CN111675647B - 2-吲哚酮类pak1抑制剂及其在抗肿瘤治疗药物中的应用 - Google Patents
2-吲哚酮类pak1抑制剂及其在抗肿瘤治疗药物中的应用 Download PDFInfo
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- CN111675647B CN111675647B CN202010593160.7A CN202010593160A CN111675647B CN 111675647 B CN111675647 B CN 111675647B CN 202010593160 A CN202010593160 A CN 202010593160A CN 111675647 B CN111675647 B CN 111675647B
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- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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Abstract
本发明涉及2‑吲哚酮类PAK1抑制剂及其在抗肿瘤治疗药物中的应用,属于抗肿瘤药学技术领域。本发明解决的技术问题是提供一种作为PAK1抑制剂的化合物。该化合物包括如下所示的化合物或其药学上可接受的盐,其中X、n、R1如权利要求和说明书所述。本发明的化合物或其药学上可接受的盐,可以作为PAK1抑制剂,用于制备抗肿瘤药物。
Description
技术领域
本发明涉及2-吲哚酮类PAK1抑制剂及其在制备抗肿瘤药物中的应用,属于肿瘤治疗药物技术领域。
背景技术
乳腺癌是临床上女性常见的高发恶性肿瘤之一,据国际癌症研究中心最新统计表明,全球每年就有170万女性被确诊为乳腺癌,占女性肿瘤发病率的25%,导致50万患者死亡。临床上根据基因表达的差异,将所有乳腺癌分为四大亚型:HER2过表达型,Luminal A型,Luminal B型以及三阴性乳腺癌(TNBC)。TNBC是指雌激素受体(ER),孕激素受体(PR)和人表皮生长因子受体2(Her-2)均为阴性的乳腺癌,占所有乳腺癌病理类型的15-20%左右,具有特殊的生物学行为和临床病理特征,与其他亚型乳腺癌相比具有细胞分化差、侵袭性病程、远端转移高等特点,因此预后较差,早期复发风险高、五年生存率极低。由于缺乏内分泌治疗和靶向治疗的有效靶标,TNBC的治疗已经成为目前乳腺癌研究领域的难点之一。
根据NCCN(National Comprehensive Cancer Network)指南,目前临床上常用的TNBC治疗手段仍然是手术和常规的全身细胞毒化疗,含蒽环和紫杉烷类药物的方案在已广泛应用于术后辅助治疗,但是密集型,高剂量的化疗会产生巨大的毒性,且肿瘤复发或转移后往往缺乏有效的药物,治疗效果并不理想,预后依然很差。近年来随着医学生物技术的高速发展,通过对TNBC发生发展的信号通路网络的基础研究,小分子靶向治疗成为TNBC治疗研究的热点,并取得了长足的进步。目前针对TNBC处于热点研究领域的相关信号通路,靶标主要有EGFR,MAPK-ERK,PI3K-AKT-mTOR,PARP,热休克蛋白(HSPs)及组蛋白去乙酰化酶(HDAC)等。尤其是PARP抑制剂如Veliparib在体外实验、动物实验以及一、二期临床试验显示出令人鼓舞的抗瘤效果,Veliparib联合化疗较单纯吉西他滨和卡铂化疗改善TNBC患者OS和PFS的相关临床实验也正在开展。因此,在TNBC药物治疗领域,如何发现新的治疗靶标,有针对性的设计出新型靶向治疗小分子药物,并深入探讨其作用机制是解决临床问题的关键,具有重要的研究意义和价值。PAK1作为一个重要的癌基因,在乳腺癌中异常高表达,针对其设计靶向性的小分子抑制剂,是治疗乳腺癌,也别是三阴性乳腺癌重要的策略。
发明内容
本发明解决的技术问题是提供一种作为PAK1抑制剂的化合物。
本发明提供结构式如式Ⅰ所示的化合物或其药学上可接受的盐:
其中,R1为6-10元芳基或5-10元杂芳基,所述的芳基或杂芳基可以被一个或多个R'取代,R'为氢、硝基、羟基、C1-C6烷基氨基、C1-C6烷基、C1-C6烷氧基、卤素、卤代C1-C6烷基;
n=0-5,优选为0-2;
X为CH2、O或S。
本发明优选如下结构的化合物或其药学上可接受的盐:
X为CH2、O或S。
本发明优选如下结构的化合物或其药学上可接受的盐:
X为CH2、O或S。
本发明优选如下结构的化合物或其药学上可接受的盐:
本发明提供了所述的化合物的药学上可接受的盐。药学上可接受的盐可以为所述化合物的硝酸盐、盐酸盐、硫酸盐、磷酸盐或柠檬酸盐等。
