CN107698648B - 含胆甾醇的萘酰亚胺类衍生物及其合成和应用 - Google Patents
含胆甾醇的萘酰亚胺类衍生物及其合成和应用 Download PDFInfo
- Publication number
- CN107698648B CN107698648B CN201710764638.6A CN201710764638A CN107698648B CN 107698648 B CN107698648 B CN 107698648B CN 201710764638 A CN201710764638 A CN 201710764638A CN 107698648 B CN107698648 B CN 107698648B
- Authority
- CN
- China
- Prior art keywords
- cholesterol
- cancer cell
- naphthalimide
- synthesis
- 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.)
- Expired - Fee Related
Links
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 title claims abstract description 53
- 235000012000 cholesterol Nutrition 0.000 title claims abstract description 26
- 238000003786 synthesis reaction Methods 0.000 title abstract description 18
- 230000015572 biosynthetic process Effects 0.000 title abstract description 17
- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical class C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 claims abstract description 20
- -1 cyclic amine Chemical class 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000004471 Glycine Substances 0.000 claims abstract description 7
- 230000001093 anti-cancer Effects 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 5
- 238000005886 esterification reaction Methods 0.000 claims abstract description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- 206010006187 Breast cancer Diseases 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 6
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 6
- 201000010881 cervical cancer Diseases 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims 1
- 238000006297 dehydration reaction Methods 0.000 claims 1
- 230000032050 esterification Effects 0.000 claims 1
- GRSMWKLPSNHDHA-UHFFFAOYSA-N Naphthalic anhydride Chemical compound C1=CC(C(=O)OC2=O)=C3C2=CC=CC3=C1 GRSMWKLPSNHDHA-UHFFFAOYSA-N 0.000 abstract description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical group OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000005556 structure-activity relationship Methods 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 31
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000004973 liquid crystal related substance Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 6
- XUGISPSHIFXEHZ-UHFFFAOYSA-N 3beta-acetoxy-cholest-5-ene Natural products C1C=C2CC(OC(C)=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XUGISPSHIFXEHZ-UHFFFAOYSA-N 0.000 description 4
