CN117285523A - 一种芹菜素衍生物及其在抗肿瘤中的应用 - Google Patents
一种芹菜素衍生物及其在抗肿瘤中的应用 Download PDFInfo
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- CN117285523A CN117285523A CN202311005296.1A CN202311005296A CN117285523A CN 117285523 A CN117285523 A CN 117285523A CN 202311005296 A CN202311005296 A CN 202311005296A CN 117285523 A CN117285523 A CN 117285523A
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- Prior art keywords
- alkyl
- substituted
- apigenin
- cycloalkyl
- compound
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- 150000001472 apigenin derivatives Chemical class 0.000 title claims abstract description 27
- 206010028980 Neoplasm Diseases 0.000 title claims description 18
- 208000008839 Kidney Neoplasms Diseases 0.000 claims abstract description 17
- 206010038389 Renal cancer Diseases 0.000 claims abstract description 17
- 201000010982 kidney cancer Diseases 0.000 claims abstract description 17
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 9
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 8
- 201000005202 lung cancer Diseases 0.000 claims abstract description 8
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 8
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 7
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 7
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 18
- 239000000543 intermediate Substances 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 17
- 238000003786 synthesis reaction Methods 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- -1 3, 4-diphenyl sulfonyl furan Chemical compound 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 229910052740 iodine Inorganic materials 0.000 claims description 11
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 6
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
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- IXOFPUCWZCAFJX-UHFFFAOYSA-N 2-phenylethanethioic s-acid Chemical compound SC(=O)CC1=CC=CC=C1 IXOFPUCWZCAFJX-UHFFFAOYSA-N 0.000 claims description 5
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- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 4
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- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 2
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 3
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- IDWLEJGVLKZNGX-UHFFFAOYSA-N [4-(methylamino)phenyl]boronic acid Chemical compound CNC1=CC=C(B(O)O)C=C1 IDWLEJGVLKZNGX-UHFFFAOYSA-N 0.000 description 14
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Abstract
本发明属于药物技术领域,具体涉及芹菜素衍生物在制备抗肿瘤药物中的应用。所述芹菜素衍生物的结构如下所示:其中,基团定义见说明书。本发明化合物在体外能够有效抑制肾癌Caki‑1细胞、人胃癌细胞SNU‑5、肺癌细胞、人结肠癌细胞HCT 116的增殖,同时在体内对肾癌Caki‑1细胞也具有较好的抑制活性,具有良好的应用前景。
Description
技术领域
本发明属于药物技术领域,具体涉及一种芹菜素衍生物及其制备方法和在制备抗肿瘤药物中的应用。
背景技术
芹菜素(Apigenin,APG)是一种重要的黄酮类化合物,在水蔓青、虎杖、车前子、络石藤等药用植物中大量存在,具有抗炎、抗氧化、抑制肿瘤生长等多种生物活性,尤其是在抗肿瘤方面具有独特优势。大量研究表明,芹菜素能够有效延缓或阻止肝癌、肺癌、前列腺癌、乳腺癌和结直肠癌等多种恶性肿瘤细胞增殖,通过阻滞细胞周期、诱导细胞凋亡、抗血管生成和抑制细胞转移等多种途径发挥抗肿瘤作用。
迄今为止,针对不同的癌症已经研发出多种不同的化疗药物,在癌症的治疗方面取得了重要进展。然而,由于常规化疗药物存在非特异性靶向、低生物利用度、低治疗指数和高剂量要求等缺点,常会引起严重的副作用,包括神经问题、脱发、体重变化、性功能障碍和贫血,目前仍然缺乏安全有效的治疗药物。因此,开发能够选择性作用于靶标而无副作用的新型抗癌药物已成为药物化学家的首要目标。相比于其他结构类型相似的天然产物,芹菜素对正常细胞毒性较小,能通过多种方式抑制肿瘤细胞的活性且无诱变性,被视为一个理想的先导化合物。