本发明还提供一种药物组合物,它是包含有效剂量的上述化合物或其药学上可接受的盐的制剂。可以通过本领域已知的方法将本发明化合物制成以下形式:片剂、胶囊剂、水性或油性溶液剂、混悬剂、乳剂、乳膏剂、软膏剂、凝胶剂、喷鼻剂、栓剂、用于吸入的细小分散的粉剂或气雾剂或喷雾剂、用于胃肠道外(包括静脉内、肌内或输注)的无菌水性或油性溶液或混悬剂或无菌乳剂。可采用无菌水或水-丙二醇溶液作为溶剂来制备液体制剂,还可将活性组分配制在聚乙二醇水溶液中。用于口服给予的水性溶液可通过将活性组分溶解在水中并按需要加入合适的着色剂、矫味剂、稳定剂和增稠剂来制备。口服使用的水性混悬剂可通过将细小分散的活性组分与粘性物质一道分散在水中,所述粘性物质如为天然合成胶、树脂、甲基纤维素、羧甲基纤维素和其他药剂领域已知的悬浮剂。
药物组合物可为单位剂量形式。在这些形式中,将所述组合物分成含适量活性组分的单位剂量。该单位剂量形式可为包装制剂,包装中包括分隔量的制剂,例如盒装片剂、胶囊剂和在管形瓶或安瓿中的粉剂。单位剂量形式还可为胶囊剂、扁囊剂或片剂或其可为适当数量的任何这些包装形式。
本发明的药物组合物,其活性成分可仅为本发明的化合物,也可与其他抗肿瘤化合物组合作为活性成分。
本发明还提供上述化合物或其药学上可接受的盐或其药物组合物在制备PAK抑制剂中的应用。
本发明进一步提供了上述化合物或其药学上可接受的盐或其药物组合物在制备PAK1抑制剂中的应用。
进一步地,本发明还提供了上述化合物或其药学上可接受的盐或其药物组合物在制备抗肿瘤药物中的应用。
所述的肿瘤为肝癌、肺癌、乳腺癌、肾癌、结肠癌。
以本发明的化合物治疗肿瘤过程中,可采用本发明的药物组合物与其他抗肿瘤药进行联合治疗。
在治疗肿瘤时,可通过同时、顺序或单独给予各种治疗成分可实现这种联合治疗。此类组合产品应用有效剂量范围内的本发明化合物和准许剂量范围内的其他药学活性剂。
附图说明
图1为MDA-MB-231细胞用0,10,20,40μM化合物ZMF-005处理24小时,Hoechst33258荧光染色图。
图2为MDA-MB-231细胞用0,10,20,40μM化合物ZMF-005处理24小时,Annexin V-PI流式检测细胞凋亡率。
图3为MDA-MB-231细胞用0,10,20,40μM化合物ZMF-005处理24小时,细胞凋亡蛋白表达水平。
图4为MDA-MB-231细胞用0,10,20,40μM化合物ZMF-005处理24小时,划痕实验检测细胞的转移。
图5为MDA-MB-231细胞用0,10,20,40μM化合物ZMF-005处理24小时,Transwell检测细胞的迁移。
具体实施方式
下面结合实施例对本发明的具体实施方式做进一步的描述,并不因此将本发明限制在所述的实施例范围之中。
实施例1化合物1-5的合成
化合物1-5采用如下反应式合成:
Scheme 1合成路线和条件试剂和条件:(i),H2SO4,KNO3,0℃,15min;(ii)10%Pd/C,H2,MeOH,室温,12h;(ⅲ)DIPEA,4-吗啉碳酰氯,THF,室温,12h;(ⅳ)哌啶,R1CHO,EtOH,回流,12h。
中间体2制备
取2-吲哚酮(5g,37.6mmol)溶于浓硫酸(50mL)中,在0℃条件下搅拌30分钟。取硝酸钾(3.04g,30mmol)的硫酸(5mL)溶液慢慢滴加至上述溶液中,混合搅拌15min。上述混合物倒入在冰水中析出沉淀,抽滤去滤饼,后用甲醇清洗,干燥得产物。淡黄色固体,4.5g,67.16%。1H NMR(400MHz,DMSO-d6)δ:11.04(s,1H),8.15(dd,J=8.6,2.3Hz,1H),8.09(d,J=2.2Hz,1H),6.98(d,J=8.6Hz,1H),3.64(s,2H);13C NMR(100MHz,DMSO-d6)δ:177.0,150.7,142.2,127.5,125.3,120.4,109.4,36.0。
中间体3制备
向5-硝基吲哚啉-2-酮(2)(4g,22.5mmol)在甲醇(200mL)中的悬浮液中加入10%Pd/C(0.2g)。在存在H2的条件下,将混合物在25℃搅拌24h。抽滤反应物,取滤液浓缩得产物。白色固体,3.1g,93.93%。1H NMR(400MHz,DMSO-d6)δ:9.90(s,1H),6.51(d,J=2.0Hz,1H),6.50(d,J=8.1Hz,1H),6.38(dd,J=8.2,2.2Hz,1H),4.68(s,2H),3.31(s,2H);13C NMR(100MHz,DMSO-d6)δ:176.2,143.6,134.0,126.9,112.8,112.0,109.7,36.5。
中间体4制备