- YEYCQJVCAMFWCO-UHFFFAOYSA-N 3beta-cholesteryl formate Natural products C1C=C2CC(OC=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 YEYCQJVCAMFWCO-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- XUGISPSHIFXEHZ-VEVYEIKRSA-N cholesteryl acetate Chemical compound C1C=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 XUGISPSHIFXEHZ-VEVYEIKRSA-N 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 239000012625 DNA intercalator Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- RRQHLOZQFPWDCA-UHFFFAOYSA-N 1-n,1-n-dimethylpropane-1,2-diamine Chemical compound CC(N)CN(C)C RRQHLOZQFPWDCA-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- DTUOTSLAFJCQHN-UHFFFAOYSA-N 4-bromo-1,8-naphthalic anhydride Chemical compound O=C1OC(=O)C2=CC=CC3=C2C1=CC=C3Br DTUOTSLAFJCQHN-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 150000001841 cholesterols Chemical class 0.000 description 2
- 238000004737 colorimetric analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000010587 phase diagram Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 235000011950 custard Nutrition 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 230000000816 effect on animals Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K19/00—Liquid crystal materials
- C09K19/04—Liquid crystal materials characterised by the chemical structure of the liquid crystal components, e.g. by a specific unit
- C09K19/36—Steroidal liquid crystal compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
发明公开了一种含胆甾醇的萘酰亚胺类衍生物及其合成和应用,属于生物有机合成领域,本发明利用分子杂交,将修饰后的胆甾醇引入萘酰亚胺母体,研发具有抗癌效果的新药。本发明所述的含胆甾醇的萘酰亚胺类衍生物,是用不同的环胺或脂肪胺基团取代萘酐末端的Br,研究药物分子的构效关系;以甘氨酸为桥链,将萘酰亚胺母体与胆甾醇通过DCC法发生酯化反应生成具有抗癌活性的新型含胆甾醇的萘酰亚胺类衍生物的目标化合物。
Description
技术领域
本发明涉及生物有机合成领域中的一类含胆甾醇的萘酰亚胺类衍生物的合成及应用。
背景技术
DNA嵌插剂作为靶向抗肿瘤药物一直是医药化学和分子生物学的研究热点。萘酰亚胺具有平面刚性结构、大π共轭体系、结构可修饰等优点,是DNA嵌入剂的典型嵌入母体,萘酰亚胺类化合物作为DNA嵌入剂已经被广泛地用于抗肿瘤、抗病毒、抗锥体虫等。胆甾醇与细胞膜、胆酸、维生素D的形成息息相关,对动物体作用重大,并且有些胆甾醇衍生物具有抗肿瘤、抗癌活性。容士宏等合成了羟基固醇类的水溶性衍生物对小鼠Krebs II具有强的抗癌作用。甘氨酸属于非必需氨基酸,结构简单,却参与了很多重要的与代谢有关的生理活性分子和蛋白质的合成,具有抗炎及免疫调节作用。治疗巴金森氏病的“L-多巴”以甘氨酸为主要合成中间体。
发明内容
本发明提供一类含胆甾醇的萘酰亚胺类衍生物的合成及应用。将修饰后的胆甾醇引入萘酰亚胺母体,研发具有抗癌效果的新药。
本发明所述的含胆甾醇的萘酰亚胺类衍生物,(1)用不同的环胺或脂肪胺基团取代萘酐末端的Br,研究药物分子的构效关系。(2)以甘氨酸为桥链,将萘酰亚胺母体与胆甾醇通过DCC法发生酯化反应生成具有抗癌活性的新型含胆甾醇的萘酰亚胺类衍生物的目标化合物。
本发明解决上述技术问题所采用的技术方案是:含胆甾醇的萘酰亚胺类衍生物,其化学分子结构通式D如下:
通式D中:
R选自N位取代的哌啶基、N位取代的吗啉基、N位取代的硫代吗啉基、N位取代的吡咯烷基、N,N-二甲基乙二胺基、N,N-二甲基丙二胺基、正丁胺基。
本发明提供上述含胆甾醇的萘酰亚胺类衍生物的制备方法,以4-溴-1,8萘酐为起始原料,与不同的环胺或链胺R’经溴代反应得到4-R-1,8-萘酐中间体,再与甘氨酸通过氨基缩合反应得到中间体N-(2’-羧基乙基)-4-R-1,8-萘酰亚胺,最后与胆甾醇通过(DCC法)发生酯化反应生成含胆甾醇的萘酰亚胺类衍生物的目标化合物。
所述R’选自哌啶、吗啉、硫代吗啉、吡咯烷、N,N-二甲基乙二胺、N,N-二甲基丙二胺、N,N-二乙基丙二胺、正丁胺。
上述的含胆甾醇的萘酰亚胺类衍生物的合成路线如下:
本发明提供上述含胆甾醇的萘酰亚胺类衍生物在抑制癌细胞药物中的应用。所述的癌细胞株为HepG2(人肝癌细胞)、Hela(人宫颈癌细胞)、MCF-7(乳腺癌细胞)、A549(肺癌细胞),正常对照细胞株是RAW264.7(小鼠单核巨噬细胞)。
用上述合成的含胆甾醇的萘酰亚胺类衍生物用MTT比色法对HepG2(人肝癌细胞)、Hela(人宫颈癌细胞)、MCF-7(乳腺癌细胞)、A549(肺癌细胞)和RAW264.7(小鼠单核巨噬细胞)进行体外抑制肿瘤细胞生长活性的测定,结果表明,该类化合物对肝癌、宫颈癌、乳腺癌、肺癌等癌细胞具有抑制生长的效果。
