓度为500ug/mL未完全溶解时,将其稀释至100ug/mL,重复此过程直至化合物溶解。
表4部分化合物溶解度评估结果
通过表4可知,该系列化合物I-12的溶解度远高于β-拉帕醌。
4.本发明化合物血液安全性评价
实验方法:收集约5mL大鼠血液,用PBS缓冲液以3000r/min的转速离心冲洗10min,重复三次。清洗后,抽取下层填充红细胞,用PBS将其制备成1%的红细胞悬液备用。将检测出化合物与1%的红细胞悬浮液在37℃下孵育3h后,3000r/min离心10min,得到上清液,在540nm处测定血红蛋白的释放量。单项实验重复3次。
表5部分化合物的溶血率
通过表5可知,该系列化合物I-12不会导致溶血性贫血,其血液安全性远高于β-拉帕醌。
5.本发明体内抗肿瘤活性
实验方法:孵育处于生长旺盛期的胰腺癌细胞,在无菌条件下,接种与裸小鼠腋下。1-2周后,用游标卡尺测量裸小鼠腋下瘤直径,将裸小鼠分为6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。空白对照组给予生理盐水;阳性对照组为吉西他滨与β-拉帕醌;化合物组配制为三种不同浓度。每组隔一天进行尾静脉注射给药,持续21天。给药完成后,处理裸小鼠并分离瘤块测量体积及称重。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6本发明代表性化合物的Mia PaCa-2移植瘤的相对肿瘤增值率
由表6可见,本发明的代表性化合物Ⅰ-12裸鼠Mia PaCa-2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。
由此可见,本发明的β-拉帕醌-氨基酸缀合物具有与β-拉帕醌相当的抗肿瘤活性,不仅在选择性以及水溶性上明显优于β-拉帕醌,且其不会造成明显的血液毒性,可用于制备抗肿瘤药物。
Claims (6)
1.一种β-拉帕醌-氨基酸缀合物,其特征在于,该缀合物为具有式(I)结构的化合物或其药学上可接受的盐:
具体选自如下任一结构式化合物或其药学上可接受的盐:
2.根据权利要求1所述的β-拉帕醌-氨基酸缀合物,其特征在于,所述药学上可接受的盐为所述化合物与碱形成的盐,所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱、胆碱或二乙醇胺。
3.一种权利要求1-2任一所述的β-拉帕醌-氨基酸缀合物的制备方法,其特征在于,该方法包括:将化合物II与天然或非天然氨基酸反应得到目标物I,反应式如下:
4.根据权利要求3所述β-拉帕醌-氨基酸缀合物的制备方法,其特征在于,反应温度为70-80℃,反应时间为4-12h。
5.一种药物组合物,其特征在于,含有权利要求1~2任一所述的β-拉帕醌-氨基酸缀合物。
6.一种权利要求1~2任一所述的β-拉帕醌-氨基酸缀合物在制备治疗胰腺癌或非小细胞肺癌药物的应用。
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WO2006020719A2 (en) * | 2004-08-11 | 2006-02-23 | Arqule, Inc. | Aminoacid conjugates of beta - lapachone for tumor targeting |
WO2012039855A1 (en) * | 2010-09-22 | 2012-03-29 | The Board Of Regents Of The University Of Texas System | Ph-sensitive compositions for delivery of beta lapachone and methods of use |
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EP0183649A1 (de) * | 1984-11-26 | 1986-06-04 | Ciba-Geigy Ag | Stickstoffderivate von Oxoverbindungen |
WO2006020719A2 (en) * | 2004-08-11 | 2006-02-23 | Arqule, Inc. | Aminoacid conjugates of beta - lapachone for tumor targeting |
WO2012039855A1 (en) * | 2010-09-22 | 2012-03-29 | The Board Of Regents Of The University Of Texas System | Ph-sensitive compositions for delivery of beta lapachone and methods of use |
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