CN109516926A - 一种荜茇明碱衍生物的制备与抗肿瘤活性 - Google Patents
一种荜茇明碱衍生物的制备与抗肿瘤活性 Download PDFInfo
- Publication number
- CN109516926A CN109516926A CN201810838717.1A CN201810838717A CN109516926A CN 109516926 A CN109516926 A CN 109516926A CN 201810838717 A CN201810838717 A CN 201810838717A CN 109516926 A CN109516926 A CN 109516926A
- Authority
- CN
- China
- Prior art keywords
- cell
- piplartine
- compound
- preparation
- human
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- VABYUUZNAVQNPG-BQYQJAHWSA-N Piplartine Chemical class COC1=C(OC)C(OC)=CC(\C=C\C(=O)N2C(C=CCC2)=O)=C1 VABYUUZNAVQNPG-BQYQJAHWSA-N 0.000 title abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 4
- 208000019065 cervical carcinoma Diseases 0.000 claims abstract description 4
- 208000032839 leukemia Diseases 0.000 claims abstract description 4
- 201000007270 liver cancer Diseases 0.000 claims abstract description 4
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 4
- 201000001441 melanoma Diseases 0.000 claims abstract description 4
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims abstract 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims abstract 2
- 239000003814 drug Substances 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims description 5
- 210000001072 colon Anatomy 0.000 claims 1
- 230000003287 optical effect Effects 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- VABYUUZNAVQNPG-UHFFFAOYSA-N Piperlongumine Natural products COC1=C(OC)C(OC)=CC(C=CC(=O)N2C(C=CCC2)=O)=C1 VABYUUZNAVQNPG-UHFFFAOYSA-N 0.000 abstract description 11
- GGOVLAUMYLPYAZ-UHFFFAOYSA-N puberulumine Natural products COC1=C(OC)C(OC)=CC(C=CC(=O)N2CCCCC2)=C1 GGOVLAUMYLPYAZ-UHFFFAOYSA-N 0.000 abstract description 11
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 210000004881 tumor cell Anatomy 0.000 abstract description 10
- 206010009944 Colon cancer Diseases 0.000 abstract description 4
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 4
- 201000002528 pancreatic cancer Diseases 0.000 abstract description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 abstract description 3
- 241001597008 Nomeidae Species 0.000 abstract 1
- 238000010276 construction Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- BPLQKQKXWHCZSS-UHFFFAOYSA-N Elemicin Natural products COC1=CC(CC=C)=CC(OC)=C1OC BPLQKQKXWHCZSS-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- VYIBCOSBNVFEIW-UHFFFAOYSA-N 3-phenylpropanamide Chemical group NC(=O)CCC1=CC=CC=C1 VYIBCOSBNVFEIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 description 2