用MTT比色法将HepG2(人肝癌细胞)、Hela(人宫颈癌细胞)、MCF-7(乳腺癌细胞)、A549(肺癌细胞)和RAW264.7(小鼠单核巨噬细胞)以5×103个细胞/孔接种于96孔板内,培养24h后加入梯度浓度药液200μL/孔,对每个肿瘤细胞株,设置5个复孔,另设无细胞调零孔;肿瘤细胞在37℃、5%CO2条件下培养24h后,加20μL的MTT液继续培养4h后,用移液枪小心地吸出上清液,加入DMSO溶解结晶,然后用酶标仪测OD490值,利用寇式改良法计算被测物对癌细胞生长的IC50值。
本发明所述的含胆甾醇的萘酰亚胺类衍生物具有液晶相,可用于液晶显示屏。
附图说明
图1为化合物D1的液晶相图;
图2为化合物D2的液晶相图。
具体实施方式
下面通过实施例对本发明作进一步的说明。
实施例1
N-(胆甾醇乙酸酯基)-4-吗啉基-1,8-萘酰亚胺(D1)的合成
(1)中间体4-R-1.8-萘酐的合成:
4-吗啉基-1.8-萘酐(中间体1)的合成:
在两口瓶中加入2.77g(10.0mmol)的4-溴-1,8萘酐,20mL
乙二醇单甲醚作溶剂,25℃搅拌,直至溶解。将0.96mL(11.0mmol)吗啉加入反应体系,油浴加热回流,TLC跟踪,4h后停止,冷却至室温,将反应液转移至盛水烧杯中,待黄色固体完全析出后过滤、干燥,得固体2.63g,黄色,产率:93.0%。熔点:210.0-212.0℃。
(2)中间体N-(2’-羧基乙基)-4-R-1,8-萘酰亚胺的合成:
N-(2’-羧基乙基)-4-吗啉基-1,8-萘酰亚胺(中间体2)的合成:
往双口瓶中加入0.57g(2.0mmol)中间体1和0.23g(3.0mmol)甘氨酸,15mL DMF作溶剂,100℃加热反应,TLC监测,9h后停止反应,自然冷却,将反应液转移至盛水烧杯中,待黄色固体完全析出后,过滤然后干燥,得固体0.58g,黄色,产率:85.0%。
(3)终产物N-(胆甾醇乙酸酯基)-4-吗啉基-1,8-萘酰亚胺(D1)的合成:
先将0.70g(1.81mmol)胆甾醇和0.51g(1.50mmol)中间体2的混合物溶于20mL干燥的二氯甲烷中,常温搅拌5min,然后加入0.02g(0.18mmol)DMAP(4-二甲氨基吡啶)和0.37g(1.81mmol)DCC(N,N'-二环己基碳二亚胺)在室温下继续反应,TLC跟踪,20h后停止。减压除去溶剂,柱层析提纯(洗脱液CH2Cl2)。得黄色固体D1 0.23g,收率:22.1%。
+ESI MS(M+Na):C45H60N2O5,计算值:708.4502,实测值:708.4352。
1H NMR(400MHz,CDCl3)δ8.61(dd,J=7.3,1.1Hz,1H),8.56(d,J=8.1Hz,1H),8.46(dd,J=8.5,1.1Hz,1H),7.73(dd,J=8.4,7.3Hz,1H),7.25(d,J=8.1Hz,1H),5.38(d,J=5.1Hz,1H),4.93(d,J=5.9Hz,2H),4.73(tt,J=10.5,5.3Hz,1H),4.06–4.02(m,4H),3.32–3.27(m,4H),2.46–2.33(m,2H),2.05–1.92(m,3H),1.90–1.80(m,2H),1.71–1.62(m,3H),1.58–1.41(m,6H),1.38–1.31(m,3H),1.27(s,2H),1.18–1.08(m,6H),1.02(s,4H),0.92(d,J=6.5Hz,3H),0.88(dd,J=6.6,1.7Hz,6H),0.69(d,J=4.4Hz,3H).
13C NMR(126MHz,CDCl3)δ167.59(s),164.05(s),163.53(s),155.97(s),139.51(s),132.89(s),131.50(s),130.47(s),130.08(s),126.00(d,J=43.6Hz),122.81(d,J=13.4Hz),116.62(s),114.94(s),75.32(s),66.95(s),56.68(s),56.13(s),53.45(s),49.98(s),42.31(s),41.53(s),39.62(d,J=26.0Hz),37.99(s),36.93(s),36.56(s),36.19(s),35.79(s),31.87(d,J=7.7Hz),29.71(s),28.23(s),28.01(s),27.72(s),24.28(s),23.83(s),22.70(d,J=32.3Hz),21.03(s),19.32(s),18.72(s),11.86(s).
化合物D1属于液晶分子,在60.8-156.7℃时出现液晶相如图1所示:
实施例2
N-(胆甾醇乙酸酯基)-4-吡咯烷基-1,8-萘酰亚胺(D2)的合成
(1)4-吡咯烷基-1.8-萘酐(中间体3)的合成:
除用0.90mL(11.0mmol)吡咯烷代替吗啉外,其它操作同实施例1中间体1的合成,得中间体3,黄色固体,产率90.8%。熔点:220.4-222.3℃。
(2)N-(2’-羧基乙基)-4-吡咯烷基-1,8-萘酰亚胺(中间体4)的合成:
除用中间体3代替实施例1中间体1,其它操作同实施例1中间体2,得黄色固体,产率:71.7%。
(3)终产物N-(胆甾醇乙酸酯基)-4-吡咯烷基-1,8-萘酰亚胺(D2)的合成:
除用中间体4代替中间体2外,其它操作同实施例1D1的合成,得目标化合物D2,黄色固体,产率:30.4%。
+ESI MS(M+H):C45H60N2O4,计算值:692.4553,实测值:692.4625。
1H NMR(400MHz,CDCl3)δ8.64–8.55(m,2H),8.43(d,J=8.6Hz,1H),7.53(t,J=7.9Hz,1H),6.81(d,J=8.6Hz,1H),5.36(s,1H),4.91(s,2H),4.76–4.66(m,1H),3.79(s,4H),2.36(d,J=13.0Hz,2H),2.11(s,4H),2.03–1.91(m,3H),1.85(d,J=13.8Hz,2H),1.58(s,6H),1.29(d,J=25.8Hz,8H),1.10(d,J=7.0Hz,6H),1.01(s,4H),0.91(d,J=6.3Hz,3H),0.86(d,J=6.1Hz,6H),0.67(s,3H).