将5-氨基吲哚啉-2-酮(中间体3)(2g,13.5mmol)和DIPEA(2.09g,16.2mmol)在四氢呋喃(50mL)中的溶液在0℃搅拌30min,然后缓慢滴入4-吗啉碳酰氯(3.04g,20.25mmol)在四氢呋喃(10mL)中的溶液,搅拌60min,TLC跟踪检测,展开剂为V(二氯甲烷):V(甲醇)=15:1。后将混合物溶解在水中(250mL),用乙酸乙酯(250mL×3)萃取水溶液。合并有机层用盐水洗涤,用无水硫酸钠干燥,抽滤并浓缩得产物。白色固体,2.5g,71.42%。1H NMR(400MHz,DMSO-d6)δ:10.21(s,1H),8.36(s,1H),7.33(d,J=2.0Hz,1H),7.17(dd,J=8.4,2.1Hz,1H),6.68(d,J=8.3Hz,1H),3.63–3.55(m,4H),3.42(s,2H),3.41–3.35(m,4H);13CNMR(100MHz,DMSO-d6)δ:176.6,155.9,138.9,134.7,126.1,119.9,118.1,109.0,66.4,44.6,36.5。
化合物1-5合成
将N-(2-氧吲哚啉-5-基)吗啉-4-甲酰胺(中间体4)(0.09g,0.35mmol)、相应醛(RCHO,0.7mmol)和哌啶(5.95mg,0.07mmol)加至乙醇(30mL)中,在回流温度下搅拌12h,TLC跟踪检测,展开剂为V(二氯甲烷):V(甲醇)=15:1。将混合物溶液浓缩,用硅胶柱层析法纯化,洗脱剂为V(二氯甲烷):V(甲醇)=20:1,得相应的化合物。
以下为化合物1-5的核磁检测结果。
化合物1,1H NMR(400MHz,DMSO-d6)δ:10.36(s,1H),10.17(s,1H),8.38(s,1H),7.92(d,J=2.0Hz,1H),7.64(d,J=8.2Hz,2H),7.50(s,1H),7.25(dd,J=8.4,2.1Hz,1H),6.89(d,J=8.2Hz,2H),6.75(d,J=8.3Hz,1H),3.59(t,J=4.7Hz,4H),3.41–3.36(m,4H).13C NMR(100MHz,DMSO-d6)δ:168.9,156.7,155.8,138.6,134.6,133.1,132.7,132.0,130.5,130.4,129.4,123.4,120.6,117.9,117.6,115.9,110.2,66.4,44.6.化合物2,1HNMR(400MHz,DMSO-d6)δ:10.40(s,1H),8.37(s,1H),7.87(d,J=2.1Hz,1H),7.73(d,J=8.7Hz,2H),7.54(s,1H),7.26(dd,J=8.4,2.1Hz,1H),7.07(d,J=8.7Hz,2H),6.76(d,J=8.4Hz,1H),3.85(s,3H),3.58(t,J=4.8Hz,4H),3.37(t,J=4.8Hz,4H).13C NMR(100MHz,DMSO-d6)δ:169.5,160.9,156.0,138.2,136.1,134.3,132.0,127.0,126.2,122.9,121.3,116.1,114.7,109.9,66.4,55.8,44.5.
化合物3,1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.37(s,1H),7.94(d,J=2.0Hz,1H),7.66(d,J=8.7Hz,2H),7.48(s,1H),7.22(dd,J=8.4,2.0Hz,1H),6.81(d,J=8.7Hz,2H),6.74(d,J=8.3Hz,1H),3.62–3.55(m,4H),3.39(t,J=4.8Hz,4H),3.03(s,6H).13C NMR(100MHz,DMSO-d6)δ:170.0,156.1,151.7,137.7,137.4,134.1,132.4,122.8,122.1,122.0,121.6,115.9,112.0,109.5,66.4,44.6,40.6.
化合物4,1H NMR(400MHz,DMSO-d6)δ:10.59(s,1H),8.90(dd,J=7.6,2.1Hz,1H),8.46(s,1H),8.35–8.27(m,1H),7.77(d,J=2.1Hz,1H),7.67(s,1H),7.53(d,J=9.1Hz,1H),7.15(dd,J=8.3,2.0Hz,1H),6.73(d,J=8.2Hz,1H),3.64–3.60(m,4H),3.43–3.41(m,4H).13C NMR(100MHz,DMSO-d6)δ:167.6,156.0(JC-F=128Hz),136.8,134.6,134.0,133.7,132.0,128.5,124.7,123.1(JC-F=18Hz),117.7,117.6(JC-F=18Hz),117.2,117.0,114.4,109.6,66.4,44.5.