肾细胞癌(renal cell carcinoma,RCC)是肾癌的一种主要形式,是全球最常见的癌症之一。全世界每年约有400,000名患者被诊断出肾癌,导致约170,000人死亡。大约65%的RCC患者有局部肿瘤,通常可以通过手术成功控,而那些在手术后出现疾病复发的患者,以及其余35%在初次诊断时已经发生癌细胞转移的患者,需要全身治疗且预后较差,据估计,局部疾病患者的五年生存率为71.0%,而发生肿瘤转移的患者五年生存率为13.9%。RCC对于传统的化疗、放疗并不敏感。
现有技术CN 115160277 A公开了一类新颖的芹菜素衍生物以及包含该类化合物的药物组合物及其抗肾癌应用。其为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药,
但该发明的芹菜素衍生物在肾癌Caki-1细胞上的抗增殖活性仍有待提升。
发明内容
本发明旨在提供一种芹菜素衍生物,及其在制备抗肿瘤药物中的应用。
为了实现上述目的,本发明所采用的技术方案是:
一种芹菜素衍生物,其为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,药学上可接受的盐或它的前药,
其中,R1选自:CONH-R3、五元含氮杂环、六元含氮杂环、NR4R5、COR7、C1-C6烷基、取代的C1-C6烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8杂环基、取代的C3-C8杂环基;取代的C1-C6烷基、取代的C3-C8环烷基、取代的C3-C8杂环基中的取代基可独立任选地选自1个或多个氢、D、F、Cl、Br、I、-OH、-NH2、-NO2、-CN、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基或C6-C10芳基;
R3选自:H、D、C1-C6烷基、取代的C1-C6烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8杂环基、取代的C3-C8杂环基;取代的C1-C6烷基、取代的C3-C8环烷基、取代的C3-C8杂环基中的取代基可独立任选地选自1个或多个氢、D、F、Cl、Br、I、-OH、-NH2、-NO2、-CN、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基或C6-C10芳基;
R4、R5分别独立的选自:H、D、C1-C6烷基、COR6;
R6选自:H、D、C1-C6烷基;
R7选自:H、D、C1-C6烷基、COR8;
R8选自:H、D、C1-C6烷基;
R2选自:C1-C8亚烷基或取代的C1-C8亚烷基;取代基可独立任选地选自1个或多个氢、D、F、Cl、Br、I、-OH、-NH2、-NO2、-CN、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基或C6-C10芳基。
优选的,R3选自:H、D、C1-C3烷基、环丙烷、环丁烷、环戊烷。
优选的,所述五元含氮杂环包括:咪唑、吡唑、噻唑。
优选的,所述六元含氮杂环包括:吡啶、吡嗪、嘧啶、哒嗪。
优选的,R4、R5、R6、R7、R8分别独立的选自:C1-C3烷基。
优选的,R2选自:C1-C5亚烷基。
优选的,所述芹菜素衍生物包括:
基于统一思路,本发明还要求保护所述芹菜素衍生物的合成路线,所述合成路线为:
(1)中间产物的合成:
将2,4,6-三羟基苯乙酮甲基化得到中间体18;
中间体18与碘单质反应得到化合物19;接着通过羟醛缩合反应生成查尔酮中间体20;
中间体20环化得到化合物21;再通过Suzuki偶联反应生成22a-q,最后通过去保护反应,生成中间体23a-q;
(2)产物的合成:
将苯硫基乙酸29通过过氧化氢和发烟硝酸的催化,生成3,4-二苯磺酰基呋喃30;3,4-二苯磺酰基呋喃30与戊二醇连接,再对连接臂进行氧化得到32;
32与中间体23a-q的4'-OH位点拼合,得到NO供体型芹菜素衍生物33a-p。
优选的,所述合成路线包括:由2,4,6-三羟基苯乙酮为起始原料通过硫酸二甲酯甲基化得到中间体18。化合物18与碘单质在碘酸的催化下得到化合物19,接着与4-苄氧基苯甲醛在碱催化下通过羟醛缩合反应生成查尔酮中间体20。以DMSO为溶剂用四水合硫酸铈在110℃回流下氧化发生环化反应得到化合物21,在四三苯基膦钯的催化下发生Suzuki偶联反应生成C-8位苯基芹菜素衍生物,最后在无水乙腈中通过三氯化铝的去保护生成了17个目标产物23a-q;
以苯硫基乙酸29为起始原料在过氧化氢及发烟硝酸的催化下生成3,4-二苯磺酰基呋喃30,在碱性条件下将其与戊二醇进行连接,进一步通过对连接臂进行氧化生成得到32;
最后在DMAP和DCC的催化下将其分别与C-8位苯基芹菜素衍生物23a-p的4'-OH位点进行拼合得到16个NO供体型芹菜素衍生物33a-p。
基于统一思路,本发明还要求保护所述芹菜素衍生物在制备抗肿瘤药物中的应用。
优选的,所述肿瘤包括:肾癌、胃癌、肺癌、结肠癌。
与现有技术相比,本发明的有益效果是:本发明化合物在体外能够有效抑制肾癌Caki-1细胞、人胃癌细胞SNU-5、肺癌细胞(NCI-H441、NCI-H1975、A549)、人结肠癌细胞HCT116的增殖,同时在体内对肾癌Caki-1细胞也具有较好的抑制活性,具有良好的应用前景。
附图说明
图1是本发明化合物用于评估体内抗肾癌Caki-1的治疗效果;
图2是本发明化合物用于抑制Caki-1细胞中AKT和ERK的磷酸化的结果;
图3是本发明化合物对Caki-1细胞中c-Met的影响。
具体实施方式
以下将参考附图并结合实施例来详细说明本发明。需要说明的是,在不冲突的情况下,本发明中的实施例及实施例中的特征可以相互组合。
实施例1
本发明的衍生物可通过下列方法制备得到:
1.I类化合物23a-q的合成
2.II类化合物33a-p的合成
由2,4,6-三羟基苯乙酮为起始原料通过硫酸二甲酯甲基化得到中间体18。化合物18与碘单质在碘酸的催化下得到化合物19,接着与4-苄氧基苯甲醛在碱催化下通过羟醛缩合反应生成查尔酮中间体20。以DMSO为溶剂用四水合硫酸铈在110℃回流下氧化发生环化反应得到化合物21,在四三苯基膦钯的催化下发生Suzuki偶联反应生成C-8位苯基芹菜素衍生物,最后在无水乙腈中通过三氯化铝的去保护生成了17个目标产物23a-q。
以苯硫基乙酸29为起始原料在过氧化氢及发烟硝酸的催化下生成3,4-二苯磺酰基呋喃30,在碱性条件下将其与戊二醇进行连接,进一步通过对连接臂进行氧化生成得到32;最后在DMAP和DCC的催化下将其分别与C-8位苯基芹菜素衍生物23a-p的4'-OH位点进行拼合得到16个NO供体型芹菜素衍生物33a-p。
以下式化合物为例,具体说明合成过程:
步骤一:称取化合物2,4,6-三羟基苯乙酮(25.2g,0.15mol,1eq)和无水碳酸钾(0.225mol,1.5eq)置于瓶中,加入丙酮240mL,在回流搅拌下通过滴液漏斗缓慢滴加硫酸二甲酯(28.4mL,0.3mmol,2eq),滴加完后继续反应3h。待反应结束,反应液冷却后过滤,收集滤液,减压蒸发溶剂,浓缩物加入5%的盐酸溶液。沉淀析出后,过滤,滤饼用水洗涤,收集滤渣用甲醇重结晶,得白色固体粉末18(27g),产率91.7%。
步骤二:称取2-羟基-4,6-二甲氧基苯乙酮18(25g,0.13mol,1eq)和碘(14.9g,0.059mol,0.45eq)置于圆底烧瓶中,加入乙醇200mL,搅拌溶解后,称取碘酸(3.5g,0.02mol,0.15eq)溶于7mL水中,滴加到反应体系中,在室温下搅拌3h。TLC监测原料点消失后,过滤,收集滤饼;滤液减压蒸发浓缩后有沉淀再次析出,过滤,合并滤饼,得白色固体产物19(39g),产率93.3%。
