CN115160364A - 一种新型的具有抗肿瘤活性三苯基膦前药合成及抗肿瘤活性研究 - Google Patents
一种新型的具有抗肿瘤活性三苯基膦前药合成及抗肿瘤活性研究 Download PDFInfo
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- CN115160364A CN115160364A CN202210788900.1A CN202210788900A CN115160364A CN 115160364 A CN115160364 A CN 115160364A CN 202210788900 A CN202210788900 A CN 202210788900A CN 115160364 A CN115160364 A CN 115160364A
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 4
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Abstract
Description
技术领域
本发明属于有机合成与药物化学技术领域,涉及一类新型的具有抗肿瘤活性的三苯基膦前药的合成和生物评价,该前药通过靶向丙酮酸脱氢酶激酶及组蛋白去乙酰化酶而发挥抗肿瘤活性。
背景技术
上个世纪20年代,德国生化学家Warburg观察到癌细胞比正常细胞消耗更多的葡萄糖,分泌更多乳酸,证明肿瘤细胞即使在氧气充足的条件下依然通过糖酵解的方式来获取能量。肿瘤细胞这种异常代谢特征使得参与糖酵解途径的各种酶和转运蛋白成为治疗癌症的潜力靶点。丙酮酸脱氢酶复合物(PDC)存在于线粒体中,能够催化丙酮酸不可逆地氧化脱羧生成乙酰辅酶A,参与三羧酸循环,为机体提供能量。丙酮酸脱氢酶激酶(PDKs)介导的磷酸化下调PDC活性,抑制细胞氧化磷酸化通路,从而增加肿瘤细胞的糖酵解。而糖酵解产生的乳酸有助于维持正反馈回路,使糖酵解酶、PDKs和多种血管生成刺激分子持续上调以促进肿瘤生长、迁移和转移。靶向PDKs能够逆转肿瘤细胞的Warburg效应,抑制或是杀死肿瘤细胞。
1996年,美国FDA批准上市的一种用于治疗慢性循环尿素紊乱小分子药物——苯丁酸(PBA)。同时,PBA作为一种PDKs抑制剂和组蛋白去乙酰化酶 (HDACs)抑制剂,其可以通过抑制丙酮酸脱氢酶激酶的活性,上调丙酮酸脱氢酶复合物活性,激活线粒体功能,重编程肿瘤代谢途径,减少乳酸的分泌,诱导肿瘤细胞凋亡;或通过影响基因转录过程中染色质折叠来抑制肿瘤细胞的生长。 PBA含有一个羧基,导致其生物膜通透性较差(Papp<0.48×10- 6cm/s,efflux ration>1.54)。而其靶点之一PDKs主要位于含有双层膜结构的线粒体中,另外的一个靶点HDACs亚型SIRT3-5也位于线粒体中。PBA因较差的膜通透性而无法有效透过生物膜进入线粒体中作用于PDKs及HDACs,从而导致抗肿瘤活性极弱,IC50为毫摩尔级别(IC50=8.0mM,A375)。这限制了其进一步在抗肿瘤领域的临床研究和发展。
三苯基膦阳离子(TPP+)作为常用的亲脂性线粒体靶向基团可以在线粒体膜电位的驱动下快速积累在线粒体中,并且因为绝大多数肿瘤细胞比正常细胞具有更高的线粒体膜电位,所以TPP+对肿瘤细胞具有更好的选择性。Mito- Chlorambucil、Mito-Lonidamine、Mito-Ciprofloxacin等化合物均是通过可断裂的酯键或酰胺键连接活性分子和线粒体靶向的TPP+进而将活性分子选择性递送到肿瘤细胞的线粒体中并提高其疗效。因此,采用可断裂的酯键或酰胺键连接PBA 和TPP+构建线粒体靶向缀合物Mito-PBA或可改善PBA的生物膜通透性并提高其抗肿瘤活性。
发明内容
1.本发明涉及具有式(TM)的化合物或其药学上可接受的盐。
其中,X为O或-NH;n为2-11;R1为H时,R2为甲氧基;R2为H时, R1独立选自以下取代基:氟、甲基、甲氧基、氰基、三氟甲基。
2.本发明优选的化合物或者其药学上可接收的盐,其选自:
3.本发明的式(TM)的化合物,可以同时抑制丙酮酸脱氢酶激酶和组蛋白去乙酰化酶,可用于但不局限于治疗癌症疾病。
4.本发明提供了一种新型的靶向于丙酮酸脱氢酶激酶的三苯基膦前药的合成方法,具体的合成路线如下:
合成路线1:
反应条件:
a:二碳酸二叔丁酯((Boc)2O),二氯甲烷;b:苯丁酸(PBA),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),4-二甲氨基吡啶(DMAP),二氯甲烷; c:三氟乙酸(TFA),二氯甲烷;d:EDCI,N-羟基-7-氮杂苯并三氮唑(HOAT), 三乙胺(TEA),乙腈。
1)化合物28的合成:将三羟甲基氨基甲烷(Tris,2.00g,16.51mmol)和(Boc)2O(3.96g,18.16mmol)加到250mL圆底烧瓶中,随后加入DCM(100mL)。在氮气的保护下室温反应12小时。LC-MS监测反应完毕,除去DCM得到固体残渣。粗产物用PE洗涤、抽滤后得到白色粉末状固体化合物28(3.29g,90%)。
2)化合物29的合成:将PBA(2.30g,14.01mmol)、EDCI(2.77g,14.46mmol) 和DMAP(15mol%)加到250mL圆底烧瓶中,随后加入DCM(100mL)。在室温下搅拌15分钟后再加入28(1.00g,4.52mmol)。在氮气的保护下室温反应 5小时。TLC监测反应完毕,除去DCM得到残液。加去离子水并用EA萃取3 次,饱和食盐水洗3次,收集、干燥并浓缩有机相,最后粗产物用硅胶柱层析(PE: EA=10:1)进一步纯化得到无色黏稠的液体29(2.74g,92%)。
3)化合物30的合成:将29(317mg,0.48mmol)加到25mL圆底烧瓶中,随后加入DCM(10mL),搅拌状态下加入TFA(2mL)。在氮气的保护下室温反应2小时。TLC监测反应完毕,饱和碳酸氢钠水溶液淬灭反应,DCM萃取3次,饱和食盐水洗3次,收集、干燥并浓缩有机相得到黄色的黏稠液体30(255mg, 95%)。
4)化合物37-40和53的合成:TPP+羧酸类似物37-40和53的合成过程类似,下面以化合物37的合成为例,介绍它们通用的合成方法。将9(200mg,0.48 mmol)、EDCI(102mg,0.53mmol)和HOAT(72mg,0.53mmol)加到50mL圆底烧瓶中,随后加入MeCN(15mL),室温搅拌15分钟后再加入30(269mg, 0.48mmol)和TEA(97mg,0.96mmol)。在氮气的保护下回流反应12小时。TLC 监测反应完毕,除去MeCN得到残液。DCM萃取3次,饱和食盐水洗3次,收集、干燥并浓缩有机相。最后浓缩液用硅胶柱层析(DCM:MeOH=20:1)进一步纯化得到黄色粘稠液体37(257mg,56%)。
合成路线2:
反应条件:
a:氯化亚砜,吡啶;b:叠氮化钠,水;c:二碳酸二叔丁酯,二氯甲烷;d: 10%Pd/C,氢气;e:苯丁酸,EDCI,DMAP,二氯甲烷;f:三氟乙酸(TFA),二氯甲烷;g:EDCI,N-羟基-7-氮杂苯并三氮唑(HOAT),三乙胺(TEA),乙腈。
1)化合物31的合成:将Tris(10.0g,82.55mmol)加到100mL三口圆底烧瓶中,随后加入吡啶(40mL)。在氮气的保护下,室温缓慢滴加SOCl2(20mL)。滴加完毕将反应转至油浴,缓慢加热到100℃,此过程中有大量气体生成,随后再加热至140℃反应4小时。LC-MS监测反应完毕,将反应冷却到30-50℃,加入去离子水并在0℃下用饱和碳酸氢钠调节pH=8。DCM萃取水相3次,饱和食盐水洗3次,收集、干燥并浓缩有机相。最后得到的浓缩液经减压蒸馏(80- 90℃收集产物)得到无色液体31(9.32g,64%)。
2)化合物32的合成:将31(5.00g,28.33mmol)和NaN3(6.08g,93.49mmol) 加到250mL圆底烧瓶中,随后加入100mL去离子水。在氮气的保护下,反应液在80℃下反应24小时。TLC监测反应毕,先将反应体系冷却至室温,再用1 M氢氧化钠水溶液淬灭反应。EA萃取3次,饱和食盐水洗3次,收集、干燥并浓缩有机相。最后得到黄色液体32(4.89g,88%)。