化合物5,1H NMR(400MHz,DMSO-d6)δ:13.36(s,1H),10.48(s,1H),8.42(s,1H),8.28(s,1H),8.24(s,1H),8.00(s,1H),7.77(s,2H),7.70(d,J=8.7Hz,1H),7.30(d,J=8.4Hz,1H),6.83(d,J=8.5Hz,1H),3.62(t,J=4.7Hz,4H),3.44–3.40(m,4H).13C NMR(100MHz,DMSO-d6)δ:169.5,155.9,140.5,138.3,137.1,135.1,134.3,128.1,126.9,126.6,123.5,123.5,122.8,121.3,116.0,110.9,109.9,66.4,44.5.
实施例2化合物6-12的合成
Scheme 2试剂和条件:(i)DIPEA,ClCH2CH2COCl,THF,0℃,1h;(ii)KI,哌啶,CH3CN,回流,6h;(iii)哌啶,R1CHO,EtOH,回流,12h。
中间体6制备
将5-氨基吲哚啉-2-酮(化合物3)(2g,13.5mmol)和DIPEA(2.09g,16.2mmol)在四氢呋喃(50mL)中的溶液在0℃下搅拌30min,然后缓慢滴入3-氯丙酰氯(2.57g,20.25mmol)在四氢呋喃(10mL)中的溶液,搅拌60min,TLC跟踪检测,展开剂为V(二氯甲烷):V(甲醇)=15:1。将混合物溶解在水中(250mL),水溶液用乙酸乙酯(250mL×3)萃取。合并有机层用盐水洗涤,用无水硫酸钠干燥,抽滤并浓缩得产物。1H NMR(400MHz,DMSO-d6)δ:10.28(s,1H),9.90(s,1H),7.52(d,J=2.0Hz,1H),7.33(dd,J=8.4,2.0Hz,1H),6.74(d,J=8.3Hz,1H),3.87(t,J=6.3Hz,2H),3.46(s,2H),2.78(t,J=6.3Hz,2H);13C NMR(100MHz,DMSO-d6)δ:176.6,167.8,139.8,133.5,126.5,119.0,117.0,109.3,41.4,36.5.
中间体7制备
在回流温度下搅拌3-氯-N-(2-氧吲哚啉-5-基)丙酰胺(化合物6)(2g,8.38mmol)、KI(0.59g,4.19mmol)和哌啶(7.33g,83.8mmol)在乙腈(50mL)中的悬浮液6h,TLC跟踪检测,展开剂为V(二氯甲烷):V(甲醇)=15:1。将混合物溶解在水中(200mL),然后用二氯甲烷(200mL×3)提取水溶液。合并有机层用盐水洗涤,用无水硫酸钠干燥,抽滤并浓缩得产物。1H NMR(400MHz,DMSO-d6)δ:10.27(s,1H),10.00(s,1H),7.50(d,J=2.1Hz,1H),7.30(dd,J=8.3,2.1Hz,1H),6.73(d,J=8.3Hz,1H),3.34(s,2H),2.64–2.54(m,2H),2.46–2.29(m,6H),1.55–1.45(m,4H),1.43–1.35(m,2H);13C NMR(100MHz,DMSO-d6)δ:176.7,170.1,139.5,133.8,126.5,118.7,116.8,109.3,54.9,54.0,36.5,34.3,26.0,24.4。
化合物6-12合成
将N-(2-氧吲哚啉-5-基)-3-(哌啶-1-基)丙酰胺(化合物7)(0.1g,0.35mmol)、相应醛(RCHO,0.7mmol)和哌啶(5.95mg,0.07mmol)在乙醇(30mL)中的溶液在回流温度下搅拌12h,TLC跟踪检测,展开剂为V(二氯甲烷):V(甲醇)=15:1。将混合物溶液浓缩,用硅胶柱层析法纯化,洗脱剂为V(二氯甲烷):V(甲醇)=20:1,得相应的化合物。
以下为化合物6-12的核磁检测结果。
化合物6,1H NMR(400MHz,DMSO-d6)δ:10.49(s,1H),10.10(s,1H),8.69(s,1H),8.01(s,1H),7.48(dd,J=8.4,2.1Hz,1H),7.33(s,1H),7.28(d,J=3.5Hz,1H),6.85–6.79(m,2H),2.94–2.56(m,6H),1.69–1.40(m,8H);13C NMR(100MHz,DMSO-d6)δ:169.7,169.2,151.1,147.2,138.8,133.6,123.1,121.7,121.4,121.0,119.9,117.1,114.1,109.8,53.8,53.5,29.4,24.7,23.2。
化合物7,1H NMR(600MHz,DMSO-d6)δ:10.43(s,1H),10.16(s,1H),10.06(s,1H),8.07(d,J=2.1Hz,1H),7.63(d,J=8.3Hz,2H),7.52(s,1H),7.42(dd,J=8.4,2.1Hz,1H),6.90(d,J=8.5Hz,2H),6.80(d,J=8.3Hz,1H),2.64–2.53(m,2H),2.45–2.32(m,6H),1.53–1.35(m,6H);13C NMR(100MHz,DMSO-d6)δ:169.6,159.7,138.6,137.1,135.3,133.4,132.35,125.3,125.1,121.7,121.0,116.1,114.4,110.1,54.8,53.9,34.2,25.9,24.3。
化合物8,1H NMR(400MHz,DMSO-d6)δ:10.54(s,1H),10.01(s,1H),7.91(dd,J=7.2,2.1Hz,1H),7.79(d,J=2.1Hz,1H),7.76–7.70(m,1H),7.55–7.50(m,2H),7.43(dd,J=8.4,2.0Hz,1H),6.81(d,J=8.4Hz,1H),2.65-2.56(m,2H),2.46-2.27(m,6H),1.49-1.35(m,6H);13C NMR(100MHz,DMSO-d6)δ:168.8,157.0,139.2,133.7,132.7,131.9,130.4,130.3,129.4,122.0,120.9,120.7,117.8,117.7,114.5,110.5,60.2,53.9,34.1,25.9,24.2.