步骤三:称取2-羟基-3-碘-4,6-二甲氧基苯乙酮19(35g,0.11mol,1eq)和4-苄氧基苯甲醛(23g,0.11mol,1eq),加入乙醇350mL,慢慢滴加30%氢氧化钾水溶液100mL,滴加完毕后,在室温下搅拌48h,反应结束后,加入10%盐酸溶液将pH调至5,期间有黄色固体析出。过滤后收集滤饼用冷水洗涤至中性,然后用甲醇重结晶得到黄色固体20(51g),产率90%。
步骤四:称取化合物20(45g,0.09mol,1eq)和四水合硫酸铈(121.6g,0.3mol,2.5eq)置于圆底烧瓶中,加入二甲基亚砜400mL,在110℃条件下反应,反应结束后,将反应体系冷却至室温,倒入冰水中,待黄色固体析出,过滤,滤渣用冰水洗涤,收集滤饼,用乙酸乙酯重结晶得到黄色固体21(40g),产率86%。
步骤五:称取化合物21(400mg,0.78mmol,1eq)、4-甲基氨基苯硼酸(167.5mg,0.94mmol,1.2eq)、四三苯基膦钯(92.4mg,0.08mmol,0.2eq)和无水碳酸铯(508.3mg,1.56mmol,2eq)置于圆底烧瓶中,加入DMF-H2O(5mL,9:1,v/v),氮气保护下在110℃反应过夜,反应结束后停止加热。将反应液冷却至室温后,加入水和乙酸乙酯(3×30mL)萃取三次,有机层用饱和氯化钠萃取,收集有机层,用无水硫酸钠干燥后减压蒸发浓缩。通过硅胶柱色谱纯化(PE/EA=2:1)得到黄色固体22a 350mg,产率86.2%。
步骤六:称取22a(250mg,0.48mmol,1eq)置于圆底烧瓶中,加入无水乙腈4mL,加入无水三氯化铝(448mg,3.36mmol,7eq),在氮气保护下回流反应过夜。反应结束后冷却至室温,加入30%盐酸溶液1mL,继续回流反应2h。停止反应后,将反应液倒入冰水中,此时有沉淀析出,过滤,收集滤饼,通过硅胶柱层析纯化(DCM/MeOH=50:1,v/v)得到黄色固体176mg,产率85%。
步骤七:称取苯硫代乙酸(6.73g,0.04mol)于100mL圆底烧瓶中,加入30mL冰醋酸,在室温搅拌下,加入30%的过氧化氢7.8mL,在60-70℃的条件下回流反应6h,反应结束后,减压蒸发溶剂,得到化合物29-1;接着,称取化合物29-1(5g,24.9mmol)于圆底烧瓶中并加入冰醋酸8mL,在0℃搅拌下将发烟硝酸15mL滴加到苯磺酰乙酸的冰醋酸水溶液中,滴加完毕后在室温下搅拌5分钟,然后于110-140℃的条件下回流反应1.5h。结束后等待15分钟,加入冰水使沉淀析出,过滤后滤渣用水洗涤,收集滤饼,干燥得化合物30。
步骤八:称取1,5-戊二醇(11.4mmol,4.22eq)于圆底烧瓶,加入四氢呋喃THF,10mL),加入化合物30(2.7mmol,1eq),在5℃条件下缓慢滴加氢氧化钠水溶液(2.5N,1mL),搅拌30分钟,通过TLC检测反应,反应结束浓缩后,用EA萃取三次,有机层用饱和NaCl洗涤,减压蒸发溶剂。最后通过硅胶柱色谱纯化(PE/EA=6/1,v/v)得到白色固体31(600mg,产率71%)。
步骤九:称取化合物31(1.5mmol,1eq)于圆底烧瓶中,加入丙酮,在0-5℃搅拌慢慢滴加琼斯试剂,滴加完毕后继续搅拌5分钟,然后在室温下搅拌,反应结束后,真空浓缩除去大部分溶剂,用EA(3×10mL)萃取,收集有机层并干燥,浓缩得粗产物。最后通过硅胶柱色谱纯化(PE/EA=4/1,v/v)得白色固体32(480mg,产率99%)。
步骤十:称取化合物23a(70mg,0.16mmol,1eq),化合物32(82mg,0.24mmol,1.5eq),4-二甲氨基吡啶(0.016mmol,0.1eq)于圆底烧瓶中,加入无水DMF,然后称取DCC(0.32mmol,2eq)加入圆底烧瓶中,室温下搅拌反应过夜,用乙酸乙酯萃取,收集有机层并用无水硫酸钠干燥,减压浓缩得粗产物,最后通过硅胶柱色谱纯化(DCM)得黄色固体33a(95mg,产率78.5%。1H NMR(500MHz,CDCl3)δ8.22(d,J=8.3Hz,1H,NH),8.07(d,J=7.9Hz,2H,Ar-H),7.82(d,J=7.8Hz,2H,Ar-H),7.75-7.72(m,2H,Ar-H),7.58(tt,J=15.8,7.8Hz,4H,Ar-H),7.12-7.07(m,2H,Ar-H),6.72(s,1H,Ar-H),6.22(s,1H,Ar-H),4.54-4.44(m,2H,OCH2),4.08(s,3H,OCH3),3.87(s,3H,OCH3),3.06(d,J=4.8Hz,3H,NCH3),2.71(t,J=7.2Hz,2H,CH2),2.03(dt,J=11.1,6.2Hz,2H,CH2),1.96(p,J=7.4Hz,2H,CH2).13C NMR(125MHz,CDCl3)δ180.74,171.43,168.08,165.04,164.53,159.32,158.93,151.13,147.52,137.98,135.71,133.99,133.38,132.37,132.14,130.67,129.74,128.51,126.44,122.09,121.42,110.47,109.62,106.63,104.92,90.08,71.04,56.47,56.40,33.62,27.79,26.94,21.14.HRMS(ESI)m/z calcd for[C38H33N3O12S+H]+,756.1858,found756.1833.
实施例2
步骤一:以4-甲酰胺基苯硼酸(0.94mmol,1.2eq)替代实施例1中的4-甲基氨基苯硼酸,其余步骤参照实施例1的合成方法制备得化合物22b,黄色固体(320mg),产率80%。
步骤二:以22b(0.48mmol,1eq)替代实施例1中的22a,参照实施例1的合成方法制备得化合物23b黄色固体173mg,产率86%。
步骤三:以23b替代实施例1中的23a,参照实施例1的合成方法制备得化合物33b(8mg),产率76.9%。1H NMR(400MHz,DMSO-d6)δ8.07(s,1H,NH),8.00(t,J=8.4Hz,4H,Ar-H),7.84(dd,J=13.6,7.9Hz,3H,Ar-H),7.72(t,J=7.8Hz,2H,Ar-H),7.66(d,J=8.0Hz,2H,Ar-H),7.44(s,1H,NH),7.17(d,J=8.2Hz,2H,Ar-H),6.73(s,1H,C=CH),6.58(s,1H,Ar-H),4.44(t,J=5.9Hz,2H,OCH2),4.02(s,3H,OCH3),3.96(s,3H,OCH3),2.69(t,J=7.3Hz,2H,CH2),1.86(p,J=6.4Hz,2H,CH2),1.75(p,J=7.6Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ179.69,171.96,168.21,165.58,164.33,159.45,159.34,151.50,147.56,137.66,136.60,134.06,133.60,132.35,130.69,130.49,130.31,128.77,127.54,122.85,110.95,108.93,106.39,104.34,92.02,71.60,57.50,56.91,33.25,27.62,20.96.HRMS(ESI)m/z calcd for[C37H31N3O12S+H]+,742.1701,found 742.1699.