13C NMR(126MHz,CDCl3)δ167.96(s),164.57(s),163.58(s),152.89(s),139.62(s),133.76(s),132.33(s),131.42(d,J=13.2Hz),122.97(s),122.62(d,J=10.6Hz),122.04(s),110.01(s),108.50(s),75.13(s),56.69(s),56.13(s),53.20(s),49.99(s),42.31(s),41.49(s),39.73(s),39.52(s),38.00(s),36.95(s),36.57(s),36.19(s),35.79(s),31.87(d,J=7.3Hz),28.23(s),28.01(s),27.72(s),26.08(s),24.28(s),23.83(s),22.82(s),22.57(s),21.03(s),19.32(s),18.72(s),11.85(s).
化合物D2属于液晶分子,如图2在120.1-149.8℃时具有液晶相。
应用例1:体外抗肿瘤活性抑制实验
本章实验选用HepG2(人肝癌细胞)、Hela(人宫颈癌细胞)、MCF-7(人乳腺癌细胞)、A549(人肺癌细胞)和RAW264.7(小鼠单核巨噬细胞)五种细胞对目标化合物D1-D2进行测试,其中RAW264.7是正常细胞,做阳性对照。采用MTT法计算相应的IC50值。
表2化合物D1-2对HepG2,Hela,MCF-7,A549和RAW264.7细胞株的IC50值
Tab.2 The values of IC50of compounds D1-2against HepG2,Hela,MCF-7,A549and RAW264.7
如上表所示,化合物D1、D2对四种癌细胞均表现出良好的抗肿瘤效果。二者均对乳腺癌细胞株MCF-7表现出最高抑制活性,IC50值接近,分别是18.44μΜ和17.58μΜ。在所有细胞株中,D1对正常细胞RAW264.7的细胞毒性均低于其它癌细胞株,特别是RAW264.7的IC50值是MCF-7的2倍,HepG2,Hela,A549的IC50值分别是MCF-7的1.7倍,1.9倍,1.4倍,具有较好的选择性。而D2对正常细胞RAW264.7的细胞毒性却高于HepG2和Hela。
Claims (3)
2.如权利要求1所述的含胆甾醇的萘酰亚胺类衍生物的制备方法,以4-溴-1,8萘酐为起始原料,与环胺经溴代反应得到4-R-1,8-萘酐中间体,再与甘氨酸通过氨基缩合反应得到中间体N-(2’-羧基亚甲基)-4-R-1,8-萘酰亚胺,最后与胆甾醇通过二环己基碳二亚胺脱水酯化法发生酯化反应生成含胆甾醇的萘酰亚胺类衍生物的目标化合物;
所述环胺选自吗啉、吡咯烷。
3.如权利要求1所述的含胆甾醇的萘酰亚胺类衍生物在制备抑制癌细胞药物中的应用;当R选自N位取代的吗啉基时,所述的癌细胞为人肝癌细胞HepG2、人宫颈癌细胞Hela、人乳腺癌细胞MCF-7、人肺癌细胞A549;当R选自N位取代的吡咯烷基时,所述的癌细胞为人乳腺癌细胞MCF-7、人肺癌细胞A549。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710764638.6A CN107698648B (zh) | 2017-08-30 | 2017-08-30 | 含胆甾醇的萘酰亚胺类衍生物及其合成和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710764638.6A CN107698648B (zh) | 2017-08-30 | 2017-08-30 | 含胆甾醇的萘酰亚胺类衍生物及其合成和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107698648A CN107698648A (zh) | 2018-02-16 |
CN107698648B true CN107698648B (zh) | 2020-08-14 |
Family
ID=61170017
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710764638.6A Expired - Fee Related CN107698648B (zh) | 2017-08-30 | 2017-08-30 | 含胆甾醇的萘酰亚胺类衍生物及其合成和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107698648B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109096357B (zh) * | 2018-08-24 | 2020-07-14 | 大连理工大学 | 含硫醚及胆甾醇酯的萘酰亚胺类衍生物合成和应用 |
CN109796517A (zh) * | 2019-02-02 | 2019-05-24 | 大连理工大学 | 一系列多羟基甾醇抗肿瘤药物及其合成方法和应用 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005016326A2 (en) * | 2003-07-11 | 2005-02-24 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Analogs of thalidomide as potential angiogenesis inhibitors |
