CN110396086B - No供体类化合物、组合物、制备方法和及其应用 - Google Patents
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Abstract
本发明的目的在于提供NO供体类化合物、组合物、制备方法和及其应用,这些化合物组合物在体外抗癌活性测试中表现了很高的抗癌活性,尤其对乳腺癌细胞MDA‑MB‑231、SUM159、MCF‑7、SKBR‑3和4T1具有抑制活性,并且有些化合物的抑制活性高达1μM,可作为治疗癌症的药物以及癌症辅助治疗的药物使用。
Description
技术领域
本发明属于化学领域,具体涉及NO供体类化合物、组合物、制备方法以及在制备治疗癌症药物或治疗癌症的辅助药物中的用途。
背景技术
乳腺癌是目前危及全球女性健康的一大问题,在2018年全球新发癌症病例中,乳腺癌约占了11.6%,在女性癌症致死率中高居第一位。临床上采用的化疗治疗方法,往往会使肿瘤细胞产生耐药性从而导致化疗失败。研究发现,低浓度的NO通过刺激癌细胞生长以及增强血管的生成和转移来促进癌细胞扩散,而较高浓度的NO通过诱导肿瘤细胞的凋亡从而抑制癌症恶化,使肿瘤对化疗、放射或免疫疗法敏感,逆转化疗的耐药性,延缓血管生成.此外,NO小分子参与调节多种与肿瘤细胞相关的信号传导途径,包括细胞外信号调节激酶(ERK)、蛋白激酶B(Akt)、细胞周期蛋白D1/视网膜母细胞瘤(Rb)、哺乳动物雷帕霉素靶蛋白(mTOR)等。因此,高浓度的外源性的NO无疑是癌症患者的一个福音,而能提供这种高浓度NO的NO供体药物的开发显得刻不容缓。黄酮是天然存在的具有广泛药理活性的化合物,例如刺芒柄花素可以通过参与细胞外信号调节激酶ERK1/2介导乳腺癌细胞MCF-7的凋亡,白杨素可以通过抑制缺氧诱导的STAT3磷酸化而抑制乳腺癌细胞的增长。因此利用拼合原理,将抗肿瘤药物与NO供体设计合成系列衍生物,为开发治疗乳腺癌的药物提供了一条新的思路。
发明内容
本发明创造的目的在于提供NO供体类化合物、组合物、制备方法和及其应用,这些化合物组合物在体外抗癌活性测试中表现了很高的抗癌活性,尤其对乳腺癌细胞DA-MB-231、SUM159、MCF-7、SKBR-3和4T1具有抑制活性,可作为治疗癌症的药物以及癌症辅助治疗的药物使用。
一种式(I)化合物或其药学上可接受的盐、溶剂化物、水合物、多晶型物、共结晶体、互变异构体、立体异构体、同位素标记的衍生物或前药。
其中:
R2为以下式中的任一个:
本发明还公开化合物(I)的制备方法,合成路线及步骤为:
化合物10a-e的路线
化合物13a-c的合成路线
化合物16a-c的合成路线
化合物21a-d的合成路线
化合物26的合成路线
化合物31的合成路线
化合物34a-e的合成路线
化合物37和37a的合成路线
化合物39和39a的合成路线
化合物43a-d的合成路线
化合物44的合成路线
化合物45的合成路线。
另外,本发明还公开化合物(I)或其药学上可接受的盐在制备抗癌药物以及作为抗癌辅助治疗药物中的应用。
优选的,所述抗癌癌症为乳腺癌。
优选的,乳腺癌细胞MDA-MB-231、SUM159、MCF-7、SKBR-3及4T1。
本发明还公开一种药物组合物,包含上述化合物(I)和/或其药学上可接受的盐,以及任选地药学上可接受的赋形剂。
所述药物组合物包括治疗有效量的所述化合物(I))和/或其药学上可接受的盐。
本发明还公开一种试剂盒,包括上述所述化合物(I))和/或其药学上可接受的盐,和/或上述的药物组合物。
进一步的,试剂盒,还包括用于指导给药所述化合物(I)、其药学上可接受的盐或药物组合物的说明书。
附图说明
图1为化合物10a的1H NMR; 图2为化合物10a的13C NMR; 图3为化合物10b的1HNMR;
图4为化合物10b的13C NMR; 图5为化合物10c的1H NMR; 图6为化合物10c的13CNMR;
图7为化合物10d的1H NMR; 图8为化合物10d的13C NMR; 图9为化合物10e1H NMR;
图10为化合物10e的13C NMR; 图11为化合物13a的1H NMR; 图12为化合物13a的13CNMR;
图13为化合物13b的1H NMR; 图14为化合物13b的13C NMR; 图15为化合物13c的1HNMR;
图16为化合物13c的13C NMR; 图17为化合物16a 1H NMR; 图18为化合物16a的13CNMR;
图19为化合物16b的1H NMR; 图20为化合物16b的13C NMR; 图21为化合物16c的1HNMR;
图22为化合物16c的13C NMR; 图23为化合物21a的1H NMR; 图24为化合物21a的13CNMR;
图25为化合物21b的1H NMR; 图26为化合物21b的13C NMR; 图27为化合物21c的1HNMR;
图28为化合物21c的13C NMR; 图29为化合物21d的1H NMR; 图30为化合物21d的13CNMR;
图31为化合物26的1H NMR; 图32为化合物26的13C NMR; 图33为化合物31的1HNMR;
图34为化合物31的13C NMR; 图35为化合物34a的1H NMR; 图36为化合物34a的13CNMR;
图37为化合物34b的1H NMR; 图38为化合物34b的13C NMR; 图39为化合物34c的1HNMR;
图40为化合物34c的13C NMR; 图41为化合物34d的1H NMR; 图42为化合物34d的13CNMR;
图43为化合物34e的1H NMR; 图44为化合物34e13C NMR; 图45为化合物37的1HNMR;
图46为化合物3713C NMR; 图47为化合物37a1H NMR; 图48为化合物37a的13C NMR;
图49为化合物39的1H NMR; 图50为化合物39的13C NMR; 图51为化合物39a的1HNMR;
图52为化合物39a的13C NMR; 图53为化合物43a的1H NMR; 图54为化合物43b的1HNMR;
图55为化合物43b的13C NMR; 图56为化合物43c的1H NMR; 图57为化合物43c的13CNMR;
图58为化合物43d的1H NMR; 图59为化合物43d的13C NMR; 图60为化合物44的1HNMR;
图61为化合物44的13C NMR; 图62为化合物45的1H NMR; 图63为化合物45的13CNMR;
图64为化合物10a对MDA-MB-231细胞的抑制; 图65为化合物10b、10c和10e对MDA-MB-231细胞的抑制; 图66为化合物13a、13b和13c对MDA-MB-231细胞的抑制;
图67为化合物16a、16b和16c对MDA-MB-231细胞的抑制; 图68为化合物21a、21b和21c对MDA-MB-231细胞的抑制; 图69为化合物21d、26和31对MDA-MB-231细胞的抑制;
图70为化合物10a对SUM159细胞的抑制; 图71为化合物10b、10c和10e对SUM159细胞的抑制; 图72为化合物13a、13b和13c对SUM159细胞的抑制;
图73为化合物16a、16b和16c对SUM159细胞的抑制; 图74为化合物21a、21b和21c对SUM159细胞的抑制; 图75为化合物21d、26和31对SUM159细胞的抑制;
图76为化合物10a对MCF-7细胞的抑制; 图77为化合物10b、10c和10e对MCF-7细胞的抑制; 图78为化合物13a、13b和13c对MCF-7细胞的抑制;
图79为化合物16a、16b和16c对MCF-7细胞的抑制; 图80为化合物21a、21b和21c对MCF-7细胞的抑制; 图81为化合物21d、26和31对MCF-7细胞的抑制;
图82为化合物10a对SKBR3细胞的抑制; 图83为化合物10b、10c和10e对SKBR3细胞的抑制; 图84为化合物13a、13b和13c对SKBR3细胞的抑制;
图85为化合物16a、16b和16c对SKBR3细胞的抑制; 图86为化合物21a、21b和21c对SKBR3细胞的抑制; 图87为化合物21d、26和31对SKBR3细胞的抑制;
图88为化合物10a对4T1细胞的抑制; 图89为化合物10b、10c和10e对4T1细胞的抑制; 图90为化合物13a、13b和13c对4T1细胞的抑制;
图91为化合物16a、16b和16c对4T1细胞的抑制; 图92为化合物21a、21b和21c对4T1细胞的抑制; 图93为化合物21d、26和31对4T1细胞的抑制。
具体实施方式
下面通过具体的实例对本发明进行详细说明,但这些实施方式的用途和目的仅用来举例说明本发明,并非对本发明的实际保护范围构成任何形式的任何限定,更非将本发明的保护范围局限于此。
化合物10a-e的路线
化合物3的合成
将刺芒柄花素(3.0g,11.19mmol)、无水碳酸钾(3.1g,22.38mmol)和18mL无水DMF加入50mL的三口圆底烧瓶中,在70℃下搅拌回流30分钟。向反应瓶中滴加溴乙酸甲酯(1.6mL,16.79mmol),然后在该温度下继续反应5小时。TLC(CH2Cl2:CH3OH=50:1)检测反应情况,反应完全后,将反应液降至室温,用200mL乙酸乙酯稀释,再用70mL 1N的盐酸溶液和70mL饱和食盐水分别洗2次,EA相用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=3:1-2:1)得到淡黄色固体3(3.31g,产率:86%)。
1H NMR(600MHz,CDCl3)δ8.24(d,J=8.9Hz,1H),7.92(s,1H),7.53–7.47(m,2H),7.03(dd,J=8.9,2.4Hz,1H),6.99–6.95(m,2H),6.84(d,J=2.4Hz,1H),4.75(s,2H),3.84(s,6H).