实施例3
步骤一:以4-吗啉苯硼酸(0.94mmol,1.2eq)替代实施例1中的4-甲基氨基苯硼酸,其余步骤参照实施例1的合成方法制备得化合物22c,黄色固体(351mg),产率82%。
步骤二:以22c(0.48mmol,1eq)替代实施例1中的22a,参照实施例1的合成方法制备得化合物23c黄色固体173mg,产率84%。
步骤三:以23c替代实施例1中的23a,参照实施例1的合成方法制备得化合物33c,黄色固体(95mg),产率75.8%。1H NMR(500MHz,CDCl3)δ8.05(d,J=7.9Hz,2H,Ar-H),7.78(dd,J=8.7,2.3Hz,2H,Ar-H),7.75-7.68(m,1H,Ar-H),7.59(t,J=8.0,2.1Hz,2H,Ar-H),7.52(d,J=8.8,2H,Ar-H),7.07(d,J=8.6,2H,Ar-H),7.01(d,J=9.6Hz,2H,Ar-H),6.71(s,1H,C=CH),6.25(s,1H,Ar-H),4.48(t,J=6.0,2.1Hz,2H,CH2),4.05(s,3H,OCH3),3.92(s,3H,OCH3),3.92-3.85(m,4H,OCH2),3.25(p,J=2.6Hz,4H,NCH2),2.70(t,J=7.2Hz,2H,CH2),2.01(p,J=6.4Hz,3H,CH2),1.95(p,J=7.5Hz,2H,CH2).13C NMR(125MHz,CDCl3)δ181.13,171.35,165.26,164.67,158.94,158.54,150.98,150.45,147.77,138.04,135.67,132.26,131.33,130.52,129.71,128.53,121.92,121.69,114.83,110.47,109.28,107.69,105.01,90.13,71.01,66.92,56.50,56.35,49.04,33.64,27.80,21.15.HRMS(ESI)m/zcalcd for[C40H37N3O12S+H]+,784.2171,found 784.2166.
实施例4
步骤一:以4-(4-甲基-1-哌嗪基)苯硼酸(0.94mmol,1.2eq)替代实施例1中的4-甲基氨基苯硼酸,其余步骤参照实施例1的合成方法制备得化合物22d,黄色固体(346mg),产率79%。
步骤二:以22d(0.48mmol,1eq)替代实施例1中的22a,参照实施例1的合成方法制备得化合物23d黄色固体173mg,产率82%。
步骤三:以23d替代实施例1中的23a,参照实施例1的合成方法制备得化合物33d,黄色固体(8mg),产率76.9%。1H NMR(500MHz,CDCl3)δ8.05(d,J=7.8Hz,2H),7.77(d,J=7.7Hz,2H),7.72(t,J=7.5Hz,1H),7.59(t,J=7.2Hz,2H),7.49(d,J=11.4Hz,2H),7.14-7.04(m,2H),7.04-6.98(m,2H),6.71(s,1H),6.24(s,1H),4.48(t,J=5.9Hz,2H),4.04(s,3H),3.92(s,3H),3.36-3.27(m,4H),2.68(dt,J=18.2,6.0Hz,5H),2.40(s,3H),2.02(p,J=6.4Hz,2H),1.95(q,J=7.6Hz,2H).13C NMR(125MHz,CDCl3)δ181.12,171.31,165.26,164.68,158.94,158.51,150.98,150.38,147.79,138.08,135.65,132.24,131.26,130.53,129.71,128.52,121.91,121.44,115.27,110.46,109.25,107.79,105.02,90.16,71.02,56.48,56.35,54.99,48.68,45.99,33.63,27.80,21.13.HRMS(ESI)m/z calcd for[C41H40N4O11S+H]+,797.2487,found 797.2489.
实施例5
步骤一:以4-二甲基氨基苯硼酸(0.94mmol,1.2eq)替代实施例1中的4-甲基氨基苯硼酸,其余步骤参照实施例1的合成方法制备得化合物22e,黄色固体(346mg),产率85%。
步骤二:以22e(0.48mmol,1eq)替代实施例1中的22a,参照实施例1的合成方法制备得化合物23e黄色固体173mg,产率84%。
步骤三:以23e替代实施例1中的23a,参照实施例1的合成方法制备得化合物33e,黄色固体(98mg),产率76.9%。1H NMR(500MHz,CDCl3)δ8.06(d,J=7.5Hz,2H,Ar-H),7.81(d,J=8.6Hz,2H,Ar-H),7.72(td,J=7.4,1.3Hz,1H,Ar-H),7.59(t,J=7.9Hz,2H,Ar-H),7.49(d,J=8.6Hz,2H,Ar-H),7.08(dp,J=124.4,8.8,8.6Hz,2H,Ar-H),6.83(d,J=8.4Hz,2H,Ar-H),6.72(s,1H,C=CH),6.25(s,1H,Ar-H),4.48(t,J=6.0Hz,2H,C=CH),4.05(s,3H,OCH3),3.93(s,3H,OCH3),2.69(t,J=7.2Hz,2H,CH2),2.07-1.99(m,2H,CH2),1.99-1.91(m,2H,CH2).13C NMR(125MHz,CDCl3)δ181.30,171.34,165.29,164.65,158.95,158.25,150.92,149.83,147.88,138.03,135.68,132.30,131.20,130.63,129.72,128.53,121.89,118.04,111.90,110.46,109.17,108.17,105.01,90.09,71.00,56.47,56.33,40.59,33.64,27.80,21.16.HRMS(ESI)m/z calcd for[C38H35N3O11S+H]+,742.2065,found742.2067.
实施例6
步骤一:以4-(N-四氢吡咯基)苯硼酸(0.94mmol,1.2eq)替代实施例1中的4-甲基氨基苯硼酸,其余步骤参照实施例1的合成方法制备得化合物22f,黄色固体(346mg),产率75%。
步骤二:以22f(0.48mmol,1eq)替代实施例1中的22a,参照实施例1的合成方法制备得化合物23f黄色固体173mg,产率85%。
步骤三:以23f替代实施例1中的23a,参照实施例1的合成方法制备得化合物33f,黄色固体(80mg),产率65%。1H NMR(500MHz,CDCl3)δ8.07(d,J=7.9Hz,2H,Ar-H),7.84(d,J=8.3Hz,2H,Ar-H),7.74(t,J=7.5Hz,1H,Ar-H),7.61(t,J=7.7Hz,2H,Ar-H),7.49(d,J=8.2Hz,2H,Ar-H),7.10(d,J=8.3Hz,2H,Ar-H),6.73(s,1H,C=CH),6.68(d,J=8.3Hz,2H,Ar-H),6.26(s,1H,Ar-H),4.50(t,J=6.0Hz,2H,OCH2),4.07(s,3H,OCH3),3.94(s,3H,OCH3),3.37(d,J=6.2Hz,4H,CH2),2.71(t,J=7.2Hz,2H,CH2),2.04(q,J=9.1,7.8Hz,6H,CH2),1.97(q,J=7.5Hz,2H,CH2).13C NMR(125MHz,CDCl3)δ181.37,171.36,165.33,164.58,158.94,158.11,150.89,147.91,147.21,138.01,135.70,132.31,131.27,130.65,129.73,128.52,121.90,116.78,111.09,110.46,109.11,108.46,104.98,90.10,71.01,56.46,56.31,47.66,33.64,27.79,25.55,21.15.HRMS(ESI)m/z calcd for[C40H37N3O11S+H]+,768.2222,found 768.2206.