- 235000002566 Capsicum Nutrition 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 239000006002 Pepper Substances 0.000 description 2
- 241000722363 Piper Species 0.000 description 2
- 235000016761 Piper aduncum Nutrition 0.000 description 2
- 235000017804 Piper guineense Nutrition 0.000 description 2
- 235000008184 Piper nigrum Nutrition 0.000 description 2
- 108700020978 Proto-Oncogene Proteins 0.000 description 2
- 102000052575 Proto-Oncogene Human genes 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 206010064912 Malignant transformation Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000758706 Piperaceae Species 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- PLZVEHJLHYMBBY-UHFFFAOYSA-N Tetradecylamine Chemical compound CCCCCCCCCCCCCCN PLZVEHJLHYMBBY-UHFFFAOYSA-N 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- -1 alkaloid compound Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- DHZBEENLJMYSHQ-XCVPVQRUSA-N cantharidin Chemical compound C([C@@H]1O2)C[C@@H]2[C@]2(C)[C@@]1(C)C(=O)OC2=O DHZBEENLJMYSHQ-XCVPVQRUSA-N 0.000 description 1
- 229940095758 cantharidin Drugs 0.000 description 1
- 229930008397 cantharidin Natural products 0.000 description 1
- DHZBEENLJMYSHQ-UHFFFAOYSA-N cantharidine Natural products O1C2CCC1C1(C)C2(C)C(=O)OC1=O DHZBEENLJMYSHQ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000004637 cellular stress Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000036212 malign transformation Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种荜茇明碱衍生物结构式，该化合物为新结构，还公开了该化合物的制备方法及其用途，在化合物对胰腺癌、宫颈癌、结肠癌、恶性黑色素瘤、肝癌、肺腺癌、白血病、卵巢癌等肿瘤细胞具有明显抑制作用。该化合物结构式为
Description
技术领域
本发明涉及一种抗肿瘤天然产物衍生物的制备及用途，属于医药技术领域。
背景技术
恶性肿瘤已经成为严重危害人类生命健康的主要疾病，是人类健康的头号杀手。虽然世界卫生组织、各国政府和科研机构始终把攻克癌症列为一项首要任务，但是时至今日仍是一场“没有获胜的战争”。而小分子抗肿瘤药物是肿瘤治疗的重要部分，寻找和开发新型的小分子抗肿瘤药物是征服恶性肿瘤的重要举措。天然产物对小分子抗肿瘤药物发现领域有着深刻影响。天然产物经过进化预选以及其他一些生物或非生物因素的共同作用,其防御体系和代谢系统高度发达，具有结构新颖，多样，活性独特等特点。天然产物及衍生物也是肿瘤治疗和化学领域的主要候选药物来源，例如紫杉醇，喜树碱，长春新碱，斑蝥素等均成为临床应用的抗肿瘤化学治疗的明星药物。它所含有的核心骨架成为人们寻找生物活性化合物的最佳向导。
荜茇明碱（Piplartine），是一种生物碱类化合物。最初在胡椒科植物荜茇Piper longum Linn.中被发现，后来发现长柄胡椒P. sylvaticumRoxb.和瘤突胡椒P.tuberculatum Jacq.的根中也存在该化合物。荜茇明碱被认为是荜茇药材的主要药效成分。药理学研究发现荜茇明碱有着多种药理学活性。其中我们最感兴趣的是其抗肿瘤活性。研究表明，荜茇明碱能够抑制肿瘤细胞的增殖，促进肿瘤细胞凋亡，对多种肿瘤产生抑制作。来自《nature》的一篇关于荜茇明碱抗肿瘤研究报道更加鼓舞人心，该研究显示荜茇明碱对肿瘤细胞具有选择性杀伤作用，而对正常细胞无影响。在浓度为10 μmol/L 的条件下对肿瘤细胞即可表现出非常强的细胞毒作用，但即使是在15 μmol/L 的浓度下对正常细胞的生存力影响仍然很小。不管是原癌基因突变还是抑癌基因突变造成的细胞恶性转化，通常都会造成细胞应激反应的增强，如氧化、复制、代谢、蛋白毒性应激和DNA 损伤等。癌细胞要生存下去就必须适应这种应激性的表型，这就导致癌细胞对某些非原癌基因因素的依赖性，而正常细胞则不具有这种依赖性，因此如果靶向特异性破坏这种恶性转化表型中的非原癌基因因素，就可以选择性的杀死癌细胞。因此荜茇明碱是一种具有良好开发前景的抗肿瘤药物的先导化合物。以荜茇明碱为先导进行结构改造和修饰，合成结构多样的衍生物可以克服荜茇明碱来源有限的和成药性不佳的问题。