13C NMR(150MHz,CDCl3)δ175.8,168.4,161.9,159.7,157.7,152.2,130.2,128.3,125.0,124.1,119.3,114.4,114.1,101.4,65.4,55.4,52.6.
化合物4的合成
将化合物3(3.4g,9.99mmol)和50mL丙酮加入250mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中滴加0.1N NaOH溶液(100mL,9.99mmol),升至室温并反应过夜。TLC(CH2Cl2:CH3OH=100:1)检测反应情况,反应完全后,向反应液中加入1N HCl直至溶液的pH=2,搅拌1小时后析出大量浅黄色固体,过滤,滤渣分别用100mL蒸馏水和100mL乙醚洗2次,50℃下真空干燥6小时后得到白色固体4(3.03g,产率:92%)。
1H NMR(600MHz,DMSO-d6)δ13.11(s,1H),8.42(s,1H),8.04(d,J=8.9Hz,1H),7.54–7.50(m,2H),7.15(d,J=2.3Hz,1H),7.11(dd,J=8.9,2.4Hz,1H),7.01–6.98(m,2H),4.89(s,2H),3.79(s,3H).
13C NMR(150MHz,DMSO-d6)δ174.6,169.5,162.1,159.0,157.2,153.6,130.1,127.0,124.0,123.4,118.0,114.9,113.6,101.5,65.0,55.2.
化合物10的合成
10a:将化合物4(50mg,0.15mmol)和1.5mL无水DMF加入10mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中依次加入化合物9a(43mg,0.15mmol)、DMAP(5.5mg,0.045mmol)和EDCI(35mg,0.18mmol),然后升至室温并反应3小时。TLC(PE:EA=1:1)检测反应情况,反应完全后,用30mL乙酸乙酯将反应液稀释,然后分别用10mL 1N HCl溶液、10mL饱和碳酸氢钠溶液、10mL饱和食盐水洗2次,用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(CH2Cl2:CH3OH=100:1)得白色固体10a(61mg,产率:67%)。
1H NMR(600MHz,CDCl3)δ8.23(d,J=8.9Hz,1H),8.08–8.04(m,2H),7.88(s,1H),7.76–7.72(m,1H),7.63–7.58(m,2H),7.50–7.46(m,2H),7.05(dd,J=8.9,2.5Hz,1H),6.98–6.95(m,2H),6.86(d,J=2.4Hz,1H),4.84(s,2H),4.71–4.66(m,4H),3.84(s,3H).
13C NMR(150MHz,CDCl3)δ175.6,167.8,161.7,159.6,158.5,157.5,152.18,137.8,135.7,130.0,129.6,128.6,128.2,124.9,124.0,119.3,114.4,113.9,110.4,101.2,68.5,65.1,61.9,55.3.
10b的合成过程同10a,白色固体,产率:71%。
1H NMR(600MHz,CDCl3)δ8.23(d,J=8.9Hz,1H),8.08–8.02(m,2H),7.91(s,1H),7.77–7.72(m,1H),7.61(dd,J=8.5,7.4Hz,2H),7.50–7.46(m,2H),7.03(dd,J=8.9,2.5Hz,1H),6.99–6.95(m,2H),6.85(d,J=2.4Hz,1H),4.77(s,2H),4.45(t,J=6.0Hz,2H),4.35(t,J=6.2Hz,2H),3.84(s,3H),1.99–1.93(m,2H),1.93–1.87(m,2H).
13C NMR(150MHz,CDCl3)δ175.7,168.0,161.9,159.6,158.9,157.6,152.2,137.9,135.7,130.1,129.7,128.6,128.2,125.0,124.0,119.3,114.4,114.0,110.5,101.4,70.8,65.4,64.9,55.4,25.1,25.0.
10c的合成过程同10a,白色固体,产率:65%。
1H NMR(600MHz,CDCl3)δ8.23(dd,J=8.9,1.4Hz,1H),8.07–8.01(m,2H),7.92(s,1H),7.78–7.71(m,1H),7.64–7.58(m,2H),7.52–7.46(m,2H),7.03(d,J=8.9,2.4Hz,1H),6.98–6.93(m,2H),6.84(d,J=2.4Hz,1H),4.75(s,2H),4.44–4.37(m,2H),4.26(t,J=6.6Hz,2H),3.84–3.82(m,3H),1.90–1.83(m,2H),1.76–1.70(m,2H),1.53–1.46(m,2H),1.46–1.39(m,2H).
13C NMR(150MHz,CDCl3)δ175.5,167.9,161.8,159.5,158.9,157.5,152.1,137.9,135.5,129.9,129.5,128.4,128.0,124.8,123.9,119.0,114.2,113.8,110.3,101.2,71.2,65.3,65.3,55.2,28.2,28.2,25.3,25.1.
10d的合成过程同10a,白色固体,产率:64%。
1H NMR(600MHz,CDCl3)δ8.23(d,J=8.9Hz,1H),8.04(dd,J=8.5,1.3Hz,2H),7.92(s,1H),7.78–7.73(m,1H),7.64–7.59(m,2H),7.49(d,J=8.7Hz,2H),7.03(dd,J=8.9,2.4Hz,1H),6.98–6.94(m,2H),6.84(d,J=2.4Hz,1H),4.74(s,2H),4.40(t,J=6.5Hz,2H),4.24(t,J=6.6Hz,2H),3.83(s,3H),1.89–1.82(m,2H),1.72–1.65(m,2H),1.49–1.40(m,2H),1.38–1.32(m,6H).
13C NMR(150MHz,CDCl3)δ176.1,168.4,162.3,160.0,159.4,158.0,152.5,138.5,135.9,130.4,130.0,128.9,128.5,125.3,124.4,119.5,114.7,114.3,110.8,101.7,71.9,66.1,65.8,55.7,29.3,29.3,28.8,28.7,26.0,25.9.
10e的合成过程同10a,白色固体,产率:62%。
1H NMR(600MHz,CDCl3)δ8.23(d,J=8.9Hz,1H),8.07–8.03(m,2H),7.92(s,1H),7.78–7.72(m,1H),7.63–7.58(m,2H),7.51–7.47(m,2H),7.02(dd,J=8.9,2.4Hz,1H),6.98–6.94(m,2H),6.84(d,J=2.5Hz,1H),4.73(s,2H),4.40(t,J=6.6Hz,2H),4.23(t,J=6.7Hz,2H),3.83(s,3H),1.89–1.82(m,2H),1.69–1.62(m,2H),1.46–1.42(m,2H),1.35–1.27(m,10H).
13C NMR(150MHz,CDCl3)δ176.0,168.4,162.3,160.0,159.4,158.0,152.5,138.5,135.9,130.4,130.0,128.9,128.5,125.3,124.4,119.5,114.7,114.3,110.8,101.7,72.0,66.1,65.8,55.7,30.0,29.7,29.5,29.4,28.8,28.8,26.1,25.9.
化合物13a-c的合成路线
化合物12的合成
12a:将化合物7(1g,2.73mmol)、二乙二醇(1.45g,13.65mmol)和27mL四氢呋喃加入100mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中滴加50%NaOH溶液(218mg,5.46mmol),然后升至室温并反应3小时,有黄色固体产生。TLC(PE:EA=10:1)检测反应情况,反应完全后旋干溶剂,混合物用100mL水稀释,然后用70mL乙酸乙酯萃取2次,合并EA相,用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=2:1-1:1)得到白色固体12a(613mg,产率:68%)。
1H NMR(600MHz,CDCl3)δ8.08–8.05(m,2H),7.77–7.74(m,1H),7.62(dd,J=8.5,7.4Hz,2H),4.60–4.56(m,2H),3.95–3.93(m,2H),3.79(dd,J=5.3,3.7Hz,2H),3.72–3.69(m,2H),1.98(s,1H).
12b的合成过程同12a,白色固体,产率:68%。
1H NMR(600MHz,CDCl3)δ8.09–8.06(m,2H),7.77–7.73(m,1H),7.64–7.60(m,2H),4.61–4.56(m,2H),3.95–3.92(m,2H),3.78–3.76(m,2H),3.75–3.73(m,2H),3.73–3.70(m,2H),3.63(dd,J=5.2,3.8Hz,2H),2.04(s,1H).