化合物9,1H NMR(400MHz,DMSO-d6)δ:10.58(s,1H),10.04(s,1H),8.32(s,1H),8.05–7.99(m,4H),7.83(dd,J=8.5,1.8Hz,1H),7.77(s,1H),7.63–7.59(m,2H),7.45(dd,J=8.4,2.1Hz,1H),6.85(d,J=8.4Hz,1H),2.97–2.53(s,6H),1.54–1.31(m,8H);13C NMR(100MHz,DMSO-d6)δ:169.2,167.6,139.3,136.3,133.7,133.4,133.1,132.2,129.9,129.1,128.7,128.2,128.1,127.8,127.2,127.0,122.1,121.3,115.1,110.4,54.1,53.6,29.4,25.2,23.5。
化合物10,1H NMR(400MHz,DMSO-d6)δ:11.43(s,1H),10.46(s,1H),10.04(s,1H),8.18(d,J=2.1Hz,1H),7.99(s,1H),7.75(s,1H),7.57–7.49(m,2H),7.46(t,J=2.7Hz,1H),7.42(dd,J=8.3,2.0Hz,1H),6.82(d,J=8.3Hz,1H),6.55(t,J=2.4Hz,1H),3.00–2.55(m,6H),1.63–1.35(m,8H);13C NMR(100MHz,DMSO-d6)δ:169.7,168.0,139.3,138.7,137.2,133.2,128.3,127.2,125.3,124.9,123.5,123.4,122.0,121.2,114.5,112.2,110.0,102.6,54.37,53.6,29.4,25.1,23.6.
化合物11,1H NMR(400MHz,DMSO-d6)δ:13.33(s,1H),10.49(s,1H),10.03(s,1H),8.19(d,J=8.8Hz,2H),8.02(s,1H),7.76–7.69(m,2H),7.65(d,J=8.6Hz,1H),7.44(dd,J=8.4,2.1Hz,1H),6.82(d,J=8.4Hz,1H),2.56–2.51(m,2H),2.42–2.26(m,6H),1.45–1.28(m,6H);13C NMR(100MHz,DMSO-d6)δ:170.2,169.4,140.5,138.8,137.6,135.1,133.4,127.9,126.8,126.5,123.5,123.5,121.6,121.4,114.4,110.9,110.2,54.8,53.9,34.2,25.9,24.3。
化合物12,1H NMR(400MHz,DMSO-d6)δ:10.56(s,1H),10.02(s,1H),9.47(s,1H),9.22(d,J=6.9Hz,1H),8.10(d,J=2.0Hz,1H),8.04(s,1H),7.78–7.74(m,1H),7.55–7.51(m,1H),7.23–7.18(m,2H),6.80(d,J=8.2Hz,1H),2.82–2.54(m,6H),1.70–1.40(m,8H);13CNMR(100MHz,DMSO-d6)δ:169.6,168.0,147.6,143.0,136.6,132.9,128.0,126.4,125.4,122.2,121.4,121.2,118.0,117.9,114.3,113.4,109.5,54.3,53.7,29.4,25.0,23.6。
实施例3化合物13-25的合成
Scheme 3试剂和条件:(i)KI,吗啉,CH3CN,回流,6h;(ii)哌啶,R1CHO,EtOH,回流,12h。
中间体9制备
将3-氯-N-(2-氧吲哚啉-5-基)丙酰胺(化合物6)(2g,8.38mmol)、KI(0.59g,4.19mmol)和吗啉(7.29g,83.8mmol)在乙腈(50mL)中的悬浮液在回流温度下搅拌6h,TLC跟踪检测,展开剂为V(二氯甲烷):V(甲醇)=15:1。将混合物溶解在水中(200mL),然后用二氯甲烷(200mL×3)提取水溶液。合并有机层用盐水洗涤,用无水硫酸钠干燥,抽滤并浓缩得产物。1H NMR(400MHz,DMSO-d6)δ:10.26(s,1H),9.86(s,1H),7.50(d,J=2.0Hz,1H),7.31(dd,J=8.4,2.0Hz,1H),6.73(d,J=8.3Hz,1H),3.57(t,J=4.6Hz,4H),3.33(s,2H),2.60(t,J=7.1Hz,2H),2.43(t,J=7.1Hz,2H),2.40(s,4H);13C NMR(100MHz,DMSO-d6)δ:176.8,170.3,139.5,133.5,126.5,118.7,116.8,109.3,66.7,66.7,54.9,54.9,54.0,36.5,34.3.