3)化合物33的合成:将32(4.00g,20.39mmol)加到250mL圆底烧瓶中,随后加入DCM(150mL)和(Boc)2O(5.79g,26.51mmol)。在氮气的保护下室温反应48小时。TLC监测反应毕,除去DCM得到残渣。残渣用PE洗涤、抽滤得到白色粉末状固体化合物33(4.83g,80%)。
4)化合物34的合成:将33(3g,10.12mmol)加到100mL圆底烧瓶中,随后再加入MeOH(50mL)和10%Pd/C(600mg,20%),置换氢气后室温反应12 小时。最后过滤反应液并浓缩滤液得到无色液体34(2.12g,96%)。
5)化合物35的合成:具体合成方法与化合物29的合成类似。
6)化合物36的合成:具体合成方法与化合物30的合成类似。
7)化合物41-52的合成:具体合成方法与化合物37的合成类似。
具体的实施方式:
实施例1:
化合物37的合成:具体合成方法参考合成路线1。1H NMR(400MHz,CDCl3)δ 8.38(s,1H),7.78(t,J=6.8Hz,3H),7.61(m,12H),7.23(d,J=6.8Hz,5H),7.15(m, 10H),4.38(s,6H),3.44(m,2H),2.81(dd,J=15.6,10.4Hz,2H),2.59(t,J=7.2Hz, 6H),2.32(t,J=7.6Hz,6H),1.87(dd,J=15.2,7.6Hz,6H).13C NMR(101MHz, CDCl3)δ172.85,170.01,169.86,141.38,135.29,133.32,133.22,130.53,130.41, 128.38,128.25,125.80,117.90,117.03,61.82,57.91,34.92,33.16,28.42,26.27,19.39, 18.84.HRMS(ESI):calcd.for C55H59NBrO7P[M-Br]+:876.40237,found:876.40231.
实施例2:
化合物38的合成:具体合成方法参考合成路线1。1H NMR(400MHz,CDCl3)δ 7.76(m,3H),7.66(m,12H),7.34(s,1H),7.23(d,J=7.6Hz,6H),7.14(m,9H),4.44 (s,6H),3.22(m,2H),2.57(t,J=7.2Hz,8H),2.29(t,J=7.6Hz,6H),1.86(m,8H). 13C NMR(101MHz,CDCl3)δ172.95,172.37,141.28,135.12,133.27,130.47,130.35, 128.40,128.31,125.87,118.33,117.47,61.81,57.88,34.93,33.21,26.28,21.26,20.75, 18.13.HRMS(ESI):calcd.for C56H61NBrO7P[M-Br]+:890.41802,found:890.41815.
实施例3:
化合物39的合成:具体合成方法参考合成路线1。1H NMR(400MHz,CDCl3)δ 7.78(m,3H),7.63(m,12H),7.23(m,7H),7.13(d,J=7.2Hz,8H),4.39(s,6H),3.21 (m,2H),2.58(t,J=7.6Hz,6H),2.30(m,8H),1.86(m,8H),1.65(s,2H).13C NMR (101MHz,CDCl3)δ172.91,141.34,135.23,133.30,133.20,130.55,130.42,128.41, 128.30,125.85,118.29,117.43,62.19,57.58,34.95,34.55,33.20,26.29,25.84,25.67, 21.88,21.53,21.37.HRMS(ESI):calcd.for C57H63NBrO7P[M-Br]+:904.43367, found:904.43384.