12c的合成过程同12a,白色固体,产率:61%。
1H NMR(600MHz,CDCl3)δ8.09–8.05(m,2H),7.77–7.73(m,1H),7.62(dd,J=8.4,7.4Hz,2H),4.60–4.57(m,2H),3.94–3.90(m,2H),3.78–3.75(m,2H),3.73–3.69(m,4H),3.70–3.67(m,4H),3.60(dd,J=8.5,4.2Hz,2H),2.13(s,1H).
化合物13的合成
13a:将化合物4(50mg,0.15mmol)和1.5mL无水DMF加入10mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中依次加入化合物12a(50mg,0.15mmol)、DMAP(5.5mg,0.045mmol)和EDCI(35mg,0.18mmol),然后升至室温并反应4小时。TLC(PE:EA=1:1)检测反应情况,反应完全后,用30mL乙酸乙酯将反应液稀释,然后分别用10mL 1N HCl溶液、10mL饱和碳酸氢钠溶液、10mL饱和食盐水洗2次,用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=1:1)得白色固体13a(80mg,产率:82%)。
1H NMR(600MHz,CDCl3)δ8.21(d,J=8.9Hz,1H),8.05(dd,J=8.5,1.2Hz,2H),7.89(s,1H),7.76–7.71(m,1H),7.60(dd,J=8.5,7.4Hz,2H),7.50–7.47(m,2H),7.02(dd,J=8.9,2.5Hz,1H),6.98–6.94(m,2H),6.85(d,J=2.4Hz,1H),4.80(s,2H),4.58–4.55(m,2H),4.46–4.43(m,2H),3.92–3.90(m,2H),3.86–3.84(m,2H),3.84(s,3H).
13C NMR(150MHz,CDCl3)δ175.8,168.1,162.0,159.8,159.1,157.7,152.3,138.0,135.8,130.2,129.8,128.7,128.2,125.1,124.2,119.3,114.6,114.1,110.7,101.6,70.61,69.3,68.5,65.4,64.4,55.5.
13b的合成过程同13a,白色固体,产率:63%。
1H NMR(600MHz,CDCl3)δ8.22(d,J=8.9Hz,1H),8.05(dd,J=8.5,1.3Hz,2H),7.91(s,1H),7.78–7.70(m,1H),7.60(dd,J=8.5,7.5Hz,2H),7.51–7.46(m,2H),7.02(dd,J=8.9,2.5Hz,1H),6.98–6.94(m,2H),6.84(d,J=2.4Hz,1H),4.77(s,2H),4.59–4.55(m,2H),4.42–4.39(m,2H),3.93–3.89(m,2H),3.84(s,3H),3.78–3.73(m,4H),3.69–3.67(m,2H).
13C NMR(100MHz,CDCl3)δ175.8,168.0,162.0,159.7,159.1,157.7,152.3,138.1,135.7,130.2,129.8,128.7,128.2,125.1,124.2,119.3,114.5,114.1,110.7,101.6,71.1,70.8,70.8,69.1,68.6,65.5,64.6,55.5.
13c的合成过程同13a,白色固体,产率:64%。
1H NMR(600MHz,CDCl3)δ8.22(d,J=8.9Hz,1H),8.07–8.03(m,2H),7.92(s,1H),7.77–7.71(m,1H),7.60(dd,J=8.4,7.4Hz,2H),7.50–7.47(m,2H),7.02(dd,J=8.9,2.4Hz,1H),6.98–6.95(m,2H),6.84(d,J=2.5Hz,1H),4.77(s,2H),4.58–4.54(m,2H),4.42–4.38(m,2H),3.92–3.88(m,2H),3.84(d,J=1.3Hz,3H),3.76–3.72(m,4H),3.70–3.67(m,2H),3.67–3.64(m,4H).
13C NMR(150MHz,CDCl3)δ175.8,168.0,162.0,159.7,159.1,157.7,152.3,138.1,135.7,130.2,129.8,128.7,128.2,125.0,124.2,119.3,114.5,114.1,110.6,101.6,71.1,70.9,70.8,70.7,70.6,69.0,68.6,65.4,64.6,55.4.
化合物16a-c的合成路线
化合物15的合成
15a:将化合物7(1g,2.73mmol)、1,4-丁炔二醇(2.35g,27.32mmol)和27mL四氢呋喃加入100mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中滴加50%NaOH溶液(218mg,5.46mmol),然后升至室温并反应3小时,有黄色固体产生。TLC(PE:EA=10:1)检测反应情况,反应完全后旋干溶剂,混合物用100mL水稀释,然后用70mL乙酸乙酯萃取2次,合并EA相,用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=3:1-2:1)得到白色固体15a(576mg,产率:68%)。
1H NMR(600MHz,CDCl3)δ8.10–8.05(m,2H),7.80–7.74(m,1H),7.66–7.60(m,2H),5.11(t,J=1.8Hz,2H),4.35(t,J=1.8Hz,2H),1.72(s,1H).
13C NMR(100MHz,CDCl3)δ158.1,137.9,135.9,129.8,128.8,110.7,88.3,77.7,59.0,51.1.
化合物15b的合成过程同15a,白色固体,产率:54%。
1H NMR(600MHz,CDCl3)δ8.07(dd,J=8.5,1.3Hz,2H),7.79–7.74(m,1H),7.63(dd,J=8.4,7.4Hz,2H),4.60(t,J=6.5Hz,2H),3.79–3.74(m,2H),3.02(t,J=6.6Hz,2H),2.90(dd,J=8.3,0.9Hz,2H),2.82(dd,J=8.2,0.9Hz,2H),2.78(t,J=5.9Hz,2H),2.22–2.18(m,1H).
化合物15c的合成过程同15a,白色固体,产率:72%。
1H NMR(600MHz,CDCl3)δ8.12–8.07(m,2H),7.78(d,J=7.5Hz,1H),7.65(dd,J=8.5,7.4Hz,2H),7.30(d,J=8.6Hz,2H),7.23(d,J=8.6Hz,2H),3.86(t,J=6.5Hz,2H),2.89(t,J=6.5Hz,2H),1.77–1.56(m,1H).
化合物16的合成
16a:将化合物4(50mg,0.15mmol)和1.5mL无水DMF加入10mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中依次加入化合物15a(47mg,0.15mmol)、DMAP(5.5mg,0.045mmol)和EDCI(35mg,0.18mmol),然后升至室温并反应3小时。TLC(PE:EA=1:1)检测反应情况,反应完全后,用30mL乙酸乙酯将反应液稀释,然后分别用10mL 1N HCl溶液、10mL饱和碳酸氢钠溶液、10mL饱和食盐水洗2次,用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(CH2Cl2:CH3OH=100:1)得白色固体16a(72mg,产率:76%)。
1H NMR(600MHz,CDCl3)δ8.25(d,J=8.9Hz,1H),8.10–8.03(m,2H),7.93(s,1H),7.79–7.72(m,1H),7.63(dd,J=8.4,7.5Hz,2H),7.52–7.46(m,2H),7.04(dd,J=8.9,2.4Hz,1H),6.99–6.94(m,2H),6.85(d,J=2.4Hz,1H),5.11(t,J=1.7Hz,2H),4.90(t,J=1.7Hz,2H),4.80(s,2H),3.84(s,3H).
13C NMR(150MHz,CDCl3)δ175.8,167.3,161.8,159.8,158.1,157.8,152.3,137.9,135.9,130.3,129.9,128.8,128.4,125.2,124.2,119.5,114.5,114.1,110.7,101.6,83.1,79.7,65.3,58.6,55.5,53.0.
化合物16b的合成过程同16a,白色固体,产率:65%。
1H NMR(600MHz,CDCl3)δ8.22(d,J=8.9Hz,1H),8.08–8.03(m,2H),7.92(s,1H),7.78–7.71(m,1H),7.61(t,J=7.9Hz,2H),7.52–7.46(m,2H),7.02(dd,J=8.9,2.5Hz,1H),7.00–6.94(m,2H),6.85(d,J=2.5Hz,1H),4.76(s,2H),4.58(t,J=6.5Hz,2H),4.40(t,J=6.7Hz,2H),3.83(s,3H),3.01(t,J=6.5Hz,2H),2.90(dd,J=8.9,5.6Hz,2H),2.87–2.80(m,4H).
13C NMR(150MHz,CDCl3)δ176.0,168.1,162.1,159.9,159.0,157.9,152.5,138.1,136.0,130.4,130.0,128.9,128.4,125.2,124.3,119.5,114.6,114.3,110.8,101.7,71.1,65.6,64.4,55.6,32.9,32.5,30.7,30.5.
化合物16c的合成过程同16a,白色固体,产率:67%。
1H NMR(600MHz,CDCl3)δ8.23(d,J=8.9Hz,1H),8.11–8.07(m,2H),7.93(s,1H),7.80–7.75(m,1H),7.64(dd,J=8.5,7.5Hz,2H),7.51–7.47(m,2H),7.26–7.23(m,4H),7.00(dd,J=8.9,2.4Hz,1H),6.97–6.94(m,2H),6.78(d,J=2.4Hz,1H),4.71(s,2H),4.47(t,J=6.8Hz,2H),3.83(s,3H),3.01(t,J=6.8Hz,2H).