化合物13-25的合成
将3-吗啉-N-(2-氧吲哚啉-5-基)丙酰胺(化合物9)(0.1g,0.35mmol)、相应醛(RCHO,0.7mmol)和哌啶(5.95mg,0.07mmol)在乙醇(30mL)中的溶液在回流温度下搅拌12h,TLC跟踪检测,展开剂为V(二氯甲烷):V(甲醇)=15:1。将混合物溶液浓缩,用硅胶柱层析法纯化,洗脱剂为V(二氯甲烷):V(甲醇)=20:1,得相应的化合物。
以下为化合物13-25的核磁检测结果。
化合物13,1H NMR(400MHz,DMSO-d6)δ:10.48(s,1H),10.21(s,1H),9.94(s,1H),8.16(d,J=2.0Hz,1H),7.69(d,J=8.2Hz,2H),7.58(s,1H),7.46(dd,J=8.3,2.0Hz,1H),6.96(d,J=8.2Hz,2H),6.85(d,J=8.3Hz,1H),3.63–3.59(m,4H),2.65(t,J=7.0Hz,2H),2.49–2.42(m,6H);13C NMR(100MHz,DMSO-d6)δ:170.0,169.6,159.7,138.6,137.1,133.4,132.3,125.3,125.1,121.7,121.1,116.1,114.6,110.0,66.6,54.6,53.4,34.2。
化合物14,1H NMR(400MHz,DMSO-d6)δ:10.41(s,1H),9.90(s,1H),9.65(s,1H),9.27(s,1H),8.04(d,J=2.0Hz,1H),7.51–7.40(m,2H),7.17–7.10(m,2H),6.86(d,J=8.3Hz,1H),6.79(d,J=8.6Hz,1H),3.59–3.52(m,4H),2.63–2.56(m,2H),2.46–2.35(m,6H);13C NMR(100MHz,DMSO-d6)δ:170.0,169.7,148.2,145.8,138.6,137.5,133.3,125.8,124.9,122.6,121.8,121.2,117.6,116.2,114.8,110.0,66.6,54.6,53.4,34.1.。
化合物15,1H NMR(400MHz,DMSO-d6)δ:10.43(s,1H),9.89(s,1H),9.77(s,1H),8.26(s,1H),7.53(s,1H),7.40–7.31(m,2H),7.24–7.20(m,1H),6.90(d,J=8.1Hz,1H),6.80(d,J=8.4Hz,1H),3.83(s,3H),3.55(t,J=4.6Hz,4H),2.59(t,J=7.2Hz,2H),2.43–2.37(m,6H);13C NMR(100MHz,DMSO-d6)δ:170.0,169.7,149.2,147.9,138.7,137.4,133.5,125.4,125.0,124.7,121.8,121.0,116.1,114.5,113.5,110.1,66.6,55.8,54.7,53.4,34.3.
化合物16,1H NMR(400MHz,DMSO-d6)δ:10.40(s,1H),9.86(s,1H),8.94(s,1H),8.38(d,J=2.0Hz,1H),7.46(s,1H),7.39(s,2H),7.20(dd,J=8.3,2.0Hz,1H),6.79(d,J=8.3Hz,1H),3.55(t,J=4.6Hz,4H),2.60(t,J=7.0Hz,2H),2.42(t,J=7.0Hz,2H),2.39(t,J=4.6Hz,4H),2.24(s,6H);13C NMR(100MHz,DMSO-d6)δ:169.7,155.9,138.5,137.4,133.4,131.0,125.3,125.1,124.9,121.8,120.8,114.9,110.0,66.6,54.7,53.4,17.1,16.8.。
化合物17,1H NMR(400MHz,DMSO-d6)δ:10.46(s,1H),9.89(s,1H),8.00(d,J=2.0Hz,1H),7.76–7.69(m,2H),7.56(s,1H),7.46(dd,J=8.4,2.0Hz,1H),7.07(d,J=8.7Hz,2H),6.80(d,J=8.4Hz,1H),3.85(s,3H),3.55(t,J=4.6Hz,4H),2.59(t,J=7.0Hz,2H),2.42(t,J=7.0Hz,2H),2.38(d,J=4.5Hz,4H);13C NMR(100MHz,DMSO-d6)δ:170.0,169.4,160.9,136.5,133.4,132.0,126.9,126.1,121.6,121.5,114.7,114.6,110.1,66.6,55.8,54.6,53.4,34.2.