实施例7
步骤一:以4-乙酰基苯硼酸(0.94mmol,1.2eq)替代实施例1中的4-甲基氨基苯硼酸,其余步骤参照实施例1的合成方法制备得化合物22g,黄色固体(346mg),产率85%。
步骤二:以22g(0.48mmol,1eq)替代实施例1中的22a,参照实施例1的合成方法制备得化合物23g黄色固体173mg,产率85%。
步骤三:以23g替代实施例1中的23a,参照实施例1的合成方法制备得化合物33g,黄色固体(100mg),产率84%。1H NMR(500MHz,CDCl3)δ8.06(dd,J=8.0,5.4Hz,4H,Ar-H),7.72(dd,J=16.0,8.2Hz,5H,Ar-H),7.59(t,J=7.7Hz,2H,Ar-H),7.07(d,J=8.3Hz,2H,Ar-H),6.74(s,1H,C=CH),6.27(s,1H,Ar-H),4.48(t,J=6.1Hz,2H,OCH2),4.07(s,3H,OCH3),3.95(s,3H,OCH3),2.68(d,J=12.9Hz,5H,CH2,,CH3),2.02(dq,J=11.2,6.3Hz,2H,CH2),1.94(dq,J=14.4,7.2Hz,2H,CH2).13C NMR(125MHz,CDCl3)δ197.88,180.73,171.33,165.11,164.72,159.55,158.94,151.18,147.49,138.05,136.06,135.97,135.66,132.22,130.81,130.23,129.71,128.53,128.50,127.98,122.06,110.46,109.89,106.71,105.12,90.14,71.02,56.58,56.48,40.97,33.61,27.80,26.74,21.12.HRMS(ESI)m/z calcd for[C38H32N2O12S+H]+,741.1749,found 741.1732.
实施例8
步骤一:以4-异丙基苯硼酸(0.94mmol,1.2eq)替代实施例1中的4-甲基氨基苯硼酸,其余步骤参照实施例1的合成方法制备得化合物22h,黄色固体(346mg),产率85%。
步骤二:以22h(0.48mmol,1eq)替代实施例1中的22a,参照实施例1的合成方法制备得化合物23h,黄色固体173mg,产率86%。
步骤三:以23h替代实施例1中的23a,参照实施例1的合成方法制备得化合物33h,黄色固体(89mg),产率75%。1H NMR(500MHz,CDCl3)δ8.05(d,J=8.0,2H,Ar-H),7.77(d,J=8.5Hz,2H,Ar-H),7.72(t,J=7.5Hz,1H),7.59(t,J=7.8Hz,2H,Ar-H),7.53(d,J=7.9Hz,2H),7.34(d,J=7.9Hz,2H),7.05(d,J=8.5Hz,2H,Ar-H),6.72(s,1H,C=CH),6.26(s,1H,Ar-H),4.48(t,J=6.0Hz,2H,OCH2),4.06(s,3H,OCH3),3.94(s,3H,OCH3),2.99(hept,J=7.0Hz,1H,CH),2.70(t,J=7.1Hz,2H,CH2),2.09-1.99(m,2H,CH2),1.95(q,J=7.5Hz,2H,CH2),1.32(d,J=6.9Hz,6H,CH3).13C NMR(125MHz,CDCl3)δ181.10,171.32,165.22,164.78,158.95,158.80,151.01,148.22,147.75,138.05,135.66,132.32,130.50,130.44,129.72,128.53,127.92,126.07,121.86,110.47,109.38,107.85,105.01,90.07,71.00,56.49,56.38,33.96,33.63,27.80,24.06,21.14.HRMS(ESI)m/z calcd for[C39H36N2O11S+H]+,741.2113,found 741.2095.
实施例10
步骤一:以4-甲氧羰基苯硼酸(0.94mmol,1.2eq)替代实施例1中的4-甲基氨基苯硼酸,其余步骤参照实施例1的合成方法制备得化合物22j,黄色固体(346mg),产率74%。
步骤二:以22j(0.48mmol,1eq)替代实施例1中的22a,参照实施例1的合成方法制备得化合物23j黄色固体173mg,产率85%。
步骤三:以23j替代实施例1中的23a,参照实施例1的合成方法制备得化合物33j,黄色固体(95mg),产率78.5%。1H NMR(400MHz,CDCl3)δ8.14(d,J=8.0Hz,2H,Ar-H),8.08-8.04(m,2H,Ar-H),7.74(dd,J=9.5,2.6Hz,2H,Ar-H),7.69(dd,J=7.3,5.7Hz,2H,Ar-H),7.62-7.56(m,2H,Ar-H),7.10-7.05(d,J=8.5Hz,2H,Ar-H),6.74(s,1H,C=CH),6.27(s,1H,Ar-H),4.48(t,J=6.0Hz,2H,OCH2),4.07(s,3H,OCH3),3.96(s,3H,OCH3),3.94(s,4H,OCH3),2.69(t,J=7.1Hz,2H,CH2),2.01(qd,J=6.4,5.8,4.2Hz,2H,CH2),1.94(qd,J=7.0,3.5Hz,2H,CH2).13C NMR(100MHz,CDCl3)δ180.75,171.30,167.02,165.12,164.71,159.49,158.94,151.17,147.50,138.07,135.82,135.65,132.22,130.61,130.26,129.71,129.19,129.06,128.53,122.06,110.46,109.85,106.82,105.11,90.13,71.01,56.57,56.47,52.21,33.61,27.81,21.12.HRMS(ESI)m/z calcd for[C38H32N2O13S+H]+,757.1698,found757.1691.