13C NMR(150MHz,CDCl3)δ176.0,168.2,162.1,160.0,158.8,157.9,152.5,151.7,138.2,136.3,136.2,130.7,130.4,130.1,129.0,128.5,125.3,124.4,120.4,119.6,114.6,114.3,111.1,101.7,65.9,65.6,55.7,34.6.
化合物21a-d的合成路线
化合物19的合成
19a:将化合物7(1g,2.73mmol)、化合物18a(1.81g,10.92mmol)和27mL四氢呋喃加入100mL单口圆底烧瓶中,在4℃下搅拌,向反应瓶中滴加50%NaOH溶液(218mg,5.46mmol),然后升至室温并反应3小时,有黄色固体产生。TLC(PE:EA=5:1)检测反应情况,反应完全后旋干溶剂,混合物用100mL水稀释,然后用70mL乙酸乙酯萃取2次,合并EA相,用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=5:1)得到白色固体19a(600mg,产率:57%)。
1H NMR(600MHz,CDCl3)δ8.12–8.03(m,2H),7.79–7.74(m,1H),7.67–7.59(m,2H),4.97(s,1H),4.47(t,J=5.1Hz,2H),3.61(q,J=5.5Hz,2H),1.46(s,9H).
13C NMR(150MHz,CDCl3)δ158.9,155.8,138.0,135.8,129.8,128.7,110.5,80.1,70.9,39.5,28.5.
19b的合成同19a,白色固体,产率:61%。
1H NMR(600MHz,CDCl3)δ8.09,8.08,8.07,8.07,7.77,7.76,7.76,7.75,7.75,7.74,7.64,7.62,7.61,4.98,4.50,4.49,4.48,3.38,3.36,3.35,3.34,2.10,2.08,2.07,2.06,2.05,1.44.
13C NMR(150MHz,CDCl3)δ159.0,156.2,138.1,135.8,129.8,128.7,110.6,79.5,69.8,37.6,29.2,28.5.
19c的合成同19a,白色固体,产率:56%。
1H NMR(600MHz,CDCl3)δ8.07–8.04(m,2H),7.78–7.74(m,1H),7.63(dd,J=8.4,7.4Hz,2H),4.44(t,J=6.3Hz,2H),4.38(t,J=6.4Hz,1H),3.24–3.19(m,2H),1.95–1.89(m,2H),1.71–1.65(m,2H),1.45(s,9H).
19d的合成同19a,白色固体,产率:47%。
1H NMR(600MHz,CDCl3)δ8.07–8.02(m,2H),7.78–7.73(m,1H),7.65–7.60(m,2H),4.60(s,1H),4.41(t,J=6.4Hz,2H),3.19–3.11(m,2H),1.89(p,J=6.7Hz,2H),1.57(q,J=7.3Hz,2H),1.53–1.46(m,2H),1.44(s,9H).
13C NMR(150MHz,CDCl3)δ159.1,156.1,138.2,135.7,129.8,128.6,110.6,79.3,71.5,40.4,29.7,28.5,28.2,23.0.
化合物20的合成
20a:将化合物19a(100mg,0.26mmol)和1mL无水二氯甲烷加入5mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中依次滴加三乙基硅烷(121mg,1.04mmol)和三氟乙酸(0.5mL),然后在该温度下反应2小时。TLC(PE:EA=3:1)检测反应情况,反应完全后,用20mL饱和碳酸氢钠溶液将,然后用15mL二氯甲烷萃取3次,将合并的二氯甲烷溶液用无水Na2SO4干燥20分钟,过滤,浓缩后得到黄色油状物20a。不用纯化,直接用于下一步。
20b的合成同20a,黄色固体。
20c的合成同20a,黄色油状物。
20d的合成同20a,黄色油状物。
化合物21的合成
21a:将化合物4(50mg,0.15mmol)和1.5mL无水DMF加入10mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中依次加入化合物20a(43mg,0.15mmol)、DMAP(5.5mg,0.045mmol)和EDCI(35mg,0.18mmol),然后升至室温并反应3小时。TLC(CH2Cl2:CH3OH=10:1)检测反应情况,反应完全后,用30mL乙酸乙酯将反应液稀释,然后分别用10mL 1N HCl溶液、10mL饱和碳酸氢钠溶液、10mL饱和食盐水洗2次,用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(CH2Cl2:CH3OH=50:1)得白色固体21a(57mg,产率:63%)。
1H NMR(600MHz,CDCl3)δ8.23(d,J=8.9Hz,1H),8.07–8.02(m,2H),7.92(s,1H),7.77–7.72(m,1H),7.62–7.57(m,2H),7.50–7.47(m,2H),7.20(t,J=6.1Hz,1H),7.10(dd,J=8.9,2.4Hz,1H),6.99–6.95(m,2H),6.93(d,J=2.4Hz,1H),4.66(s,2H),4.56(t,J=5.0Hz,2H),3.90(d,J=5.4Hz,2H),3.84(s,3H).
13C NMR(150MHz,CDCl3)δ175.8,167.6,161.2,159.8,158.8,157.8,152.4,137.9,135.9,130.2,129.9,128.7,128.6,125.2,124.1,119.7,114.6,114.1,110.5,101.7,70.1,67.6,55.5,37.8.
21b的合成同21a,白色固体,产率:62%。
1H NMR(600MHz,CDCl3)δ8.22(d,J=8.9Hz,1H),8.07–8.03(m,2H),7.92(s,1H),7.78–7.73(m,1H),7.65–7.60(m,2H),7.50–7.46(m,2H),7.04(dd,J=8.9,2.4Hz,1H),6.98–6.95(m,2H),6.93(t,J=6.3Hz,1H),6.89(d,J=2.4Hz,1H),4.63(s,2H),4.50(t,J=5.9Hz,2H),3.84(s,3H),3.62(q,J=6.4Hz,2H),2.18(p,J=6.2Hz,2H).
13C NMR(150MHz,CDCl3)δ175.8,167.6,161.3,159.8,159.0,157.8,152.4,137.9,135.9,130.2,129.9,128.7,128.5,125.2,124.1,119.6,114.6,114.1,110.6,101.6,69.5,67.7,55.5,36.3,28.7.
21c的合成同21a,白色固体,产率:45%。
1H NMR(600MHz,CDCl3)δ8.23(d,J=8.9Hz,1H),8.06–8.03(m,2H),7.93(s,1H),7.78–7.73(m,1H),7.64–7.58(m,2H),7.51–7.46(m,2H),7.05(dd,J=8.9,2.4Hz,1H),7.00–6.95(m,2H),6.91(d,J=2.4Hz,1H),6.81(t,J=6.1Hz,1H),4.62(s,2H),4.46(t,J=6.1Hz,2H),3.84(s,3H),3.50(q,J=6.8Hz,2H),1.97–1.92(m,2H),1.85–1.79(m,2H).
13C NMR(150MHz,CDCl3)δ175.6,167.2,161.1,159.6,158.8,157.6,152.2,137.7,135.6,130.0,129.6,128.5,128.3,125.0,123.8,119.4,114.4,113.9,110.4,101.4,71.1,67.5,55.3,38.5,26.1,25.6.
21d的合成同21a,白色固体,产:57%。
1H NMR(600MHz,CDCl3)δ8.18(dd,J=8.9,1.4Hz,1H),8.04–7.99(m,2H),7.91(s,1H),7.77–7.71(m,1H),7.63–7.58(m,2H),7.50–7.45(m,2H),7.00(dd,J=8.9,2.4Hz,1H),6.98–6.94(m,2H),6.87(d,J=2.4Hz,1H),6.76–6.67(m,2H),4.59(s,2H),4.41(t,J=6.2Hz,2H),3.83(s,3H),3.43(q,J=6.8Hz,2H),1.94–1.88(m,2H),1.72–1.65(m,2H),1.58–1.51(m,2H).
13C NMR(150MHz,CDCl3)δ176.0,167.4,161.5,160.0,159.3,158.0,152.6,138.2,136.0,130.4,130.0,128.8,128.6,125.3,124.2,119.7,114.8,114.3,110.8,101.8,71.7,67.9,55.7,39.1,29.4,28.2,23.4.
化合物26的合成路线
化合物24的合成
将化合物7(1g,2.73mmol)、化合物23(2.2g,10.92mmol)和27mL四氢呋喃加入100mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中滴加50%NaOH溶液(218mg,5.46mmol),然后升至室温并反应3小时,有黄色固体产生。TLC(PE:EA=5:1)检测反应情况,反应完全后旋干溶剂,混合物用100mL水稀释,然后用70mL乙酸乙酯萃取2次,合并EA相,用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=8:1)得到白色固体24(546mg,产率:47%)。
1H NMR(600MHz,CDCl3)δ8.07–8.02(m,2H),7.76(s,1H),7.65–7.60(m,2H),5.12–5.05(m,1H),3.71–3.62(m,2H),3.47–3.38(m,2H),2.01(tt,J=7.9,3.8Hz,2H),1.90(dq,J=10.4,3.5Hz,2H),1.48(s,9H).