CN100398540C (zh) * | 2006-04-03 | 2008-07-02 | 大连理工大学 | 芳杂环基咪唑并萘酰亚胺类化合物及其应用 |
CN101323591A (zh) * | 2008-07-23 | 2008-12-17 | 大连理工大学 | 一类5-位或6-位取代的萘酰亚胺化合物及抗肿瘤应用 |
CN101575315B (zh) * | 2009-06-09 | 2011-05-25 | 北京大学 | 一种萘酰亚胺衍生物及其制备方法和用途 |
CN101628912B (zh) * | 2009-06-25 | 2012-07-25 | 大连理工大学 | 一类抗肿瘤含三氮唑杂环结构的化合物及其应用 |
CN102702297B (zh) * | 2012-06-20 | 2014-07-02 | 河南省科学院化学研究所有限公司 | 胆酸-萘酰亚胺类化合物的制备方法 |
CN106520139B (zh) * | 2016-09-13 | 2019-02-12 | 大连理工大学 | 含有4-(联苯乙炔基)-1,8萘酰亚胺类液晶化合物,其制备方法及应用 |
-
2017
- 2017-08-30 CN CN201710764638.6A patent/CN107698648B/zh not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN107698648A (zh) | 2018-02-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101580477A (zh) | 脱氢枞胺衍生物及其在杀菌抗肿瘤药物中的应用 | |
CN106432190B (zh) | 一类含2-氨基嘧啶的萘酰亚胺化合物,其制备方法及应用 | |
CN108147995A (zh) | 一种毒性低的1,8-萘二甲酰亚胺衍生物及其合成方法和应用 | |
CN113666824B (zh) | 一种大麻二酚-2-丙酸酯及其应用 | |
CN106432259B (zh) | 一种岩白菜素类衍生物及其合成方法与应用 | |
CN107698648B (zh) | 含胆甾醇的萘酰亚胺类衍生物及其合成和应用 | |
CN113735709A (zh) | 一种大麻二酚-2-丁酸酯及其应用 | |
CN104557887A (zh) | 一种1,8-萘二甲酰亚胺衍生物及其合成方法和应用 | |
CN106632379A (zh) | 一种具抗肿瘤活性的岩白菜素氮杂肉桂酸酯类化合物及其合成方法 | |
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 | |
CN108033912A (zh) | 一种毒性低的1,8-萘二甲酰亚胺衍生物及其制备方法和应用 | |
CN108164463A (zh) | 一种具有非小细胞肺癌选择性抑制作用的1,8-萘二甲酰亚胺衍生物及其合成方法和应用 | |
CN107652342A (zh) | 核苷氨基磷酸酯类前药的多晶型及其制备方法 | |
CN108467394B (zh) | 一类α-硫辛酸类H2S供体与吴茱萸碱拼合物及其制备方法和用途 | |
CN107286220B (zh) | 1,2,4-三氮唑偶联的二氢杨梅素衍生物及其制备方法和应用 | |
CN109096357B (zh) | 含硫醚及胆甾醇酯的萘酰亚胺类衍生物合成和应用 | |
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 | |
CN105693609B (zh) | 多取代苯基烷氨基吖啶酮-4-酰胺类化合物及其制备方法和用途 | |
CN110804039B (zh) | 一类含邻苯二甲酰亚胺的1,8-萘酐类衍生物,其药学可接受的盐及其抗肿瘤药物应用 | |
CN103896918A (zh) | 化合物及其制备方法和用途 | |
CN109180583B (zh) | 含杂环砜基及n-氧化物的萘酰亚胺衍生物合成及应用 | |
CN108148080B (zh) | 金属有机金(iii)配合物及其合成方法和应用 | |
CN108329300B (zh) | 硝基苯并[d]氮杂*基喹唑啉类化合物及其制备方法和应用 | |
CN106946974B (zh) | 一类含吡唑杂环的熊果酰胺衍生物及其合成与应用 | |
CN106632405B (zh) | 一种鬼臼毒素与去甲斑蝥素的拼合物及其制备与应用 |
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: 20200814 Termination date: 20210830 |
|
CF01 | Termination of patent right due to non-payment of annual fee |