实施例11
步骤一:以4-乙酰胺基苯硼酸(0.94mmol,1.2eq)替代实施例1中的4-甲基氨基苯硼酸,其余步骤参照实施例1的合成方法制备得化合物22k,黄色固体(346mg),产率85%。
步骤二:以22k(0.48mmol,1eq)替代实施例1中的22a,参照实施例1的合成方法制备得化合物23k黄色固体173mg,产率80%。
步骤三:以23k替代实施例1中的23a,参照实施例1的合成方法制备得化合物33k,黄色固体(83mg),产率68.6%。1H NMR(500MHz,DMSO-d6)δ10.05(s,1H),8.02(d,J=7.8Hz,2H),7.85(td,J=11.5,8.6,5.2Hz,3H),7.74-7.68(m,4H),7.50(dd,J=8.3,3.0Hz,2H),7.13(d,J=7.6Hz,2H),6.73(d,J=3.1Hz,1H),6.57(d,J=3.1Hz,1H),4.44(q,J=5.1Hz,2H),4.01(s,3H),3.95(s,3H),2.69(d,J=8.0Hz,2H),2.07(s,3H),1.86(q,J=7.0Hz,2H),1.76(d,J=7.9Hz,3H).13C NMR(125MHz,DMSO-d6)δ179.80,171.90,168.80,165.63,164.27,159.34,158.92,151.42,147.68,138.97,137.70,136.57,132.35,131.17,130.47,128.76,125.41,122.68,118.98,110.95,108.66,107.01,104.30,92.02,71.61,57.40,56.85,33.29,27.63,24.50,20.99.HRMS(ESI)m/z calcd for[C38H33N3O12S+H]+,756.1858,found 756.1849.
实施例12
步骤一:以4-(环丙基氨基甲酰)苯硼酸(0.94mmol,1.2eq)替代实施例1中的4-甲基氨基苯硼酸,其余步骤参照实施例1的合成方法制备得化合物22l,黄色固体(346mg),产率85%。
步骤二:以22l(0.48mmol,1eq)替代实施例1中的22a,参照实施例1的合成方法制备得化合物23l黄色固体173mg,产率82%。
步骤三:以23l替代实施例1中的23a,参照实施例1的合成方法制备得化合物33l,黄色固体(87mg),产率69.6%。1H NMR(500MHz,CDCl3)δ8.06(d,J=7.9Hz,2H,Ar-H),7.84(d,J=8.1Hz,2H,Ar-H),7.73(dd,J=8.1,4.9Hz,3H,Ar-H),7.64(d,J=8.0Hz,2H,Ar-H),7.60(t,J=7.8Hz,2H,Ar-H),7.08(d,J=8.4Hz,2H,Ar-H),6.74(s,1H,C=CH),6.25(s,1H,Ar-H),4.48(dt,J=15.6,6.1Hz,2H,OCH2),4.07(s,3H,OCH3),3.92(s,3H,OCH3),2.94(tt,J=7.3,3.7Hz,1H,NCH),2.70(t,J=7.2Hz,2H,CH2),2.03(dq,J=11.2,6.2Hz,2H,CH2),1.95(dq,J=14.9,7.3Hz,2H,CH2),0.89(p,J=7.5,7.0Hz,2H,CH2),0.67(dd,J=6.5,4.1Hz,2H,CH2).13C NMR(125MHz,CDCl3)δ180.80,171.37,168.64,165.09,164.67,159.39,158.94,151.14,147.52,138.03,135.67,133.21,132.21,130.75,130.26,129.72,128.54,126.50,122.09,110.47,109.85,106.77,105.09,90.06,71.03,56.53,56.46,33.62,27.81,23.22,21.15,6.85.HRMS(ESI)m/z calcd for[C40H35N3O12S+H]+,782.2014,found 782.2008.
实施例14
步骤一:以4-乙基苯硼酸(0.94mmol,1.2eq)替代实施例1中的4-甲基氨基苯硼酸,其余步骤参照实施例1的合成方法制备得化合物22n,黄色固体(346mg),产率87%。
步骤二:以22n(0.48mmol,1eq)替代实施例1中的22a,参照实施例1的合成方法制备得化合物23n黄色固体173mg,产率82%。
步骤三:以23n替代实施例1中的23a,参照实施例1的合成方法制备得化合物33n,黄色固体(86mg),产率74%。1H NMR(500MHz,CDCl3)δ8.01(d,J=7.9Hz,2H,Ar-H),7.73(d,J=8.2Hz,2H,Ar-H),7.68(t,J=7.5Hz,1H,Ar-H),7.55(t,J=7.8Hz,2H,Ar-H),7.47(d,J=7.7Hz,2H,Ar-H),7.27(d,J=7.7Hz,2H,Ar-H),7.02(d,J=8.2Hz,2H,Ar-H),6.67(s,1H,C=CH),6.22(s,1H,Ar-H),4.44(t,J=6.2Hz,2H,OCH2),4.01(s,3H,OCH3),3.89(s,3H,OCH3),2.70-2.64(m,4H,CH2),1.97(t,J=7.4Hz,2H,CH2),1.90(d,J=7.9Hz,2H,CH2),1.26(td,J=7.6,2.1Hz,3H,CH3).13C NMR(125MHz,CDCl3)δ181.10,171.35,165.27,164.73,158.95,158.80,151.01,147.75,143.63,138.01,135.70,132.29,130.48,130.45,129.73,128.52,127.79,127.52,121.91,110.47,109.37,107.82,104.97,90.08,71.03,56.51,56.37,33.63,28.74,27.79,21.13,15.58.HRMS(ESI)m/z calcd for[C38H34N2O11S+H]+,727.1956,found 727.1949.