实施例4:
化合物40的合成:具体合成方法参考合成路线1。1H NMR(400MHz,CDCl3)δ 7.80(t,J=7.2Hz,3H),7.63(m,12H),7.24(m,6H),7.15(t,J=4.8Hz,9H),6.76(s, 1H),4.41(s,6H),3.12(m,2H),2.60(t,J=7.6Hz,6H),2.32(t,J=7.6Hz,6H),2.20 (m,2H),1.90(m,6H),1.56(m,6H).13C NMR(101MHz,CDCl3)δ173.95,172.90, 141.15,135.28,133.16,133.06,130.54,130.42,128.33,128.27,125.85,118.03,117.18, 62.23,57.78,35.79,34.87,33.13,29.59,29.43,26.21,24.28,22.38,21.90.HRMS (ESI):calcd.forC58H65NBrO7P[M-Br]+:918.44932,found:918.44933.
实施例5:
化合物41的合成:具体合成方法参考合成路线2。1H NMR(400MHz,CDCl3)δ 7.83(s,1H),7.73(dt,J=21.2,6.4Hz,5H),7.59(m,10H),7.24(m,6H),7.16(d,J= 7.2Hz,9H),3.52(dd,J=15.6,12Hz,2H),3.42(d,J=5.6Hz,6H),2.61(t,J=7.6Hz, 6H),2.55(m,2H),2.28(t,J=7.6Hz,6H),1.92(m,6H).13C NMR(101MHz,CDCl3) δ175.00,141.56,135.25,133.27,133.17,130.53,130.41,128.42,128.26,125.78, 117.96,117.10,61.43,39.81,35.98,35.30,28.96,27.31,19.01,18.46.HRMS(ESI): calcd.for C55H62BrN4O4P[M-Br]+:873.45032,found:873.45418.
实施例6:
化合物42的合成:具体合成方法参考合成路线2。1H NMR(400MHz,CDCl3)δ 7.72(m,11H),7.63(d,J=4.0Hz,5H),7.49(s,1H),7.23(d,J=6.8Hz,5H),7.16(m, 9H),3.48(d,J=4.8Hz,6H),3.39(m,2H),2.60(t,J=7.6Hz,6H),2.47(s,2H),2.27 (t,J=7.2Hz,6H),1.90(dt,J=14.4,7.2Hz,6H),1.83(s,2H).13C NMR(101MHz, CDCl3)δ174.92,172.50,141.53,134.99,133.42,133.32,130.40,130.28,128.41, 128.26,125.79,118.55,117.70,60.90,39.90,36.03,35.28,27.29,21.16,20.64,18.24. HRMS(ESI):calcd.forC56H64BrN4O4P[M-Br]+:887.46576,found:887.46976.
实施例7:
化合物43的合成:具体合成方法参考合成路线2。1H NMR(400MHz,CDCl3)δ 7.80(m,5H),7.73(s,1H),7.65(m,10H),7.22(m,6H),7.14(m,9H),3.42(d,J=6.0 Hz,6H),3.26(t,J=15.2Hz,2H),2.60(m,6H),2.31(m,2H),2.26(m,6H),1.92(m, 6H),1.80(m,2H),1.66(m,2H).13C NMR(101MHz,CDCl3)δ174.61,173.76,141.67, 135.17,133.34,133.24,130.51,130.38,128.42,128.21,125.72,118.31,117.45,61.17, 40.78,36.03,35.31,34.85,27.33,25.83,25.66,21.91,21.40.HRMS(ESI):calcd.for C57H66BrN4O4P[M-Br]+:901.48162,found:901.48489.
实施例8:
化合物44的合成:具体合成方法参考合成路线2。1H NMR(400MHz,CDCl3)δ 7.79(m,5H),7.62(m,12H),7.22(m,5H),7.13(m,8H),5.59(m,3H),3.46(d,J=6.0 Hz,6H),3.19(m,2H),2.60(t,J=7.6Hz,6H),2.27(t,J=7.6Hz,6H),2.14(m,2H), 1.93(dt,J=15.2,8.0Hz,6H),1.55(m,6H).13C NMR(101MHz,CDCl3)δ174.81, 174.32,141.60,135.25,133.26,133.16,130.55,130.42,128.39,128.21,125.73,118.21, 117.36,61.51,41.01,36.33,36.00,35.26,29.45,29.29,27.32,24.22,22.25,21.85, 21.74.HRMS(ESI):calcd.for C58H68BrN4O4P[M-Br]+:915.49727,found:915.49951.