化合物25的合成
将化合物24(100mg,0.24mmol)和1mL无水二氯甲烷加入5mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中依次滴加三乙基硅烷(109mg,0.94mmol)和三氟乙酸(0.5mL),然后在该温度下反应2小时。TLC(PE:EA=5:1)检测反应情况,反应完全后,用20mL饱和碳酸氢钠溶液将反应液稀释,然后用15mL二氯甲烷萃取3次,将合并的二氯甲烷溶液用无水Na2SO4干燥20分钟,过滤,浓缩后得到淡黄色固体25。不用纯化,直接用于下一步。
化合物26的合成
将化合物4(50mg,0.15mmol)和1.5mL无水DMF加入10mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中依次加入化合物25(49mg,0.15mmol)、DMAP(5.5mg,0.045mmol)和EDCI(35mg,0.18mmol),然后升至室温并反应3小时。TLC(CH2Cl2:CH3OH=10:1)检测反应情况,反应完全后,用30mL乙酸乙酯将反应液稀释,然后分别用10mL 1N HCl溶液、10mL饱和碳酸氢钠溶液、10mL饱和食盐水洗2次,用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=1:1)得淡黄色油状物26(62mg,产率:64%)。
1H NMR(600MHz,CDCl3)δ8.24(d,J=8.9Hz,1H),8.03(dd,J=8.5,1.3Hz,2H),7.93(s,1H),7.78–7.74(m,1H),7.64–7.59(m,2H),7.51–7.47(m,2H),7.05(dd,J=8.9,2.4Hz,1H),6.99–6.97(m,2H),6.96(d,J=2.1Hz,1H),5.18(p,J=4.8Hz,1H),4.85(q,J=6.2Hz,2H),3.89–3.85(m,1H),3.84(s,3H),3.83–3.77(m,1H),3.74–3.62(m,2H),2.06(q,J=5.4Hz,2H),2.00(t,J=5.7Hz,2H).
13C NMR(150MHz,CDCl3)δ175.8,165.5,162.1,159.7,157.9,157.8,152.3,138.1,135.9,130.2,129.8,128.6,128.3,125.1,124.1,119.3,114.5,114.1,110.5,101.6,76.5,67.9,55.5,41.7,38.6,30.7,29.7.
化合物31的合成路线
化合物29的合成
将化合物7(1g,2.73mmol)、化合物28(2.51g,10.92mmol)和27mL四氢呋喃加入100mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中滴加50%NaOH溶液(218mg,5.46mmol),然后升至室温并反应3小时,有黄色固体产生。TLC(PE:EA=3:1)检测反应情况,反应完全后旋干溶剂,混合物用100mL水稀释,然后用70mL乙酸乙酯萃取2次,合并EA相,用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=3:1-1:1)得到无色油状物29(595mg,产率:48%)。
1H NMR(600MHz,CDCl3)δ8.07–8.01(m,2H),7.77–7.73(m,1H),7.63–7.59(m,2H),4.54(t,J=5.6Hz,2H),3.41(t,J=5.0Hz,4H),2.86(t,J=5.5Hz,2H),2.51(t,J=5.1Hz,4H),1.45(s,9H).
13C NMR(150MHz,CDCl3)δ159.0,154.8,138.2,135.8,129.8,128.6,110.6,79.9,69.3,56.3,53.3,29.8,28.5.
化合物30的合成
将化合物29a(100mg,0.22mmol)和1mL无水二氯甲烷加入5mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中依次滴加三乙基硅烷(102mg,0.88mmol)和三氟乙酸(0.5mL),然后在该温度下反应2小时。TLC(PE:EA=1:1)检测反应情况,反应完全后,用20mL饱和碳酸氢钠溶液将反应液稀释,然后用15mL二氯甲烷萃取3次,将合并的二氯甲烷溶液用无水Na2SO4干燥20分钟,过滤,浓缩后得到黄色油状物30。不用纯化,直接用于下一步。
化合物31的合成
将化合物4(50mg,0.15mmol)和1.5mL无水DMF加入10mL单口圆底烧瓶中,在0℃下搅拌,向反应瓶中依次加入化合物30(53mg,0.15mmol)、DMAP(5.5mg,0.045mmol)和EDCI(35mg,0.18mmol),然后升至室温并反应3小时。TLC(CH2Cl2:CH3OH=10:1)检测反应情况,反应完全后,用30mL乙酸乙酯将反应液稀释,然后分别用10mL 1N HCl溶液、10mL饱和碳酸氢钠溶液、10mL饱和食盐水洗2次,用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(CH2Cl2:CH3OH=100:1)得黄色油状物31(69mg,产率:68%)。
1H NMR(600MHz,CDCl3)δ8.21(d,J=8.9Hz,1H),8.06–8.02(m,2H),7.91(s,1H),7.78–7.73(m,1H),7.64–7.58(m,2H),7.52–7.45(m,2H),7.03(dd,J=8.9,2.4Hz,1H),6.97(d,J=2.1Hz,1H),6.96–6.94(m,2H),4.81(s,2H),4.55(t,J=5.3Hz,2H),3.83(s,3H),3.67–3.62(m,2H),3.61–3.56(m,2H),2.88(t,J=5.3Hz,2H),2.64(t,J=4.9Hz,2H),2.57(t,J=5.1Hz,2H).
13C NMR(150MHz,CDCl3)δ175.7,165.3,162.1,159.6,158.9,157.7,152.3,130.1,129.7,128.5,128.0,124.9,124.1,119.1,114.6,114.0,110.5,101.5,69.3,67.5,56.0,55.4,53.5,53.0,45.3,42.2.
化合物34a-34e的合成路线
化合物33的合成
33a:将化合物4(200mg,0.61mmol)、三乙胺(257uL,1.84mmol)和6mL无水DMF加入50mL三口圆底烧瓶中,在60℃下回流搅拌30分钟,向反应瓶中滴加1,2-二溴乙烷(345mg,1.84mmol),然后保持该温度反应5小时。TLC(CH2Cl2:CH3OH=5:1)检测反应情况,反应完全后,用100mL乙酸乙酯将反应液稀释,然后用40mL 1N HCl溶液洗3次,无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(CH2Cl2:CH3OH=200:1)得白色固体33a(200mg,产率:75%)。
1H NMR(600MHz,CDCl3)δ8.24(d,J=8.9Hz,1H),7.92(s,1H),7.54–7.45(m,2H),7.04(dd,J=8.9,2.5Hz,1H),7.00–6.93(m,2H),6.86(d,J=2.5Hz,1H),4.79(s,2H),4.55(t,J=6.0Hz,2H),3.84(s,3H),3.55(t,J=6.0Hz,2H).
13C NMR(150MHz,CDCl3)δ175.9,167.7,161.9,159.8,157.8,152.3,130.3,128.4,125.2,124.2,119.5,114.5,114.1,101.6,65.3,64.8,55.5,28.3.
33b:合成方法同33a,淡黄色固体,产率:61%。
1H NMR(600MHz,CDCl3)δ8.24(d,J=8.9Hz,1H),7.92(s,1H),7.52–7.46(m,2H),7.02(dd,J=8.9,2.5Hz,1H),6.99–6.94(m,2H),6.84(d,J=2.4Hz,1H),4.75(s,2H),4.38(t,J=6.1Hz,2H),3.84(s,3H),3.41(t,J=6.4Hz,2H),2.21(p,J=6.2Hz,2H).
13C NMR(150MHz,CDCl3)δ176.0,168.1,162.2,160.0,158.0,152.5,130.5,128.6,125.4,124.4,119.6,114.6,114.3,101.7,65.7,63.7,55.7,31.7,29.2.
33c:合成方法同33a,白色固体,产率:57%。
1H NMR(600MHz,CDCl3)δ8.23(d,J=8.9Hz,1H),7.91(s,1H),7.48(d,J=8.2Hz,2H),7.02(dd,J=8.9,2.4Hz,1H),6.96(d,J=8.3Hz,2H),6.83(d,J=2.4Hz,1H),4.74(s,2H),4.27(t,J=6.2Hz,2H),3.83(s,3H),3.40(t,J=6.4Hz,2H),1.89(q,J=7.0Hz,2H),1.86–1.81(m,2H).
13C NMR(150MHz,CDCl3)δ176.1,168.2,162.2,160.0,158.0,152.5,130.5,128.6,125.4,124.4,119.6,114.6,114.3,101.7,65.7,65.0,55.7,33.1,29.4,27.5.