发明内容
本发明提供了一种α，β不饱和苯丙酰胺结构的荜茇明碱衍生物，其化学结构式如下式I所示
本发明的化合物可以一种或多种异构体的形式存在。异构体包括对映异构体、非对映异构体、几何异构体。如本发明的式I所示的化合物，由于一个碳原子上连接四个不同的取代基而形成立体异构体(分别以R和S来表示不同的构型)，本发明包括R型异构体和S型异构体以及它们任何比例的混合物。
本发明提供N-十四烷基-3,4,5-三甲氧基苯丙酰胺的制备和抗肿瘤用途
具体实施方式
下面结合具体实施，进一步阐明本发明。这些实施例应理解为仅用于说明本发明而不是用于限制本发明的保护范围。在阅读了本发明记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等效变化和修饰同样落入本发明权利要求书所限定的范围。
化合物N-十四烷基-3,4,5-三甲氧基苯丙烯酰胺的制备
3,4,5-三甲氧基苯丙烯酸的制备。将3,4,5-三甲氧基苯甲醛 (0.1 mol，19.60 g)、丙二酸(0.1 mol，10.40 g)与催化剂乙醇胺(0.1 mol,6.11 g)溶于25 mL水中, 于100 mL圆底烧瓶中回流反应, TLC监测反应进行状况，待反应结束后冷却后放置过夜待结晶。用布氏漏斗过滤, 用0℃水25mL, 水洗2次, 得粗品,所得产物经50mL乙醇+水[ V(乙醇)：V(水) =6：4]重结晶，即得相应的纯品，产率91%。
3,4,5-三甲氧基苯丙烯酰氯的制备。将SOCl2（0.1 mol，11.79 g）缓慢加入含有3,4,5-三甲氧基苯丙烯酸（0.1mol，23.81 g）的CH2Cl2中溶液中，室温搅拌过夜，旋干，无需分离，备用。
N-十四烷基-3,4,5-三甲氧基苯丙酰胺的制备将十四烷基胺（0.1mol，19.92 g）溶于200ml 无水处理的CH2Cl2中加入0.11mol三乙胺，N2保护，边搅拌缓慢地加入上一步反应的干燥处理的烧瓶中，0℃搅拌2小时。TLC检测反应结束后，将反应物倒入500ml水中，然后搅拌萃取，分离有机层，旋干，得粗品，再用CH2Cl2重结晶即得纯品，产率95%。
N-十四烷基-3,4,5-三甲氧基苯丙烯酰胺的化学表征如下：(E)-N-tetradecyl-3-(3,4,5-trimethoxyphenyl)acrylamide，1H-NMR(DMSO) δ：7.55（d，J=1.5 Hz，1H，AR-CH）7.17（s，2H，AR-H3-6）6.30（s，1H，NH）, 6.19（d，J=15.6 Hz，1H，C=O-CH），3.99（s，6H，AR-3,5-OCH3），3.93（s，3H，AR-4-OCH3）,3.26（m，2H，N-CH2），1.53（m，2H，CH2），1.29（m，24H，CH2），0.96（m，3H，CH3）；EI-MS m/z: 434.31[M+1]+,calcd for C26H43NO4：433.32
细胞培养将本实验需要的人胰腺癌细胞PANC-1、人宫颈癌细胞Hela、人结肠癌细胞HCT116、人恶性黑色素瘤细胞A375、人肝癌细胞HepG2、人肺腺癌细胞A549、人白血病细胞K562、人卵巢癌细胞SKOV-3等8种肿瘤细胞株用含12.5%马血清、2.5%胎牛血清、青霉素100U/ml、链霉素100U/ml的DMEM培养液培养，于37 ℃、5% CO2孵化箱中孵化，待细胞贴壁生长时进行传代处理，传代期间2～3天更换培养液，选取对数生长期细胞进行实验。
抗肿瘤活性测试取对数生长期各肿瘤细胞接种于96孔细胞培养板，密度为5×104个/ml。药物处理组和细胞对照组分别加入每孔100 μl细胞悬液，并将每组设3个平行孔，空白对照组只加入DMEM全培养基，每孔100μl，同样设3个平行孔。细胞培养24h后，药物处理组分别加入终浓度为20 μg/ml的药物溶液100 ul，细胞对照组和空白对照组加入与处理组等量细胞培养液。将96孔培养板置于37℃、5% CO2培养箱培养24 h后，加入10 μl MTT(5 mg/ml)溶液，继续培养4h，每孔加入100 μl DMSO溶解液，直至完全溶解。置于酶标仪，用空白矫正基线，测定570nm的吸光度(A)值，按照下示公式[抑制率=(1-实验组A值/对照组A值)×100%]计算抑制率。
结果显示，我们合成的化合物对人胰腺癌细胞PANC-1、人宫颈癌细胞Hela、人结肠癌细胞HCT116、人恶性黑色素瘤细胞A375、人肝癌细胞HepG2、人肺腺癌细胞A549、人白血病细胞K562、人卵巢癌细胞SKOV-3等8种肿瘤细胞株具有不同程度的抑制作用，10μM时抑制率在18.3%-96.7% 不等，其中对人结肠癌细胞HCT116抑制率最高，达96.7%。
表1本发明化合物浓度为10μM时对多种肿瘤细胞株的抑制率
| 细胞株 | PANC-1 | Hela | HCT116 | A375 | HepG2 | A549 | K562 | SKOV-3 |
| 抑制率% | 83.4 | 63.5 | 96.7 | 18.3 | 81.9 | 77.6 | 43.7 | 88.2 |
半数抑制率IC50 的测试按照上述方法，测定0.01μM、0.1μM、0.5μM、1μM、5μM、10μM、20μM、40μM浓度下该化合物的对HCT116细胞的抑制率，利用GraphPad Prism 5 软件计算化合物对HCT116的半数抑制IC50值。结果显示该化合物对HCT116的IC50值为0.77 μM，高于天然产物荜茇明碱的6.82 μM。
N-十四烷基-3,4,5-三甲氧基苯丙烯酰胺具对多种肿瘤细胞具有抑制作用，可用于制备抗肿瘤药物。
Claims (3)
1.一种具有如下结构的化合物或所述化合物的光学异构体、顺反异构体或药
学上可接受的盐：
。
2.如权利要求1所述的药物结构，合成路线为
。