实施例15
步骤一:以4-戊基苯硼酸(0.94mmol,1.2eq)替代实施例1中的4-甲基氨基苯硼酸,其余步骤参照实施例1的合成方法制备得化合物22o,黄色固体(346mg),产率87%。
步骤二:以22o(0.48mmol,1eq)替代实施例1中的22a,参照实施例1的合成方法制备得化合物23o黄色固体173mg,产率86%。
步骤三:以23o替代实施例1中的23a,参照实施例1的合成方法制备得化合物33o,黄色固体(91mg),产率74%。1H NMR(500MHz,DMSO-d6)δ8.02(d,J=7.9Hz,2H,Ar-H),7.85(t,J=7.5Hz,1H,Ar-H),7.80(d,J=8.3Hz,2H,Ar-H),7.71(t,J=7.7Hz,2H,Ar-H),7.41(d,J=7.7Hz,2H,Ar-H),7.24(d,J=7.8Hz,2H,Ar-H),7.09(d,J=8.3Hz,2H,Ar-H),6.69(s,1H,C=CH),6.51(s,1H,Ar-H),4.43(t,J=6.1Hz,2H,OCH2),3.99(s,3H,OCH3),3.95(s,3H,OCH3),2.67(t,J=7.3Hz,2H,CH2),2.58(t,J=7.6Hz,2H,CH2),1.85(dt,J=11.9,6.1Hz,2H,CH2),1.75(p,J=7.6Hz,2H,CH2),1.58(p,J=7.4Hz,2H,CH2),1.27(dtd,J=14.2,10.4,9.7,4.3Hz,4H,CH2),0.83(t,J=6.8Hz,3H,CH3).13C NMR(125MHz,DMSO-d6)δ208.70,207.88,184.46,182.23,179.77,171.84,165.47,164.24,159.32,158.90,153.44,151.33,147.66,141.92,137.68,136.56,132.34,130.69,130.45,130.42,128.76,128.26,128.16,122.59,110.92,108.56,107.09,104.22,91.80,71.56,57.25,56.74,35.36,33.26,31.26,31.11,27.60,22.47,21.02,14.34.HRMS(ESI)m/z calcd for[C41H40N2O11S+H]+,769.2426,found 769.2435.实施例17生物实验
评价化合物对人肾癌细胞Caki-1、人胃癌细胞SNU-5、人肺癌细胞(NCI-H441、NCI-H1975、A549)、人结肠癌细胞HCT 116和人正常肝细胞L-02的增殖抑制作用。
实验目的:
运用CCK-8实验测定化合物对人肾癌细胞Caki-1、人胃癌细胞SNU-5、人肺癌细胞(NCI-H441、NCI-H1975、A549)、人结肠癌细胞HCT 116和人正常肝细胞L-02增殖的抑制作用。
实验方法:
体外抗肿瘤活性筛选采用CCK-8法,取对数生长期的细胞,用PBS洗涤两次洗去死细胞和残余培养基,加入1mL胰蛋白酶进行消化,消化完成后加入2mL对应细胞所需的完全培养基终止消化并重悬细胞,转移至15mL离心管中,1000r离心3分钟,去掉上清,加入4mL完全培养基吹打混匀,计数后调整细胞密度到适宜浓度(HepG2:6000/well,Caki-1:6000/well、SNU-5:7000/well、NCI-H441:7000/well、NCI-H1975:6000/well、A549:7000/well、L-02:7000/well、HCT 116:6000/well),并接种至96孔板,每孔100μL,在37℃、5% CO2的细胞培养箱中孵育过夜。然后将培养基更换为含有所需浓度目标化合物的培养基,继续在37℃、5% CO2的细胞培养箱中培养72小时,然后加入终浓度为10%(v/v)的CCK-8溶液,在37℃、5% CO2的调件下孵育0.5-2小时,然后用酶标仪在450nm的波长下测定每一个孔的吸光度值。计算半数抑制率IC50。
数据处理:
根据所测吸光度值计算各化合物的细胞增殖抑制率(inhibition ratio,IR),计算公式如下:
IR%=[AC-AD]/[AC-AB]×100%
AB:空白组,含0.5% DMSO、CCK-8和无细胞的培养基的孔的吸光度;
AD:实验组,含0.5% DMSO、CCK-8、药物和有细胞的培养基的孔的吸光度;
实验组中包括两组阳性对照组,阳性药物为APG和15c。
APG和15c的结构式为
AC:对照组,含0.5% DMSO、CCK-8和有细胞的培养基的孔的吸光度;
采用Graph Pad Prism5软件分析数据及作图,计算各化合物在72小时的半数抑制浓度(IC50)。实验结果见表1。
表1化合物33a-p的细胞毒性
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数据通过平均值±SD的形式表示,n=3,给药组VS空白组
药理实验证明,本发明的目标衍生物具有良好的抗肿瘤作用,尤其对于肾癌Caki-1细胞和结肠癌细胞,其抗增殖活性明显优于APG和15c,并且对肿瘤细胞和正常细胞具有一定的选择性,可以用于进一步制备抗肿瘤药物。在人胃癌细胞SNU-5中,化合物33a、33b、33c、33d、33f、33g、33k、33l、33o的抗增殖活性优于APG。在人肺癌细胞NCI-H441中,化合物33a、33b、33c、33d、33e、33f、33g、33h、33j、33k、33l、33n、33o的抗增殖活性优于APG。在NCI-H1975细胞中,化合物33b、33c的抗增殖活性优于APG。在A549细胞中,化合物33a的抗增殖活性优于APG。
实施例18移植瘤实验
基于体外细胞毒性评价,选择化合物33d用于进一步评估体内抗肾癌Caki-1的治疗效果。
实验方法
将Caki-1细胞以1×107个/只的数目悬浮于50μL基质胶和50μLDMEM无血清培养基中,通过皮下注射的方式接种至裸鼠右背部皮下。待移植瘤生长至100mm3时,将动物随机分为四组,每只老鼠每天一次通过腹腔注射给药的方式给予33d(15mg/kg和5mg/kg)、APG(15mg/kg)和同样体积的溶媒(5% DMSO和20% PEG 400的生理盐水),每隔一天测量裸鼠肿瘤体积以及称量体重,使用公式1/2ab2(a:肿瘤长径,mm;b:肿瘤短径,mm)计算肿瘤体积。连续给药18天后,取出肿瘤,对其拍照并称重。
结果如图1所示,图1的A、B和C中,与溶媒对照组相比,15mg/kg的33d显著抑制肿瘤的生长,而5mg/kg的33d和15mg/kg APG的抑制效果并不显著。计算肿瘤生长抑制率可以发现如图1D,33d(15mg/kg)显示出显著的抗肿瘤活性,抑制率为58.3%(w/w),远高于5mg/kg的33d(8.82%)和15mg/kg的APG(13.68%);另一方面,5mg/kg的33d和15mg/kg的APG处理的小鼠体重无明显变化,而33d在15mg/kg剂量下导致了及其轻微不显著的裸鼠体重变化(如图1E),但在停止给药后体重便恢复到正常值。因此可以得出结论,化合物33d在体内对肾癌Caki-1肿瘤具有有效的治疗作用。说明本发明化合物抗肿瘤活性好,具有良好的抗肾癌前景。
