CN113121612A - 一类含氟铂配合物及其应用 - Google Patents
一类含氟铂配合物及其应用 Download PDFInfo
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 18
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 15
- 239000011737 fluorine Substances 0.000 title claims abstract description 15
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 8
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 6
- 201000007270 liver cancer Diseases 0.000 claims abstract description 6
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 4
- 201000005202 lung cancer Diseases 0.000 claims abstract description 4
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 11
- -1 halogen ions Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 34
- 210000004027 cell Anatomy 0.000 abstract description 28
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- YBJHBAHKTGYVGT-UHFFFAOYSA-N 5-(2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl)pentanoic acid Chemical compound N1C(=O)NC2C(CCCCC(=O)O)SCC21 YBJHBAHKTGYVGT-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 238000001035 drying Methods 0.000 description 14
- NDBYXKQCPYUOMI-UHFFFAOYSA-N platinum(4+) Chemical class [Pt+4] NDBYXKQCPYUOMI-UHFFFAOYSA-N 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000000967 suction filtration Methods 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000005303 weighing Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- OAAKZKGKPMPJIF-UHFFFAOYSA-N [Cl].[I] Chemical compound [Cl].[I] OAAKZKGKPMPJIF-UHFFFAOYSA-N 0.000 description 6
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N biotin Natural products N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
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- 201000011510 cancer Diseases 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 description 3
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 229910001961 silver nitrate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- UZKBSZSTDQSMDR-UHFFFAOYSA-N 1-[(4-chlorophenyl)-phenylmethyl]piperazine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)N1CCNCC1 UZKBSZSTDQSMDR-UHFFFAOYSA-N 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- IIMIOEBMYPRQGU-UHFFFAOYSA-L picoplatin Chemical compound N.[Cl-].[Cl-].[Pt+2].CC1=CC=CC=N1 IIMIOEBMYPRQGU-UHFFFAOYSA-L 0.000 description 2
- 229950005566 picoplatin Drugs 0.000 description 2
- 150000003057 platinum Chemical class 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 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
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000012136 culture method Methods 0.000 description 1