33d:合成方法同33a,白色固体,产率:60%。
1H NMR(600MHz,CDCl3)δ8.23(d,J=8.9Hz,1H),7.92(s,1H),7.52–7.46(m,2H),7.02(dd,J=8.9,2.4Hz,1H),6.98–6.94(m,2H),6.84(d,J=2.4Hz,1H),4.74(s,2H),4.24(t,J=6.5Hz,2H),3.83(s,3H),3.38(t,J=6.6Hz,2H),1.90–1.82(m,2H),1.74–1.67(m,2H),1.53–1.46(m,2H).
13C NMR(150MHz,CDCl3)δ175.8,168.1,162.0,159.8,157.8,152.3,130.2,128.3,125.1,124.2,119.3,114.5,114.1,101.5,65.5,65.4,55.5,33.4,32.3,27.8,24.6.
33e:合成方法同33a,白色固体,产率:64%。
1H NMR(600MHz,CDCl3)δ8.24(d,J=8.9Hz,1H),7.92(s,1H),7.52–7.46(m,2H),7.03(dd,J=8.9,2.4Hz,1H),6.99–6.94(m,2H),6.84(d,J=2.4Hz,1H),4.73(s,2H),4.24(t,J=6.6Hz,2H),3.84(s,3H),3.39(t,J=6.7Hz,2H),1.83(p,J=6.9Hz,2H),1.68(p,J=6.7Hz,2H),1.50–1.41(m,2H),1.39–1.31(m,2H).
13C NMR(150MHz,CDCl3)δ176.1,168.3,162.3,160.0,158.0,152.5,130.5,128.5,125.4,124.4,119.6,114.7,114.3,101.7,65.9,65.8,55.7,33.9,32.9,28.7,28.0,25.4.
化合物34的合成
34a:避光条件下,将化合物33a(100mg,0.23mmol)和2mL无水乙腈加入25mL三口圆底烧瓶中,升温至70℃时,向反应瓶中滴加硝酸银(157mg,0.92mmol)的乙腈溶液(1mL),然后保持该温度反应1小时。TLC(PE:EA=2:1)检测反应情况,反应完全后,过滤除去黑色沉淀,滤液浓缩后经柱层析纯化(CH2Cl2:CH3OH=100:1)得黄色固体34a(86mg,产率:90%)。
1H NMR(600MHz,CDCl3)δ8.24(d,J=8.9Hz,1H),7.92(s,1H),7.53–7.45(m,2H),7.02(dd,J=8.9,2.4Hz,1H),6.99–6.95(m,2H),6.84(d,J=2.5Hz,1H),4.78(s,2H),4.73–4.69(m,2H),4.55–4.50(m,2H),3.84(s,3H).
13C NMR(150MHz,CDCl3)δ175.8,167.8,161.8,159.8,157.7,152.3,130.3,128.4,125.2,124.2,119.5,114.4,114.1,101.5,70.0,65.2,61.4,55.5.
34b:合成方法同34a,白色固体,产率:92%。
1H NMR(600MHz,CDCl3)δ8.24(d,J=8.9Hz,1H),7.92(s,1H),7.49(d,J=8.7Hz,2H),7.02(dd,J=8.9,2.4Hz,1H),6.98–6.95(m,2H),6.84(d,J=2.4Hz,1H),4.76(s,2H),4.50(t,J=6.2Hz,2H),4.35(t,J=6.1Hz,2H),3.84(s,3H),2.12(p,J=6.2Hz,2H).
13C NMR(150MHz,CDCl3)δ175.8,167.9,161.9,159.8,157.8,152.3,130.3,128.4,125.2,124.2,119.5,114.4,114.1,101.5,69.6,65.4,61.8,55.5,26.5.
34c:合成方法同34a,白色固体,产率:92%。
1H NMR(600MHz,CDCl3)δ8.23(d,J=1.8Hz,1H),7.91(s,1H),7.50–7.46(m,2H),7.02(dd,J=6.4,1.1Hz,1H),6.98–6.95(m,2H),6.83(d,J=1.1Hz,1H),4.74(s,2H),4.47–4.44(m,2H),4.28–4.25(m,2H),3.83(s,3H),1.81–1.77(m,4H).
13C NMR(150MHz,CDCl3)δ175.7,167.9,161.8,159.6,157.6,152.2,130.1,128.2,125.0,124.0,119.3,114.3,114.0,101.3,72.4,65.3,64.7,55.3,24.9,23.5.
34d:合成方法同34a,淡黄色固体,产率:85%。
1H NMR(600MHz,CDCl3)δ8.24(d,J=8.8Hz,1H),7.92(s,1H),7.52–7.45(m,2H),7.02(dd,J=8.9,2.4Hz,1H),6.98–6.95(m,2H),6.83(d,J=2.4Hz,1H),4.74(s,2H),4.43(t,J=6.5Hz,2H),4.24(t,J=6.5Hz,2H),3.83(s,3H),1.77–1.70(m,4H),1.49–1.43(m,2H).
13C NMR(151MHz,CDCl3)δ176.0,168.3,162.2,160.0,158.0,152.5,130.5,128.5,125.3,124.4,119.6,114.7,114.3,101.7,73.2,65.7,65.5,55.7,28.4,26.7,22.6.
34e:合成方法同34a,白色固体,产率:93%。
1H NMR(600MHz,CDCl3)δ8.23(d,J=8.0Hz,1H),7.92(s,1H),7.51–7.47(m,2H),7.02(dd,J=6.4,0.9Hz,1H),6.98–6.94(m,2H),6.84(d,J=1.9Hz,1H),4.73(s,2H),4.45–4.40(m,2H),4.23(t,J=6.6Hz,2H),3.84(s,3H),1.73–1.66(m,4H),1.45–1.39(m,2H),1.39–1.35(m,2H).
13C NMR(150MHz,CDCl3)δ176.0,168.3,162.3,160.0,158.0,152.5,130.4,128.5,125.4,124.4,119.6,114.7,114.3,101.7,73.4,65.8,65.7,55.7,28.6,27.0,25.8,25.6.
化合物37和37a的合成路线
化合物36的合成
将刺芒柄花素(300mg,1.12mmol)、无水碳酸钾(309mg,2.24mmol)和11mL无水DMF加入50mL的三口圆底烧瓶中,在70℃下搅拌回流10分钟。向反应瓶中滴加烯丙基溴(145uL,1.68mmol),然后在该温度下继续反应1小时。TLC(CH2Cl2:CH3OH=50:1)检测反应情况,反应完全后,将反应液降至室温,用100mL乙酸乙酯稀释,再用40mL 1N的盐酸溶液和40mL饱和食盐水分别洗2次,EA相用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=7:1-5:1)得到白色固体36(300mg,产率:87%)。
1H NMR(600MHz,CDCl3)δ8.21(d,J=8.9Hz,1H),7.91(s,1H),7.52–7.47(m,2H),7.01(dd,J=8.9,2.4Hz,1H),6.98–6.95(m,2H),6.86(d,J=2.4Hz,1H),6.07(ddt,J=17.3,10.6,5.3Hz,1H),5.46(dq,J=17.3,1.6Hz,1H),5.36(dq,J=10.5,1.4Hz,1H),4.64(dt,J=5.4,1.6Hz,2H),3.84(s,3H).
13C NMR(150MHz,CDCl3)δ176.0,163.0,159.7,158.0,152.2,132.2,130.3,128.0,125.0,124.4,118.7,115.0,114.1,101.2,69.4,55.5.
化合物37的合成
避光条件下,将化合物36(100mg,0.33mmol)、碘(84mg,0.66mmol)和3mL无水乙腈加入25mL三口圆底烧瓶中,升温至70℃时,向反应瓶中滴加硝酸银(224mg,1.32mmol)的乙腈溶液(1mL),然后保持该温度反应10小时。TLC(PE:EA=5:1)检测反应情况,反应完全后,过滤除去黑色沉淀,将滤液旋干,用100mL乙酸乙酯稀释,再用40mL水洗2次,无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=5:1)得黄色固体37(104mg,产率:74%)。
1H NMR(600MHz,CDCl3)δ8.22(d,J=8.9Hz,1H),7.93(s,1H),7.51–7.47(m,2H),7.00–6.95(m,3H),6.85(d,J=2.4Hz,1H),5.66–5.62(m,1H),4.93(dd,J=12.9,3.6Hz,1H),4.79(dd,J=13.0,6.2Hz,1H),4.33(d,J=4.9Hz,2H),3.84(s,3H).
13C NMR(150MHz,CDCl3)δ175.8,161.6,159.8,157.7,152.3,130.2,128.5,125.2,124.0,119.5,114.3,114.1,101.4,76.4,68.7,65.2,55.5.