实施例9:
化合物45的合成:具体合成方法参考合成路线2。1H NMR(400MHz,CDCl3)δ 7.79(t,J=7.2Hz,3H),7.66(m,10H),7.27(m,9H),7.15(m,8H),6.96(s,1H),3.39 (d,J=6.4Hz,6H),3.10(m,2H),2.63(t,J=7.6Hz,6H),2.28(t,J=6.8Hz,6H),2.10 (m,2H),1.95(dt,J=15.2,8.0Hz,6H),1.54(m,6H),1.25(m,4H).13C NMR(101 MHz,CDCl3)δ175.04,141.45,135.22,135.19,133.31,133.21,130.61,130.48,128.44, 128.31,125.86,118.28,117.43,61.94,41.28,36.94,36.10,35.28,29.89,29.73,28.30, 27.83,27.29,25.04,22.30,22.25,22.12,21.62.HRMS(ESI):calcd.for C60H72BrN4O4P[M-Br]+:943.52857,found:943.52869.
实施例10:
化合物46的合成:具体合成方法参考合成路线2。1H NMR(400MHz,CDCl3)δ 8.02(m,3H),7.85(s,1H),7.72(m,14H),7.23(m,5H),7.14(m,8H),3.51(d,J=6.0 Hz,8H),2.60(t,J=7.6Hz,6H),2.28(t,J=7.2Hz,6H),2.22(t,J=6.8Hz,2H),1.92 (dt,J=15.2,8.0Hz,6H),1.83(s,3H),1.55(m,6H),1.25(m,8H).13C NMR(101 MHz,CDCl3)δ174.85,174.47,141.71,135.20,135.18,133.34,133.24,130.53,130.41, 128.37,128.16,125.64,118.38,117.52,61.70,41.66,36.91,36.10,35.30,30.06,29.90, 29.58,28.21,28.08,27.88,27.38,25.15,22.37,22.19,22.14,21.86.HRMS(ESI): calcd.for C62H76BrN4O4P[M-Br]+:971.55987,found:971.55936.
实施例11:
化合物47的合成:具体合成方法参考合成路线2。1H NMR(400MHz,CDCl3)δ 7.78(t,J=7.2Hz,3H),7.65(m,11H),7.33(m,3H),7.23(d,J=8.4Hz,5H),7.16(d, J=6.0Hz,8H),3.36(d,J=6.4Hz,6H),3.10(m,2H),2.62(t,J=7.2Hz,6H),2.28 (t,J=7.6Hz,6H),2.09(t,J=7.2Hz,2H),1.95(dt,J=15.2,7.6Hz,6H),1.53(m, 6H),1.20(m,12H).13C NMR(101MHz,CDCl3)δ175.15,141.31,135.20,133.30, 133.21,130.62,130.50,128.42,128.35,125.94,118.30,117.44,62.31,41.64,37.59, 36.15,35.29,30.32,30.17,29.17,29.16,29.07,29.04,28.91,28.84,27.28,25.59,22.47, 22.42,22.31,22.29,21.79.HRMS(ESI):calcd.for C64H80BrN4O4P[M-Br]+: 999.59117,found:999.59139.
实施例12:
化合物48的合成:具体合成方法参考合成路线2。1H NMR(400MHz,CDCl3)δ 7.69(d,J=44.8Hz,8H),7.38(m,6H),7.23(d,J=6.4Hz,5H),7.15(d,J=6.4Hz, 8H),3.44(m,8H),2.62(m,6H),2.27(m,6H),2.10(m,2H),1.94(m,6H),1.51(m, 6H),1.23(m,8H).13C NMR(101MHz,CDCl3)δ174.87,168.09,165.50,141.44, 136.46,128.36,128.25,125.80,118.75,118.62,118.54,118.40,114.15,113.24,61.86, 41.58,37.14,36.05,35.27,30.25,30.10,29.60,28.48,28.40,28.27,27.28,25.27,23.04, 22.38.HRMS(ESI):calcd.for C62H73BrF3N4O4P[M-Br]+:1025.53160,found: 1025.53189.