- IRXRGVFLQOSHOH-UHFFFAOYSA-L dipotassium;oxalate Chemical compound [K+].[K+].[O-]C(=O)C([O-])=O IRXRGVFLQOSHOH-UHFFFAOYSA-L 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000011354 first-line chemotherapy Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (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
本发明公开了一类结构式为式1a、式1b、式2a或式2b所示的含氟铂配合物:
Description
技术领域
本发明涉及一类含氟铂配合物及其抗肿瘤活性,属于医药技术领域。
背景技术
铂类药物作为一线化疗药物,广泛用于临床治疗多种癌症。在最近铂类药物的研究中,铂(Ⅳ)配合物、反式铂配合物、空间位阻铂配合物、多核铂配合物等被纷纷报道。大量研究表明,铂(Ⅳ)配合物是一类具有克服经典铂(Ⅱ)缺陷的铂药,与经典铂(Ⅱ)类药物相比,其在体内生理环境中具有更高的稳定性,良好的脂溶性以及与顺铂无交叉耐药性等优势,且与肿瘤靶向基团的结合避免了诸如血液中不稳定,与血浆蛋白不可逆结合,肾脏快速清除以及正常组织中非特异性分布等缺点。铂(Ⅳ)配合物作用机制与铂(Ⅱ)配合物略有不同,在进入细胞后还原为铂(Ⅱ)配合物,与DNA形成加合物,抑制DNA复制诱导肿瘤细胞凋亡。
近年来,已经批准的氟化药物或进入临床试验的候选药物的数量不断增加,药物氟化可以通过阻断代谢不稳定的位置来提高药物的生物稳定性。生物活性小分子选择性氟化是提高药代动力学性质、生物半衰期和生物吸收,提高药物小分子的物理化学特性,例如脂溶性、溶解度,生物利用度的有效策略,是药物化学结构改造重要策略之一。
发明内容
本发明供了一类含氟铂配合物,其结构式如式1a、式1b、式2a、式2b所示:
本发明另一目的是将上述含氟铂配合物应用在制备治疗结肠癌、肺癌、乳腺癌、肝癌药物中。
本发明的优点和效果如下:
本发明的含氟铂配合物利用小分子氟的良好脂溶性与铂配合物抗肿瘤作用协同加合,其轴向基团的选择性键接使其具有靶向癌细胞的作用;胺配体为含氟吡啶衍生物,具有优化其脂溶性、溶解度、生物利用度的能力;本发明化合物是一类低毒、高效、具有良好脂溶性、选择性高、与顺铂无交叉耐药的优势候选药物;将本发明化合物应用在抑制结肠癌细胞、人肺癌细胞、人乳腺癌细胞、人肝癌细胞等肿瘤细胞中,实验结果显示这类型化合物具有明显的体外抑制活性。
具体实施方式
下面通过实施例对本发明作进一步详细说明,但本发明保护范围不局限于所述内容,实施例中制备的化合物用红外光谱、核磁共振氢谱、质谱确定化合物的结构;
实施例1:铂(II)配合物,化合物C1的合成(C5H7Cl2FN2Pt,分子量:379.0)
将(3.5g,9.79mmol)三氯氨铂酸钾用50mL温水溶解,加入(3.35g,10.05mmol)碘化钾30℃下反应1h,然后加入(1.1g,11.33mmol)2-氟吡啶,继续反应1.5h,抽滤,固体水洗两次,乙醇洗涤一次,40℃烘干得3.45g碘氯中间体,产率:98.88%;将(4.56g,9.68mmol)碘氯中间体用100mL纯化水溶解,加入(3.13g,18.41mmol)硝酸银反应1h,抽滤除去沉淀,加入(1.44g,19.32mmol)氯化钾反应1h,抽滤得到C1粗品,C1粗品用100℃沸水溶解,抽滤,滤液在冰浴条件下析出固体,固体烘干得C1纯品2.06g,浅绿色固体,产率:56%;IR(KBr,cm-1):v(NH)br 3266,3201cm-1,v(CH),v(CH):2922,2859cm-1,δ(NH):1453cm-1,v(C-C):1299cm-1,v(C=N):1521cm-1,v(C-F):1129cm-1,v(Pt-Cl):783cm-1,v(Pt-N):534cm-1.1H-NMR(DMSO,ppm):δ4.21~4.49(S,3H,NH3),7.11~7.48(m,2H,CHCHCHCHCFN),7.71~8.31(m,1H,CHCHCHCHCFN),8.37~8.68(m,1H,CHCHCHCHCFN).ESI-MS m/z:[M+H]+=380.0(65%).
实施例2:铂(II)配合物,化合物C2的合成(C7H7FN2O4Pt,分子量:397.0)
将(5.99g,15.95mmol)三氯氨铂酸钾用100mL温水溶解,加入(5.95g,17.92mmol)碘化钾35℃下反应1h,继续加入(1.78g,18.33mmol)2-氟吡啶,接着反应1.5h,抽滤,水洗两次,乙醇洗一次,40℃烘干得7.54碘氯中间体,产率:95.56%;将(7.54g,16mmol)碘氯中间体用150mL纯化水溶解,加入(5.12g,15.06mmol)硝酸银反应1h,抽滤除去沉淀,加入(2.95g,16.03mmol)草酸钾反应1h,抽滤得到C2粗品,将粗品用100℃沸水溶解,抽滤,滤液在冰浴条件下析出固体,固体烘干得C2纯品4.36g,浅绿色固体,产率:68.6%;IR(KBr,cm-1):v(NH)br 3267,3116cm-1,v(CH),v(CH):2936,2854cm-1,δ(NH):1448cm-1,v(C-O):1696,1586cm-1,v(C-C):1248cm-1,v(C=N):1549cm-1,v(C-F):1139cm-1,v(Pt-O):807cm-1,v(Pt-N):633cm-1.1H-NMR(DMSO,ppm):δ4.58~4.72(S,3H,NH3),7.43~7.54(m,2H,CHCHCHCHCFN),8.23~8.26(m,1H,CHCHCHCHCFN),8.65~8.72(m,1H,CHCHCHCHCFN).ESI-MSm/z:[M+H]+=398.0(58%).