化合物37a的合成
避光条件下,将化合物36(100mg,0.33mmol)、碘(84.0mg,0.660mmol)和3.0mL无水乙腈加入25mL三口圆底烧瓶中,升温至70℃时,向反应瓶中滴加硝酸银(224mg,1.32mmol)的乙腈溶液(1.0mL),然后保持该温度反应3小时。TLC(PE:EA=5:1)检测反应情况,待原料点消失,过滤除去黑色沉淀,将滤液旋干,用100mL乙酸乙酯稀释,再用40mL蒸馏水洗2次,无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=6:1)得黄色固体37a(85mg,产率:52%)。
1H NMR(600MHz,CDCl3)δ8.23(dd,J=8.9,1.6Hz,1H),7.93(d,J=1.1Hz,1H),7.52–7.47(m,2H),7.00(ddd,J=8.9,2.4,1.3Hz,1H),6.98–6.96(m,2H),6.86(dd,J=2.4,1.3Hz,1H),4.90(ddd,J=12.2,5.6,1.3Hz,1H),4.87(ddd,J=12.2,7.5,1.2Hz,1H),4.54–4.48(m,1H),4.40(ddd,J=10.3,4.6,1.6Hz,1H),4.33(ddd,J=10.3,6.6,1.5Hz,1H),3.84(s,3H).
13C NMR(151MHz,CDCl3)δ175.71,161.61,159.66,157.69,152.18,130.12,128.26,125.03,124.01,119.26,114.40,114.00,101.35,73.25,69.91,55.35,18.15.
化合物39和39a的合成路线
化合物38的合成
将化合物4(300mg,0.92mmol)、无水碳酸钾(254mg,1.84mmol)和9mL无水DMF加入50mL的三口圆底烧瓶中,在70℃下搅拌回流10分钟。向反应瓶中滴加烯丙基溴(120uL,1.38mmol),然后在该温度下继续反应3小时。TLC(CH2Cl2:CH3OH=5:1)检测反应情况,反应完全后,将反应液降至室温,用100mL乙酸乙酯稀释,再用40mL 1N的盐酸溶液和40mL饱和食盐水分别洗2次,EA相用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=7:1-5:1)得到白色固体38(306mg,产率:91%)。
1H NMR(400MHz,CDCl3)δ8.24(d,J=8.9Hz,1H),7.91(s,1H),7.52–7.45(m,2H),7.03(dd,J=8.9,2.5Hz,1H),6.99–6.95(m,2H),6.84(d,J=2.4Hz,1H),5.99–5.87(m,1H),5.40–5.27(m,2H),4.76(s,2H),4.73(dt,J=5.9,1.4Hz,2H),3.84(s,3H).
13C NMR(150MHz,CDCl3)δ176.1,167.9,162.2,160.0,158.0,152.5,131.5,130.5,128.5,125.3,124.4,119.8,119.6,114.7,114.3,101.8,66.5,65.7,55.7.
化合物39的合成
避光条件下,将化合物38(100mg,0.27mmol)、碘(69mg,0.55mmol)和3mL无水乙腈加入25mL三口圆底烧瓶中,升温至70℃时,向反应瓶中滴加硝酸银(183mg,1.08mmol)的乙腈溶液(1mL),然后保持该温度反应10小时。TLC(PE:EA=2:1)检测反应情况,反应完全后,过滤除去黑色沉淀,将滤液旋干,用100mL乙酸乙酯稀释,再用40mL水洗2次,无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=3:1)得黄色固体39(103mg,产率:77%)。
1H NMR(600MHz,CDCl3)δ8.25(d,J=8.9Hz,1H),7.93(s,1H),7.52–7.47(m,2H),7.02(dd,J=8.9,2.4Hz,1H),6.99–6.96(m,2H),6.84(d,J=2.4Hz,1H),5.49(tt,J=5.8,3.8Hz,1H),4.80(s,2H),4.74(dd,J=12.9,3.9Hz,1H),4.64(dd,J=12.6,3.8Hz,1H),4.59(dd,J=12.9,6.3Hz,1H),4.41(dd,J=12.6,5.6Hz,1H),3.84(s,3H).
13C NMR(150MHz,CDCl3)δ176.0,167.7,161.8,160.0,158.0,152.6,130.5,128.8,125.4,124.3,119.8,114.5,114.4,101.7,76.1,68.6,65.3,61.9,55.7.
化合物39a的合成
避光条件下,将化合物38(100mg,0.27mmol)、碘(69.0mg,0.550mmol)和3.00mL无水乙腈加入25mL三口圆底烧瓶中,升温至70℃时,向反应瓶中滴加硝酸银(183mg,1.08mmol)的乙腈溶液(1.0mL),然后保持该温度反应10小时。TLC(PE:EA=2:1)检测反应情况,反应完全后,过滤除去黑色沉淀,将滤液旋干,用100mL乙酸乙酯稀释,再用40mL蒸馏水洗2次,无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=5:1)得黄色固体39a(84mg,产率:64%)。
1H NMR(600MHz,CDCl3)δ8.28–8.21(m,1H),7.92(d,J=2.3Hz,1H),7.49(dd,J=8.7,1.9Hz,2H),7.04(dt,J=9.0,2.3Hz,1H),6.97(dd,J=8.7,2.0Hz,2H),6.86(t,J=2.4Hz,1H),4.79(dd,J=6.4,2.4Hz,2H),4.78–4.75(m,1H),4.61(ddd,J=12.2,8.5,1.6Hz,1H),4.53(dd,J=5.9,2.6Hz,2H),4.38(dtd,J=8.1,5.4,2.0Hz,1H),3.84(s,3H).
13C NMR(151MHz,CDCl3)δ176.02,167.48,161.96,159.98,157.95,152.52,130.45,128.65,125.36,124.34,119.71,114.62,114.32,101.75,73.87,66.77,65.44,55.69,17.73.
化合物43a-d的合成路线
化合物41的合成
将白杨素(5.0g,18.64mmol)、无水碳酸钾(5.15g,37.28mmol)和18mL无水DMF加入50mL的三口圆底烧瓶中,在70℃下搅拌回流30分钟,待反应液澄清,向反应瓶中滴加溴乙酸甲酯(2.7mL,27.96mmol),然后在该温度下继续反应6小时。TLC(CH2Cl2:CH3OH=50:1)检测反应情况,反应完全后,将反应液降至室温,用200mL乙酸乙酯稀释,有机相用70mL 1N的盐酸溶液和70mL饱和食盐水分别洗3次,EA相用无水Na2SO4干燥20分钟,过滤,浓缩后经柱层析纯化(PE:EA=5:1-3:1)得到亮黄色固体41(5.8g,产率:92%)。
1H NMR(600MHz,Chloroform-d)δ12.77(s,1H),7.92–7.88(m,2H),7.59–7.52(m,3H),6.69(d,J=1.9Hz,1H),6.53(d,J=2.3Hz,1H),6.38(d,J=2.3Hz,1H),4.74(s,2H),3.86(s,3H).
化合物42的合成
将化合物41(5.0g,15.33mmol)和50mL甲醇加入500mL单口圆底烧瓶中,在60℃下加热回流,向反应瓶中滴加0.1N NaOH溶液(200mL,20.0mmol),待反应3个小时,TLC(CH2Cl2:CH3OH=100:1)检测反应情况,反应完全后,冷却至室温,向反应液中加入1N HCl直至溶液的pH=2,搅拌1小时后析出大量浅黄色固体,过滤,滤渣分别用100mL蒸馏水和100mL乙醚洗2次,50℃下真空干燥6小时后得到黄色色固体42(4.6g,产率:96%)
1H NMR(600MHz,DMSO-d6)δ12.79(s,1H),8.07(d,J=7.9Hz,2H),7.59(dq,J=15.1,7.5,7.1Hz,3H),7.02(d,J=6.2Hz,1H),6.80(d,J=5.2Hz,1H),6.42–6.37(m,1H),4.84(s,2H).
化合物43的合成
43a:将化合物42(50mg,0.16mmol)和1.6mL无水DMF加入10mL单口圆底烧瓶中,在室温下搅拌,向反应瓶中依次加入化合物20a(50mg,0.18mmol)、DMAP(19.5mg,0.16mmol)和EDCI(61.34mg,0.32mmol),室温搅拌过夜。TLC(CH2Cl2:CH3OH=10:1)检测反应情况,待反应完全后,用30mL乙酸乙酯将反应液稀释,然后分别用10mL 1N HCl溶液、10mL饱和碳酸氢钠溶液、10mL饱和食盐水洗2次,用无水Na2SO4干燥20分钟,过滤,浓缩,经柱层析纯化(CH2Cl2:CH3OH=200:1-100:1)得到米白色固体43a(63mg,产率:68%)。
1H NMR(600MHz,DMSO-d6)δ12.80(s,1H),8.41(t,J=5.6Hz,1H),8.08(d,J=7.4Hz,2H),8.03(d,J=7.7Hz,2H),7.89–7.82(m,1H),7.71(t,J=7.7Hz,2H),7.62(t,J=6.8Hz,1H),7.58(d,J=7.7Hz,2H),7.05(s,1H),6.85(s,1H),6.45(s,1H),4.70(s,2H),4.49(s,2H),3.63(s,2H).