化合物18,1H NMR(400MHz,DMSO-d6)δ:10.40(s,1H),9.86(s,1H),8.94(s,1H),8.38(d,J=2.0Hz,1H),7.46(s,1H),7.39(s,2H),7.20(dd,J=8.3,2.0Hz,1H),6.79(d,J=8.3Hz,1H),3.55(t,J=4.6Hz,4H),2.60(t,J=7.0Hz,2H),2.42(t,J=7.0Hz,2H),2.39(t,J=4.6Hz,4H)2.24(s,6H).13C NMR(100MHz,DMSO-d6)δ:169.7,155.9,138.5,137.4,133.4,131.0,125.3,125.1,124.9,121.8,120.8,114.9,110.0,66.6,54.7,53.4,17.1,16.8。
化合物19,1H NMR(400MHz,DMSO-d6)δ:10.40(s,1H),9.86(s,1H),8.94(s,1H),8.38(d,J=2.0Hz,1H),7.46(s,1H),7.39(s,2H),7.20(dd,J=8.3,2.0Hz,1H),6.79(d,J=8.3Hz,1H),3.55(t,J=4.6Hz,4H),2.60(t,J=7.0Hz,2H),2.42(t,J=7.0Hz,2H),2.39(t,J=4.6Hz,4H)2.24(s,6H);13C NMR(100MHz,DMSO-d6)δ:169.7,155.9,153.8,138.5,137.4,133.4,131.0,125.3,125.1,124.9,121.8,120.8,114.9,110.0,66.6,54.7,53.4,53.4,17.1,16.8。
化合物20,1H NMR(400MHz,DMSO-d6)δ:10.67(s,1H),9.94(s,1H),8.40(d,J=8.7Hz,2H),8.02(d,J=8.5Hz,2H),7.79(d,J=2.0Hz,1H),7.72(s,1H),7.57(dd,J=8.4,2.0Hz,1H),6.89(d,J=8.4Hz,1H),3.57(t,J=4.6Hz,4H),2.62(t,J=7.0Hz,2H),2.50–2.36(m,6H);13C NMR(100MHz,DMSO-d6)δ:170.,168.7,147.8,141.8,139.6,133.7,133.4,130.9,130.8,124.3,122.6,120.6,114.9,110.6,66.6,54.5,53.4,34.2。
化合物21,1H NMR(400MHz,DMSO-d6)δ:10.40(s,1H),9.86(s,1H),8.94(s,1H),8.38(d,J=2.0Hz,1H),7.46(s,1H),7.39(s,2H),7.20(dd,J=8.3,2.0Hz,1H),6.79(d,J=8.3Hz,1H),3.55(t,J=4.6Hz,4H),2.60(t,J=7.0Hz,2H),2.42(t,J=7.0Hz,2H),2.39(t,J=4.6Hz,4H),2.24(s,6H);13C NMR(100MHz,DMSO-d6)δ:169.7,155.9,138.5,137.4,133.4,131.0,125.3,125.1,124.9,121.8,120.8,114.9,110.0,66.6,54.7,53.4,17.1,16.8。
化合物22,1H NMR(400MHz,DMSO-d6)δ:10.55(s,1H),9.86(s,1H),7.91(dd,J=7.2,2.1Hz,1H),7.84(d,J=2.0Hz,1H),7.77–7.70(m,1H),7.56–7.50(m,2H),7.43(dd,J=8.4,2.0Hz,1H),6.81(d,J=8.4Hz,1H),3.54(t,J=4.6Hz,4H),2.58(t,J=7.1Hz,2H),2.43–2.36(m,6H);13C NMR(100MHz,DMSO-d6)δ:170.1,168.9,152.3(JC-F=229Hz),139.3,133.7,132.8,132.0,129.4,122.1(JC-F=19Hz),118.0,117.7(JC-F=19Hz),114.7,110.6,66.6,54.7,53.5,34.2。
化合物23,1H NMR(400MHz,DMSO-d6)δ:13.93(s,1H),10.54(s,1H),10.07(s,1H),9.22(d,J=2.0Hz,1H),8.06(d,J=8.1Hz,1H),7.87(s,1H),7.68(d,J=8.3Hz,1H),7.49(t,J=7.6Hz,1H),7.42(dd,J=8.3,2.1Hz,1H),7.32(t,J=7.5Hz,1H),6.84(d,J=8.2Hz,1H),2.62(t,J=7.1Hz,2H),2.47(t,J=7.1Hz,2H),2.45–2.35(m,4H),1.55–1.46(m,4H);13C NMR(100MHz,DMSO-d6)δ170.2,169.9,141.1,139.9,139.2,133.3,127.2,126.5,124.6,122.8,122.5,122.4,119.8,119.6,111.3,109.5,55.1,54.1,34.3,26.1,24.5。