实施例13:
化合物49的合成:具体合成方法参考合成路线2。1H NMR(400MHz,CDCl3)δ 7.55(m,15H),7.22(m 4H),7.14(m,8H),6.22(s,4H),3.45(s,6H),3.02(s,2H),2.61 (t,J=7.2Hz,6H),2.47(s,9H),2.27(m,6H),2.12(s,2H),1.95(m,6H),1.54(m,6H), 1.22(m,8H).13C NMR(101MHz,CDCl3)δ174.97,146.58,141.39,133.05,132.95, 131.21,131.09,128.29,128.15,125.69,114.95,114.06,61.84,41.48,37.03,35.92, 35.19,30.31,30.16,29.53,28.59,28.52,28.33,27.21,25.36,23.13,22.61,22.19,21.65. HRMS(ESI):calcd.forC65H82BrN4O4P[M-Br]+:1013.60682,found:1013.60635.
实施例14:
化合物50的合成:具体合成方法参考合成路线2。1H NMR(400MHz,CDCl3)δ 7.61(m,6H),7.29(d,J=8.0Hz,3H),7.16(m,18H),3.81(s,9H),3.44(d,J=6.0Hz, 6H),3.13(s,2H),2.61(t,J=7.6Hz,6H),2.28(t,J=7.2Hz,6H),2.11(t,J=7.2Hz, 2H),1.94(m,6H),1.57(m,6H),1.22(m,8H).13C NMR(101MHz,CDCl3)δ175.01, 160.61,160.45,141.40,131.94,131.79,128.31,128.18,125.72,124.93,124.84, 120.07,119.18,119.03,118.91,118.32,61.85,55.66,41.44,37.04,35.92,35.20,30.20, 30.05,29.55,28.58,28.53,28.29,27.22,25.35,22.57,22.37,22.33,22.06.HRMS (ESI):calcd.forC65H82BrN4O7P[M-Br]+:1061.59156,found:1061.59150.
实施例15:
化合物51的合成:具体合成方法参考合成路线2。1H NMR(400MHz,CDCl3)δ 7.94(m,12H),7.51(m,3H),7.43(s,1H),7.22(m,7H),7.13(d,J=6.8Hz,8H),3.69 (m,2H),3.41(m,6H),2.59(t,J=7.6Hz,6H),2.24(t,J=7.2Hz,6H),2.06(m,2H), 1.92(m,6H),1.50(m,6H),1.19(m,8H).13C NMR(101MHz,CDCl3)δ174.91, 141.32,134.44,134.33,133.97,133.84,128.35,128.30,125.89,122.19,121.35,119.30, 119.27,116.40,61.80,41.39,37.18,36.00,35.22,30.13,29.96,29.60,28.51,28.24, 27.27,25.30,22.20,20.88,20.42.HRMS(ESI):calcd.for C65H73BrN7O4P[M-Br]+: 1046.54562,found:1046.54531.
实施例16:
化合物52的合成:具体合成方法参考合成路线2。1H NMR(400MHz,CDCl3)δ 7.95(d,J=6.8Hz,12H),7.45(m,4H),7.24(m,7H),7.15(d,J=6.8Hz,7H),3.69 (m,2H),3.40(d,J=4.8Hz,6H),2.62(t,J=7.2Hz,6H),2.26(t,J=7.2Hz,6H),2.09 (m,2H),1.93(m,6H),1.52(m,6H),1.22(m,8H).13C NMR(101MHz,CDCl3)δ 174.89,141.32,137.56,137.53,137.22,137.19,136.89,136.86,136.55,136.52, 134.32,134.22,128.30,128.22,127.52,127.48,127.39,127.35,125.80,123.92, 123.91,121.78,121.20,121.19,120.93,61.79,41.42,37.11,35.94,35.19,30.11,29.94, 28.65,28.49,28.44,28.24,27.22,25.27,22.22,22.17,21.20,20.73.HRMS(ESI): calcd.for C65H73BrF9N4O4P[M-Br]+:1175.52206,found:1175.52267.