43b:合成方法同43a,米白色固体,产率:62%。
1H NMR(600MHz,DMSO-d6)δ12.79(s,1H),8.29(t,J=5.8Hz,1H),8.09–8.06(m,2H),8.04–8.00(m,2H),7.89–7.85(m,1H),7.76–7.71(m,2H),7.64–7.60(m,1H),7.60–7.55(m,2H),7.05(s,1H),6.82(d,J=2.2Hz,1H),6.43(d,J=2.2Hz,1H),4.67(s,2H),4.38(t,J=6.1Hz,2H),3.33–3.30(m,2H),1.96(p,J=6.5Hz,2H).
13C NMR(151MHz,DMSO)δ182.07,167.01,163.63,163.57,161.10,158.84,157.18,137.12,136.09,132.17,130.53,130.02,129.14,128.35,126.42,110.44,105.41,105.28,98.79,93.57,69.12,67.24,34.81,28.15.
43c:合成方法同43a,米白色固体,产率:52%
1H NMR(600MHz,Chloroform-d)δ12.75(d,J=4.2Hz,1H),8.05–8.02(m,2H),7.89–7.85(m,2H),7.74(t,J=7.5Hz,1H),7.61(t,J=7.8Hz,2H),7.56(dd,J=8.4,6.0Hz,1H),7.52(t,J=7.4Hz,2H),6.76(t,J=5.9Hz,1H),6.68(s,1H),6.56(d,J=2.3Hz,1H),6.41(d,J=2.3Hz,1H),4.60(s,2H),4.46(t,J=6.1Hz,2H),3.50(q,J=6.7Hz,2H),1.97–1.91(m,2H),1.82(p,J=7.2Hz,2H).
13C NMR(151MHz,CDCl3)δ182.59,167.44,164.48,162.87,162.60,159.00,157.90,138.00,135.80,132.19,131.16,129.81,129.29,128.68,126.47,106.70,106.13,99.05,93.34,71.33,67.62,38.71,26.24,25.79.
43d:合成方法同43a,米白色固体,产率:73%
1H NMR(600MHz,DMSO-d6)δ12.78(s,1H),8.19(t,J=5.8Hz,1H),8.07(dt,J=7.1,1.4Hz,2H),7.98(dt,J=7.2,1.3Hz,2H),7.89–7.86(m,1H),7.76–7.70(m,2H),7.63–7.59(m,1H),7.59–7.55(m,2H),7.03(s,1H),6.81(d,J=2.3Hz,1H),6.44(d,J=2.3Hz,1H),4.64(s,2H),4.33(t,J=6.3Hz,2H),3.18(q,J=6.6Hz,2H),1.74(p,J=6.5Hz,2H),1.51(p,J=7.1Hz,2H),1.34(p,J=7.9Hz,2H).
13C NMR(151MHz,DMSO)δ182.07,166.66,163.66,163.56,161.10,158.80,157.16,137.20,136.09,132.17,130.53,130.00,129.14,128.24,126.41,110.40,105.41,105.25,99.52,98.80,93.62,71.35,67.26,38.09,28.51,27.51,22.39.
化合物44的合成路线
化合物44的合成
将化合物42(50mg,0.16mmol)和1.6mL无水DMF加入10mL单口圆底烧瓶中,在室温下搅拌,向反应瓶中依次加入化合物15a(49.7mg,0.16mmol)、DMAP(19.5mg,0.16mmol)和EDCI(61.34mg,0.32mmol),室温搅拌过夜。TLC(PE:EA=1:1)检测反应情况,待反应完全后,用25mL乙酸乙酯将反应液稀释,然后分别用10mL 1N HCl溶液、10mL饱和碳酸氢钠溶液、10ml饱和食盐水洗三次,有机相用无水Na2SO4干燥,过滤,浓缩,经硅胶柱层析纯化(CH2Cl2:CH3OH=200:1-100:1)得到米白色固体44(40mg,产率:41%)。
1H NMR(600MHz,Chloroform-d)δ12.77(s,1H),8.08–8.04(m,2H),7.88(dt,J=6.9,1.5Hz,2H),7.78–7.74(m,1H),7.63(t,J=7.9Hz,2H),7.56–7.50(m,3H),6.68(s,1H),6.53(d,J=2.3Hz,1H),6.36(d,J=2.3Hz,1H),5.11(t,J=1.7Hz,2H),4.90(t,J=1.7Hz,2H),4.77(s,2H).
13C NMR(101MHz,CDCl3)δ182.63,167.30,164.41,163.39,162.56,158.02,157.80,137.94,135.87,132.12,131.28,129.85,129.27,128.78,126.47,110.70,106.55,106.12,98.52,93.74,83.10,79.71,65.14,58.59,52.99.
化合物45的合成路线
化合物45的合成
将化合物42(75.6mg,0.24mmol)和2.1mL无水DMF加入10mL单口圆底烧瓶中,在室温下搅拌,向反应瓶中依次加入化合物12a(80mg,0.24mmol)、DMAP(29.32mg,0.24mmol)和EDCI(60.6mg,0.48mmol),室温搅拌过夜。TLC(CH2Cl2:CH3OH=10:1)检测反应情况,待反应完全后,用25mL乙酸乙酯将反应液稀释,然后分别用10mL 1N HCl溶液、10mL饱和碳酸氢钠溶液、10ml饱和食盐水洗三次,有机相用无水Na2SO4干燥,过滤,浓缩,经硅胶柱层析纯化(纯CH2Cl2),得到米白色固体45(67mg,产率:45%)。
1H NMR(600MHz,DMSO-d6)δ12.78(s,1H),8.08–8.03(m,2H),8.01–7.97(m,2H),7.88–7.84(m,1H),7.74–7.69(m,2H),7.62–7.58(m,1H),7.55(td,J=7.3,2.0Hz,2H),7.01(q,J=2.2Hz,1H),6.83–6.77(m,1H),6.40(dp,J=4.9,1.8Hz,1H),4.97(d,J=1.4Hz,2H),4.52–4.46(m,2H),4.34–4.30(m,2H),3.83–3.79(m,2H),3.78–3.72(m,2H).
13C NMR(151MHz,DMSO)δ182.07,168.05,163.58,163.52,161.19,158.86,157.16,137.19,136.09,132.17,130.52,129.97,129.11,128.28,126.43,110.49,105.39,105.32,98.51,93.61,70.82,68.32,67.76,64.96,64.02.
活性测试
以MDA-MB-231细胞的测试方法为例,SUM159、MCF-7、SKBR-3、4T1细胞的测试方法与MDA-MB-231细胞的方法一致):
(1)选取处于对数生长期的MDA-MB-231细胞,按每孔3×103接种于96孔板,5%CO2,37℃孵育培养过夜。
(2)加药,本实验中设置了6-9个浓度梯度,根据需要采用不同的浓度梯度,每个浓度5个复孔,同时设置对照组(不加药仅接种细胞)及空白孔(未接种细胞仅加培养基),5%CO2,37℃培养箱孵育48小时。
(3)每孔再加入20μL MTT溶液(5mg/ml,即0.5%MTT),继续培养4小时。若药物与MTT能够反应,可先离心后弃去培养液,小心用PBS冲洗2-3遍后,再加入含MTT的培养液。
(4)4小时后终止培养,小心地吸去孔内的液体。并向每孔加入150μL的二甲基亚砜。然后置于摇床上低速振荡15min左右,使结晶物充分溶解。采用酶联免疫检测仪MULTISKAN FC(Thermo scientific)测定490nm处及570nm各孔的吸光度值,测量时以空白孔作为调零孔。
(5)处理数据。以药物浓度为横坐标,细胞数为纵坐标,用数据处理软件Graphpad软件进行几率单位加权回归法(Bliss法)进行数据处理,计算IC50值,见表1及图64-93。
表1
由表1的IC50的数据可知,合成的化合物对乳腺癌细胞MDA-MB-231、SUM159、MCF-7、SKBR-3和4T1具有抑制活性,并且有些化合物的抑制活性高达1μM,可以应用于治疗乳腺癌。
以上所述仅为本发明创造的较佳实施例而已,并不用以限制本发明创造,凡在本发明创造的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明创造的保护范围之内。
Claims (9)
3.权利要求1所述的化合物(I)或其药学上可接受的盐在制备抗癌药物或制备抗癌辅助治疗药物中的应用。
4.根据权利要求3所述的应用,其特征在于:所述抗癌癌症为乳腺癌。
5.根据权利要求4所述的应用,其特征在于:乳腺癌细胞MDA-MB-231、SUM159、MCF-7、SKBR-3及4T1。
6.一种药物组合物,其特征在于:包含权利要求1所述化合物(I)或其药学上可接受的盐,以及任选地药学上可接受的赋形剂。
7.根据权利要求6所述的药物组合物,其特征在于:所述药物组合物包括治疗有效量的所述化合物(I)或其药学上可接受的盐。
8.一种试剂盒,其特征在于:包括权利要求1中的所述化合物(I)或其药学上可接受的盐,或权利要求6-7中任一项的药物组合物。
9.根据权利要求8所述的试剂盒,其特征在于:还包括用于指导给药权利要求1所述化合物(I)或其药学上可接受的盐或权利要求6-7中任一项的药物组合物的说明书。
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