实施例3:铂(II)配合物,化合物C3的合成(C11H13FN2O4Pt,分子量:451.1)
将(3.57g,10mmol)三氯氨铂酸钾用70mL温水溶解,加入(3.32g,20mmol)碘化钾35℃下反应1.5h,继续加入(1.16g,11.95mmol)2-氟吡啶,接着反应1.5h,抽滤,水洗两次,乙醇洗一次,40℃烘干得4.12g碘氯中间体,产率:87.47%;将(4.12g,8.75mmol)碘氯中间体用70mL纯化水溶解,加入(2.83g,16.62mmol)硝酸银反应1.5h,抽滤除去沉淀,加入(3.13g,8.75mmol)1,1-环丁二羧酸银反应1h,抽滤得到C3粗品,将粗品用100℃沸水溶解,抽滤,滤液在冰浴条件下析出固体,固体烘干得C3纯品2.16g,浅绿色固体,产率:54.75%。IR(KBr,cm-1):v(NH)br 3235,3117cm-1,v(CH),v(CH):2927,2848cm-1,δ(NH):1453cm-1,v(C-O):1639,1566cm-1,v(C-C):1275cm-1,v(C=N):1489cm-1,v(C-F):1205cm-1,v(Pt-O):807cm-1,v(Pt-N):565cm-1.1H-NMR(DMSO,ppm):δ1.68~1.72(d,2H,COOCCH2CH2CH2COO),2.69~2.72(d,4H,COOCCH2CH2CH2COO),4.45~4.62(S,3H,NH3),7.41~7.52(m,2H,CHCHCHCHCFN),8.21~8.37(m,1H,CHCHCHCHCFN),8.51~8.59(m,1H,CHCHCHCHCFN).ESI-MS m/z:[M+H]+=452.1(28%),[M+Na]+=474.1(43%).
实施例4:铂(IV)中间体,化合物C4的合成
称取(3.79g,10mmol)实施例1化合物C1,加入约50mL的纯化水,40℃水浴搅拌,将30mL过氧化氢(30%)缓慢滴加至反应液中,有大量的气泡产生,反应液呈淡黄色,反应3h,过滤,得产物为黄色沉淀,水洗2次,乙醇洗1次,40℃干燥,得2.68g化合物C4,产率:64.89%,作为中间体无需表征。
实施例5:铂(IV)中间体,化合物C5的合成
称取(3.79g,10mmol)实施例2化合物C2,加入约50mL的纯化水,40℃水浴搅拌,然后将35mL过氧化氢(30%)缓慢滴加至反应液中,有大量的气泡产生,反应液呈浅黄色,反应3h,过滤,得产物为黄色沉淀,水洗2次,乙醇润洗1次,40℃干燥,得2.73g化合物C5,产率:63.65%,作为中间体无需表征。
实施例6:铂(IV)中间体,化合物C6的合成
称取(3.79g,10mmol)实施例1化合物C1,加入约50mL的纯化水,25℃水浴搅拌,称取(1.33g,10mmol)N-氯代丁二酰亚胺缓慢加于反应液中,避光反应12h,抽滤除去反应液中未溶的固体,蒸发浓缩除去所有的液体,有大量的黄色固体析出,40℃干燥得2.56g化合物C6,产率:59.39%,作为中间体无需表征。
实施例7:铂(IV)中间体,化合物C7的合成
称取(3.97g,10mmol)实施例2化合物C2,加入约50mL的纯化水,25℃水浴搅拌,称取(1.52g,10mmol)N-氯代丁二酰亚胺缓慢加于反应液中,避光反应12h,抽滤除去反应液中未溶的固体,蒸发浓缩除去所有的液体,有大量的黄色固体析出,40℃干燥得2.63g化合物C7,产率:58.78%,作为中间体无需表征。
实施例8:铂(IV)配合物,化合物C8的合成(C15H23Cl2FN4O4PtS,分子量:639.0)
称取(4.11g,10mmol)实施例4化合物C4溶于20mL DMSO中,加入(3.41g,10mmol)生物素酯,在60℃反应20h,过滤除去不溶物,用甲醇-乙醚混合液(体积比1:1)析出固体沉淀,抽滤,固体40℃烘干得灰色固体,2.35g化合物C8,产率:36.77%。