3.根据权利要求1所述的药物用途，其特征在于：所述抗肿瘤药物胰腺癌、宫颈癌、结肠癌、恶性黑色素瘤、肝癌、肺腺癌、白血病、卵巢癌中的任意一种或两种以上肿瘤的药物。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810838717.1A CN109516926B (zh) | 2018-07-27 | 2018-07-27 | 一种荜茇明碱衍生物制备及用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810838717.1A CN109516926B (zh) | 2018-07-27 | 2018-07-27 | 一种荜茇明碱衍生物制备及用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109516926A true CN109516926A (zh) | 2019-03-26 |
| CN109516926B CN109516926B (zh) | 2021-09-17 |
Family
ID=65771037
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810838717.1A Expired - Fee Related CN109516926B (zh) | 2018-07-27 | 2018-07-27 | 一种荜茇明碱衍生物制备及用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109516926B (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110922349A (zh) * | 2019-11-29 | 2020-03-27 | 四川大学 | 一种抗肿瘤化合物的合成及其在多发性骨髓瘤中的应用 |
| CN111759842A (zh) * | 2020-08-04 | 2020-10-13 | 广州医科大学附属第二医院 | 荜茇酰胺促进自噬及治疗口腔鳞状细胞癌的用途 |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3133964A (en) * | 1962-09-18 | 1964-05-19 | Abbott Lab | Benzamides |
| CN101641341A (zh) * | 2007-03-13 | 2010-02-03 | 希格马托制药工业公司 | 酰胺化合物及其作为抗肿瘤剂的用途 |
| WO2010043953A2 (en) * | 2008-10-15 | 2010-04-22 | Orchid Research Laboratories Ltd. | Novel bridged cyclic compounds as histone deacetylase inhibitors |
| EP2205563A2 (en) * | 2007-10-10 | 2010-07-14 | Orchid Research Laboratories Limited | Novel histone deacetylase inhibitors |
| CN102617391A (zh) * | 2012-04-13 | 2012-08-01 | 合肥工业大学 | 一种白藜芦醇苯丙烯酰胺类衍生物、其制备方法及其用途 |
| CN103601670A (zh) * | 2012-11-20 | 2014-02-26 | 中国人民解放军第二军医大学 | 荜拔酰胺类似物及其制备方法与应用 |
| CN104415035A (zh) * | 2013-08-19 | 2015-03-18 | 江苏靶标生物医药研究所有限公司 | 荜茇酰胺在制备抗肿瘤转移药物中的运用 |
| CN107260734A (zh) * | 2017-06-30 | 2017-10-20 | 佛山市第五人民医院 | 一种具有抗肺癌作用的复方药物组合物及其用途 |
-
2018
- 2018-07-27 CN CN201810838717.1A patent/CN109516926B/zh not_active Expired - Fee Related
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3133964A (en) * | 1962-09-18 | 1964-05-19 | Abbott Lab | Benzamides |
| CN101641341A (zh) * | 2007-03-13 | 2010-02-03 | 希格马托制药工业公司 | 酰胺化合物及其作为抗肿瘤剂的用途 |
| EP2205563A2 (en) * | 2007-10-10 | 2010-07-14 | Orchid Research Laboratories Limited | Novel histone deacetylase inhibitors |
| WO2010043953A2 (en) * | 2008-10-15 | 2010-04-22 | Orchid Research Laboratories Ltd. | Novel bridged cyclic compounds as histone deacetylase inhibitors |
| CN102617391A (zh) * | 2012-04-13 | 2012-08-01 | 合肥工业大学 | 一种白藜芦醇苯丙烯酰胺类衍生物、其制备方法及其用途 |
| CN103601670A (zh) * | 2012-11-20 | 2014-02-26 | 中国人民解放军第二军医大学 | 荜拔酰胺类似物及其制备方法与应用 |
| CN104415035A (zh) * | 2013-08-19 | 2015-03-18 | 江苏靶标生物医药研究所有限公司 | 荜茇酰胺在制备抗肿瘤转移药物中的运用 |