化合物24,1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),10.47(s,1H),9.88(s,1H),9.46(d,J=2.6Hz,1H),8.06(d,J=5.7Hz,1H),7.98(d,J=3.5Hz,2H),7.56–7.50(m,1H),7.29–7.21(m,3H),6.79(d,J=8.2Hz,1H),3.60(t,J=4.5Hz,4H),2.66(t,J=7.1Hz,2H),2.50–2.41(m,6H);13C NMR(100MHz,DMSO-d6)δ:170.1,168.6,136.3,135.8,134.1,133.1,128.5,127.2,126.0,122.9,121.3,119.7,119.6,118.4,112.8,111.5,111.4,109.3,66.6,54.8,53.6,34.2。
化合物25,1H NMR(400MHz,DMSO-d6)δ:13.33(s,1H),10.49(s,1H),9.86(s,1H),8.22–8.15(m,2H),8.07(s,1H),7.77–7.70(m,2H),7.65(d,J=8.7Hz,1H),7.42(d,J=8.4Hz,1H),6.82(d,J=8.4Hz,1H),3.50(t,J=4.7Hz,4H),2.60–2.53(m,2H),2.43–2.32(m,6H);13C NMR(100MHz,DMSO-d6)δ:170.0,169.4,167.9,140.5,138.9,137.6,135.1,133.4,127.9,126.9,126.5,123.5,121.6,121.5,114.6,110.9,110.2,66.6,54.6,53.4,34.2。
试验例1化合物1~25的PAK1激酶抑制活性及抗增殖活性
本实验的目的是检测本发明的化合物对体外PAK1抑制活性(表1)。
所有酶反应均在30℃下进行40min。50μL反应混合物包含40mmol/LTris pH 7.4、10mmol/L MgCl2、0.1mg/mL BSA、1mmol/L DTT、50μmol/L ATP、0.2μg/ml PAK1和100μmol/L脂质底物。将化合物及对照化合物(FRAX597)在10%二甲基亚砜中稀释,并将5μL稀释液添加到50μL反应中,以便让所有反应中DMSO的最终浓度为1%。反应液室温条件下孵育60min,加入5μL的ADP-Glo+和激酶Glo+反应试剂。培养板在室温下孵育40分钟,然后加入10μL的激酶检测试剂。在室温下孵育30分钟后,测定荧光强度。它通过定量激酶反应后溶液中残留的ATP量来测量激酶活性。分析的发光信号与存在的ATP量相关,与激酶活性量呈负相关。IC50值使用非线性回归计算,并使用GraphPad软件进行归一化剂量-响应拟合。
表1化合物1~25激酶激动活性及抗肿瘤抑制活性
实验结果表明,本发明的化合物大多对PAK1具有抑制活性,其中,化合物23(ZMF-005)、化合物24显示出纳摩尔级的抑制活性,且具有良好的抗肿瘤细胞增殖活性。
试验例2化合物ZMF-005诱导乳腺癌细胞凋亡
为了检测化合物ZMF-005是否能够诱导肿瘤细胞凋亡,我们使用Hoechst 33258对不同浓度的化合物23处理后的MDA-MB-231细胞进行荧光染色,结果显示随着化合物23浓度的增加,荧光染色亮度增强,证明化合物ZMF-005诱导了MDA-MB-231细胞DNA片段化,即凋亡的发生(见图1)。随后,应用Annexin V-PI双染的流式细胞术检测了不同浓度化合物ZMF-005处理后MDA-MB-231细胞的凋亡率,结果表明随着化合物23浓度升高,凋亡率增加(见图2)。随后对凋亡路通相关的marker蛋白的表达水平进行了检测,结果表明化合物ZMF-005能够诱导乳腺癌细胞发生经典的细胞凋亡(见图3)。
试验例3化合物ZMF-005的抑制肿瘤细胞转移
划痕实验检验化合物ZMF-005对细胞的转移能力的影响。将细胞接种在6孔板中,当细胞达到融合后,用移液管尖端手工刮除细胞单层造成伤口。然后用PBS清洗井,加入DMSO对照或化合物。孵育24h后,补充PBS,用相差显微镜拍摄。结果显示化合物ZMF-005可以剂量依赖的抑制MDA-MB-231细胞转移,结果见图4。
试验例4化合物ZMF-005的抑制肿瘤细胞迁移
Transwell实验检验化合物ZMF-005对细胞的迁移能力的影响。细胞以每孔1.5×104个细胞的密度被播种到Transwell膜的上腔,DMEM(500mL)和10%FBS被添加到下腔,24孔培养板孵育24h,用DMSO对照或化合物处理24h,用棉签将未迁移的细胞刮离膜的上表面,用结晶紫染色。用PBS冲洗后用相差显微镜拍摄。结果显示化合物ZMF-005可以剂量依赖的抑制MDA-MB-231细胞转移,结果见图5。
Claims (6)
4.药物组合物,包含权利要求1或2的化合物或其药学上可接受的盐和药学上可接受的载体。
5.权利要求1或2所述的化合物或其药学上可接受的盐或权利要求4所述的药物组合物在制备PAK1抑制剂中的应用。
6.权利要求1或2所述的化合物或其药学上可接受的盐或权利要求4所述的药物组合物在制备治疗与PAK1相关的乳腺癌药物中的应用。
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