IR(KBr,cm-1):δv(NH)br 3378,3220cm-1,v(CH),v(CH):2930,2855cm-1,(NH):1453cm-1,v(C-O):1685,1622cm-1,v(C-C):1265cm-1,v(C=N):1561cm-1,v(C-F):1145cm-1,v(Pt-O):891cm-1,v(Pt-Cl):675cm-1,v(Pt-N):579cm-1.1H-NMR(DMSO,ppm):δ1.21~1.65(m,6H,3CH2 of C10H16N2O3S)2.15~2.21(m,2H,CH2 of C10H16N2O3S),2.52~2.82(m,2H,CH2 ofC10H16N2O3S),3.05~3.14(m,1H,CH of C10H16N2O3S),4.12~4.29(m,2H,2CH ofC10H16N2O3S),6.32~6.51(m,2H,2NH of C10H16N2O3S),7.02~7.26(m,3H,NH3),7.41~7.52(m,2H,2CH of C5H4NF),7.68~8.09(m,2H,2CH of C5H4NF).ESI-MS m/z:[M+H]+=640.0(22%),[M+Na]+=662.0(31%).
实施例9:铂(IV)配合物,化合物C9的合成(C17H23FN4O8PtS分子量:657.1)
称取(4.31g,10mmol)化合物C4溶于20mL DMSO中,加入(3.41g,10mmol)生物素酯,在60℃反应20h,过滤除去不溶物,用甲醇-乙醚混合液(体积比1:1)析出固体沉淀,抽滤,固体40℃烘干得灰色固体,2.53g化合物C9,产率:36.86%。IR(KBr,cm-1):v(NH)br 3246,3071cm-1,v(CH),v(CH):2933,2853cm-1,δ(NH):1443cm-1,v(C-O):1697,1615cm-1,v(C-C):1254cm-1,v(C=N):1564cm-1,v(C-F):1154cm-1,v(Pt-O):934cm-1,v(Pt-Cl):745cm-1,v(Pt-N):534cm-1.1H-NMR(DMSO,ppm):δ1.35~1.61(m,6H,3CH2 of C10H16N2O3S)2.21~2.28(m,2H,CH2 of C10H16N2O3S),2.53~2.58(m,2H,CH2 of C10H16N2O3S),3.11~3.34(m,1H,CH ofC10H16N2O3S),4.21~4.49(m,2H,2CH of C10H16N2O3S),6.41~6.62(m,2H,2NH ofC10H16N2O3S),6.76~7.24(m,3H,NH3),7.26~8.02(m,4H,4CH of C5H4NF).ESI-MS m/z:[M+Na]+=680.1(27%).
实施例10:铂(IV)配合物,化合物C10的合成(C15H22Cl3FN4O4PtS,分子量:657.0)
称取(4.29g,10mmol)化合物C6,加入缩合剂TBTU(4.82g,15mmol)和三乙胺(0.11g,10mmol),溶于DMF溶剂中,称取生物素(2.44g,10mol)加入反应体系中,均匀搅拌,60℃反应24h;反应结束后,将反应液中加入适量的二氯甲烷,然后加入纯化水进行萃取,蒸发浓缩除去反应液中的缩合剂,用甲醇-乙醚混合液(体积比1:1)析出固体,抽滤,固体40℃烘干得灰色固体,2.61g化合物C10,产率:36.66%。IR(KBr,cm-1):v(NH)br 3389,3224cm-1,v(CH),v(CH):2932,2856cm-1,δ(NH):1454cm-1,v(C-O):1711,1682cm-1,v(C-C):1264cm-1,v(C=N):1539cm-1,v(C-F):1209cm-1,v(Pt-O):897cm-1,v(Pt-N):578cm-1.1H-NMR(DMSO,ppm):δ1.11~1.54(m,6H,3CH2 of C10H16N2O3S)2.05~2.19(m,2H,CH2 of C10H16N2O3S),2.49~2.76(m,2H,CH2 of C10H16N2O3S),3.11~3.17(m,1H,CH of C10H16N2O3S),4.09~4.31(m,2H,2CH of C10H16N2O3S),6.35~6.61(m,2H,2NH of C10H16N2O3S),7.06~7.32(m,3H,NH3),7.54~8.06(m,2H,4CH of C5H4NF).ESI-MS m/z:[M+Na]+=680.0(19%).