| CN107260734A (zh) * | 2017-06-30 | 2017-10-20 | 佛山市第五人民医院 | 一种具有抗肺癌作用的复方药物组合物及其用途 |
Non-Patent Citations (3)
| Title |
|---|
| YUE‑HU WANG等: "Anticancer Principles from Medicinal Piper (胡椒 Hú Jiāo) Plants", 《JOURNAL OF TRADITIONAL AND COMPLEMENTARY MEDICINE》 * |
| 姚志峰等: "荜茇明碱抗肿瘤作用及其机制", 《国际肿瘤学杂志》 * |
| 左建: "苯丙烯酰胺类化合物的设计、合成及抗血小板聚集活性研究", 《中国优秀硕士学位论文全文数据库 工程科技第I辑》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110922349A (zh) * | 2019-11-29 | 2020-03-27 | 四川大学 | 一种抗肿瘤化合物的合成及其在多发性骨髓瘤中的应用 |
| CN110922349B (zh) * | 2019-11-29 | 2022-04-26 | 四川大学 | 一种抗肿瘤化合物的合成及其在多发性骨髓瘤中的应用 |
| CN111759842A (zh) * | 2020-08-04 | 2020-10-13 | 广州医科大学附属第二医院 | 荜茇酰胺促进自噬及治疗口腔鳞状细胞癌的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109516926B (zh) | 2021-09-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Khelifi et al. | Design, synthesis and anticancer properties of IsoCombretaQuinolines as potent tubulin assembly inhibitors | |
| ES2924065T3 (es) | Hidroxiestilbenos sustituidos y sus aplicaciones terapéuticas | |
| Shi et al. | Antitumor agents. 172. Synthesis and biological evaluation of novel deacetamidothiocolchicin-7-ols and ester analogs as antitubulin agents | |
| CN103450176B (zh) | 一类含2-（4-氨基苯基）苯并噻唑萘酰亚胺化合物及其应用 | |
| CN112707833B (zh) | 组蛋白去乙酰酶抑制剂及其制备和应用 | |
| CN104072493B (zh) | 一类含2-巯基苯并噻唑和三唑杂环的萘酰亚胺化合物，其制备方法及其应用 | |
| CN102863376A (zh) | N-取代甲基-3,5-双取代苄叉基-4-哌啶酮及制备和应用 | |
| CN109516926A (zh) | 一种荜茇明碱衍生物的制备与抗肿瘤活性 | |
| CN106432259B (zh) | 一种岩白菜素类衍生物及其合成方法与应用 | |
| EP2480235A2 (en) | Novel iodo pyrimidine derivatives useful for the treatment of macrophage migration inhibitory factor (mif)-implicated diseases and conditions | |
| CN102617391A (zh) | 一种白藜芦醇苯丙烯酰胺类衍生物、其制备方法及其用途 | |
| CN104151391B (zh) | 一种具有抗肿瘤作用的齐墩果酸衍生物及其制备方法和用途 | |
| CN104910212B (zh) | 一种席夫碱铂配合物及其制备方法和应用 | |
| CN102153508B (zh) | 3,5-(e)-二亚苄基-n-环丙基哌啶-4-酮及其在制备治疗抗肿瘤药物中的应用 | |
| CN107573318A (zh) | 一种具抗肿瘤活性的新型棉酚席夫碱类衍生物及其合成方法 | |
| CN104844526B (zh) | 一种4,6-嘧啶二胺类化合物及其制备方法和应用 | |
| CN107827934B (zh) | 具有抗癌活性的四价铂配合物、制备方法及应用 | |
| CN101235003B (zh) | 3,4,5,4'-四甲氧基-α,β-二苯乙烷-3'-O-硫酸酯钠盐及其应用 | |
| Thakor et al. | Synthesis and cell line study of pyrazole substituted coumarin derivatives | |
| CN103012394B (zh) | 一种罗丹宁衍生物及其制备方法 | |
| CN103864720B (zh) | 苯丙烯酸类法尼基硫代水杨酸衍生物及制备方法和用途 | |
| US20210017200A1 (en) | Hydrocarbyl Tin Complex with Antitumor Activity and Preparation Method Thereof | |
| CN105732476B (zh) | 一种咔唑‑靛红型化合物及其制法和用途 | |
| CN108148080B (zh) | 金属有机金(iii)配合物及其合成方法和应用 | |
| CN103833766B (zh) | 阿格拉滨二甲胺富马酸盐及其在药物制备中的用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210917 |