实施例17:
化合物53的合成:具体合成方法参考合成路线1。1H NMR(400MHz,CDCl3)δ 7.97(d,J=6.4Hz,12H),7.25(q,J=7.2Hz,6H),7.16(m,9H),6.06(m,1H),4.40 (m,6H),3.58(m,2H),2.60(dd,J=15.2,7.6Hz,6H),2.30(m,6H),2.14(t,J=7.2 Hz,2H),1.90(m,6H),1.54(m,6H),1.21(m,8H).13C NMR(101MHz,CDCl3)δ 173.81,173.03,141.05,137.70,137.40,137.37,137.06,137.03,136.73,134.36, 134.26,127.62,127.58,127.49,127.45,126.00,123.98,121.78,121.26,120.93,62.51, 58.06,36.82,34.95,33.24,30.15,29.99,28.59,28.55,28.51,28.32,26.25,25.23,22.30, 22.26,21.47,20.99.HRMS(ESI):calcd.for C65H70F9NBrO7P[M-Br]+:1178.47407, found:1178.47427.
实施例18:
MTT比色法:细胞融合度为80%-90%时,将细胞以每孔3-6×103个细胞的密度接种到96孔板。放置于饱和湿度、37℃、含5%CO2培养箱中培养24小时。然后将化合物配成梯度浓度的溶液加入到上述培养板中,放回培养箱继续培养。 48小时后移除含药培养基,加入含有0.5mg/mL MTT的完全培养基继续孵育细胞4小时。之后移除悬浮液并加入100μLDMSO溶解蓝紫色结晶,振荡15分钟。最后用酶标仪在490nm处测定吸光度。数据用Excel处理得到后得到细胞存活率。细胞存活率=(处理组OD值-空白组OD值/(溶剂对照组OD值-空白组OD 值)×100%。最后以药物浓度为横坐标,细胞存活率为纵坐标绘制浓度效应曲线,用GraphPad Prism 6求回归方程,得出50%抑制浓度(50%inhibiting concentration,IC50)。实验最终得到的IC50是三次独立实验得出的平均值。
附图说明
图1:化合物37-53对A375、A549、MCF7、MDA-MB-231的IC50值。
注:Dox为阿霉素,作为阳性对照;数据以平均值±标准差(mean±SD)表示,n=3。
Claims (4)
3.本发明的式(TM)的化合物,可以同时抑制丙酮酸脱氢酶激酶和组蛋白去乙酰化酶,可用于但不局限于治疗癌症疾病。
4.本发明提供了一种新型的靶向于丙酮酸脱氢酶激酶的三苯基膦前药的合成方法,具体的合成路线如下:
合成路线1:
反应条件:
a:二碳酸二叔丁酯((Boc)2O),二氯甲烷;b:苯丁酸(PBA),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),4-二甲氨基吡啶(DMAP),二氯甲烷;c:三氟乙酸(TFA),二氯甲烷;d:EDCI,N-羟基-7-氮杂苯并三氮唑(HOAT),三乙胺(TEA),乙腈。
1)化合物28的合成:将三羟甲基氨基甲烷(Tris,2.00g,16.51mmol)和(Boc)2O(3.96g,18.16mmol)加到250mL圆底烧瓶中,随后加入DCM(100mL)。在氮气的保护下室温反应12小时。LC-MS监测反应完毕,除去DCM得到固体残渣。粗产物用PE洗涤、抽滤后得到白色粉末状固体化合物28(3.29g,90%)。