实施例19 33d抑制Caki-1细胞中AKT和ERK的磷酸化
为了阐明33d抑制Caki-1细胞的增殖、迁移和诱导Caki-1细胞凋亡的机制,选择33d检测其对Caki-1细胞中AKT和ERK信号传导的调节作用。
实验方法
收集处于对数生长期的Caki-1细胞以2×105个/孔的细胞数量接种到6孔板中,37℃、5% CO2条件下在培养箱贴壁培养过夜。然后倒掉培养基,用PBS洗涤一次,加入含有目标浓度33d或含有DMSO溶媒对照的完全培养基,在培养箱中孵育24小时。倒掉培养基,PBS洗涤后加入裂解液快速裂解细胞,4℃下离心20分钟,上清液转移至新的EP管中。然后,通过BCA试剂盒对蛋白含量进行测定,按每孔30μg的含量进行蛋白定量。采用SDS-PAGE电泳,在100V电压下电泳110min,然后在110V电压下将胶转膜至Polyvinylidene膜上,接着将膜用5% BSA/PBST溶液进行封闭。1小时后,将膜用5% BSA/PBST溶液稀释后的一抗在4℃下进行孵育过夜。将一抗回收,用PBST溶液每10min洗涤一次,共三次。接着将膜用二抗在室温下孵育1小时后再用PBST溶液每10min洗涤一次,共三次,然后用显影剂在化学发光系统下进行显影拍照,通过Image J进行灰度值定量。
结果如图2显示,尽管33d没有改变Caki-1细胞中AKT和ERK的表达水平,但其可剂量依赖性的方式下调AKT和ERK的磷酸化水平,进一步说明33d可能通过影响Akt和Erk发挥抗增殖、迁移和诱导细胞凋亡。
实施例20 33d对Caki-1细胞中c-Met的影响
为了验证结构修饰后的NO供体型芹菜素衍生物是否通过抑制MET的磷酸化来发挥抗Caki-1作用,我们通过蛋白免疫印迹实验研究了33d对MET蛋白表达的影响。
实验方法
收集处于对数生长期的Caki-1细胞以2×105个/孔的细胞数量接种到6孔板中,37℃、5% CO2条件下在培养箱贴壁培养过夜。然后倒掉培养基,用PBS洗涤一次,加入含有目标浓度33d或含有DMSO溶媒对照的完全培养基,在培养箱中孵育24小时。倒掉培养基,PBS洗涤后加入裂解液快速裂解细胞,4℃下离心20分钟,上清液转移至新的EP管中。然后,通过BCA试剂盒对蛋白含量进行测定,按每孔30μg的含量进行蛋白定量。采用SDS-PAGE电泳,在100V电压下电泳110min,然后在110V电压下将胶转膜至Polyvinylidene膜上,接着将膜用5% BSA/PBST溶液进行封闭。1小时后,将膜用5% BSA/PBST溶液稀释后的一抗在4℃下进行孵育过夜。将一抗回收,用PBST溶液每10min洗涤一次,共三次。接着将膜用二抗在室温下孵育1小时后再用PBST溶液每10min洗涤一次,共三次,然后用显影剂在化学发光系统下进行显影拍照,通过Image J进行灰度值定量。
实验结果如图3显示,33d处理的Caki-1细胞的总MET水平未发生明显变化,但MET的磷酸化水平下调,说明33d可能对MET的磷酸化水平有抑制作用。
上述实施例阐明的内容应当理解为这些实施例仅用于更清楚地说明本发明,而不用于限制本发明的范围,在阅读了本发明之后,本领域技术人员对本实施例的各种等价形式的修改均落入本发明所附权利要求所限定的范围。
Claims (10)
1.一种芹菜素衍生物,其特征在于,结构如下所示:
其中,R1选自:CONH-R3、五元含氮杂环、六元含氮杂环、NR4R5、COR7、C1-C6烷基、取代的C1-C6烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8杂环基、取代的C3-C8杂环基;取代的C1-C6烷基、取代的C3-C8环烷基、取代的C3-C8杂环基中的取代基可独立任选地选自1个或多个氢、D、F、Cl、Br、I、-OH、-NH2、-NO2、-CN、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基或C6-C10芳基;
R3选自:H、D、C1-C6烷基、取代的C1-C6烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8杂环基、取代的C3-C8杂环基;取代的C1-C6烷基、取代的C3-C8环烷基、取代的C3-C8杂环基中的取代基可独立任选地选自1个或多个氢、D、F、Cl、Br、I、-OH、-NH2、-NO2、-CN、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基或C6-C10芳基;
R4、R5分别独立的选自:H、D、C1-C6烷基、COR6;
R6选自:H、D、C1-C6烷基;
R7选自:H、D、C1-C6烷基、COR8;
R8选自:H、D、C1-C6烷基;
R2选自:C1-C8亚烷基或取代的C1-C8亚烷基;取代基可独立任选地选自1个或多个氢、D、F、Cl、Br、I、-OH、-NH2、-NO2、-CN、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基或C6-C10芳基。
2.根据权利要求1所述的芹菜素衍生物,其特征在于,R3选自:H、D、C1-C3烷基、环丙烷、环丁烷、环戊烷。
3.根据权利要求1所述的芹菜素衍生物,其特征在于,所述五元含氮杂环包括:咪唑、吡唑、噻唑。
4.根据权利要求1所述的芹菜素衍生物,其特征在于,所述六元含氮杂环包括: 吡啶、吡嗪、嘧啶、哒嗪。
5.根据权利要求1所述的芹菜素衍生物,其特征在于,R4、R5、R6、R7、R8分别独立的选自:C1-C3烷基。
6.根据权利要求1所述的芹菜素衍生物,其特征在于,R2选自:C1-C5亚烷基。
7.根据权利要求1-6任一项所述的芹菜素衍生物,其特征在于,所述芹菜素衍生物包括:
8.根据权利要求1-7任一项所述的芹菜素衍生物的合成路线,其特征在于,所述合成路线包括:
(1)中间产物的合成:
将2,4,6-三羟基苯乙酮甲基化得到中间体18;
中间体18与碘单质反应得到化合物19;接着通过羟醛缩合反应生成查尔酮中间体20;
中间体20环化得到化合物21;再通过Suzuki偶联反应生成22a-q,最后通过去保护反应,生成中间体23a-q;
(2)产物的合成:
将苯硫基乙酸29通过过氧化氢和发烟硝酸的催化,生成3,4-二苯磺酰基呋喃30;3,4-二苯磺酰基呋喃30与戊二醇连接,再对连接臂进行氧化得到32;
32与中间体23a-q的4'-OH位点拼合,得到NO供体型芹菜素衍生物33a-p。
9.根据权利要求1-7任一项所述的芹菜素衍生物在制备抗肿瘤药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述肿瘤包括:肾癌、胃癌、肺癌、结肠癌。
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