2)化合物29的合成:将PBA(2.30g,14.01mmol)、EDCI(2.77g,14.46mmol)和DMAP(15mol%)加到250mL圆底烧瓶中,随后加入DCM(100mL)。在室温下搅拌15分钟后再加入28(1.00g,4.52mmol)。在氮气的保护下室温反应5小时。TLC监测反应完毕,除去DCM得到残液。加去离子水并用EA萃取3次,饱和食盐水洗3次,收集、干燥并浓缩有机相,最后粗产物用硅胶柱层析(PE:EA=10:1)进一步纯化得到无色黏稠的液体29(2.74g,92%)。
3)化合物30的合成:将29(317mg,0.48mmol)加到25mL圆底烧瓶中,随后加入DCM(10mL),搅拌状态下加入TFA(2mL)。在氮气的保护下室温反应2小时。TLC监测反应完毕,饱和碳酸氢钠水溶液淬灭反应,DCM萃取3次,饱和食盐水洗3次,收集、干燥并浓缩有机相得到黄色的黏稠液体30(255mg,95%)。
4)化合物37-40和53的合成:TPP+羧酸类似物37-40和53的合成过程类似,下面以化合物37的合成为例,介绍它们通用的合成方法。将9(200mg,0.48mmol)、EDCI(102mg,0.53mmol)和HOAT(72mg,0.53mmol)加到50mL圆底烧瓶中,随后加入MeCN(15mL),室温搅拌15分钟后再加入30(269mg,0.48mmol)和TEA(97mg,0.96mmol)。在氮气的保护下回流反应12小时。TLC监测反应完毕,除去MeCN得到残液。DCM萃取3次,饱和食盐水洗3次,收集、干燥并浓缩有机相。最后浓缩液用硅胶柱层析(DCM:MeOH=20:1)进一步纯化得到黄色粘稠液体37(257mg,56%)。
合成路线2:
反应条件:
a:氯化亚砜,吡啶;b:叠氮化钠,水;c:二碳酸二叔丁酯,二氯甲烷;d:10%Pd/C,氢气;e:苯丁酸,EDCI,DMAP,二氯甲烷;f:三氟乙酸(TFA),二氯甲烷;g:EDCI,N-羟基-7-氮杂苯并三氮唑(HOAT),三乙胺(TEA),乙腈。
1)化合物31的合成:将Tris(10.0g,82.55mmol)加到100mL三口圆底烧瓶中,随后加入吡啶(40mL)。在氮气的保护下,室温缓慢滴加SOCl2(20mL)。滴加完毕将反应转至油浴,缓慢加热到100℃,此过程中有大量气体生成,随后再加热至140℃反应4小时。LC-MS监测反应完毕,将反应冷却到30-50℃,加入去离子水并在0℃下用饱和碳酸氢钠调节pH=8。DCM萃取水相3次,饱和食盐水洗3次,收集、干燥并浓缩有机相。最后得到的浓缩液经减压蒸馏(80-90℃收集产物)得到无色液体31(9.32g,64%)。
2)化合物32的合成:将31(5.00g,28.33mmol)和NaN3(6.08g,93.49mmol)加到250mL圆底烧瓶中,随后加入100mL去离子水。在氮气的保护下,反应液在80℃下反应24小时。TLC监测反应毕,先将反应体系冷却至室温,再用1M氢氧化钠水溶液淬灭反应。EA萃取3次,饱和食盐水洗3次,收集、干燥并浓缩有机相。最后得到黄色液体32(4.89g,88%)。
3)化合物33的合成:将32(4.00g,20.39mmol)加到250mL圆底烧瓶中,随后加入DCM(150mL)和(Boc)2O(5.79g,26.51mmol)。在氮气的保护下室温反应48小时。TLC监测反应毕,除去DCM得到残渣。残渣用PE洗涤、抽滤得到白色粉末状固体化合物33(4.83g,80%)。
4)化合物34的合成:将33(3g,10.12mmol)加到100mL圆底烧瓶中,随后再加入MeOH(50mL)和10%Pd/C(600mg,20%),置换氢气后室温反应12小时。最后过滤反应液并浓缩滤液得到无色液体34(2.12g,96%)。
5)化合物35的合成:具体合成方法与化合物29的合成类似。
6)化合物36的合成:具体合成方法与化合物30的合成类似。
7)化合物41-52的合成:具体合成方法与化合物37的合成类似。
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