实施例11:铂(IV)配合物,化合物C11的合成(C17H22ClFN4O7PtS分子量:675.1)
称取(4.49g,10mmol)化合物C7,加入缩合剂TBTU(4.82g,15mmol)和三乙胺(0.11g,10mmol),溶于DMF溶剂中,称取生物素(2.44g,10mol)加入反应体系中,均匀搅拌,60℃反应24h;反应结束后,将反应液中加入适量的二氯甲烷,然后加入纯化水进行萃取,蒸发浓缩除去反应液中的缩合剂。用甲醇-乙醚混合液(体积比1:1)析出固体,抽滤,固体40℃烘干得灰色固体,2.49g化合物C11,产率:37.90%。IR(KBr,cm-1):v(NH)br 3425,3250cm-1,v(CH),v(CH):2933,2859cm-1,δ(NH):1464cm-1,v(C-O):1693,1557cm-1,v(C-C):1263cm-1,v(C=N):1576cm-1,v(C-F):1225cm-1,v(Pt-O):869cm-1,v(Pt-Cl):743cm-1,v(Pt-N):668cm-1.1H-NMR(DMSO,ppm):δ1.29~1.69(m,6H,3CH2 of C10H16N2O3S)2.16~2.27(m,2H,CH2ofC10H16N2O3S),2.51~2.60(m,2H,CH2 of C10H16N2O3S),3.18~3.29(m,1H,CH ofC10H16N2O3S),4.19~4.37(m,2H,2CH of C10H16N2O3S),6.37~6.58(m,2H,2NH ofC10H16N2O3S),6.61~7.27(m,3H,NH3),7.66~8.12(m,4H,4CH of C5H4NF).ESI-MS m/z:[M+Na]+=698.1(18%).
表1中部分化合物的制备工艺与上述实施例中方法雷同,在此不作累述,参照上述方法制备;
采用MTT法方法测试了上述含氟铂配合物对人结肠癌细胞HCT-116、人肝癌细胞HepG-2、人肺腺癌细胞A549、人乳腺癌细胞MCF-7、结肠癌细胞SW480的体外抑制作用,分别以顺铂、甲啶铂作为阳性对照。肿瘤细胞株培养及试验方法如下:
本实验选用了SW480(人结直肠癌细胞)、HCT116(人结直肠癌细胞)、MCF-7(人乳腺癌细胞)、A549(人非小细胞肺癌细胞)、HepG2(人肝癌细胞)5种不同的人癌细胞系,并接种在含有10%(v/v)胎牛血清、100μg/mL青霉素和100μg/mL的链霉素DMEM培养基中,在饱和湿度、37℃、5%CO2的环境中进行培养;
(1)先将所得铂配合物配置浓度为100mmol/L的原液,随后用培养基将原液分别稀释成浓度梯度为0.064、0.32、1.6、8.0和40.0μmol/L的工作液,为了消除DMSO对细胞活性的影响,所有测试中DMSO的浓度限制在0.10%(v/v)内。
(2)将处于对数生长期的5种人肿瘤细胞系,每孔以2000~6000个细胞接种到96孔板中,其中每孔体积为100μL;将不同浓度梯度的工作液分别一次加入到对应的培养基中,在37℃环境下培养48h后,每孔加入20μL 5mg/mL MTS(MTT类似物)溶液和100μL DEME培养液;设置三个空白对照复孔(均加入20μL的MTS溶液和100μL DEME培养液),共培养3h,充分反应后测定光吸收值;
(3)选择位于492nm的波长,使用多功能酶标仪(MULTISKAN FC)读取各孔的光吸收值,记录数据,数据处理后以Pt配合物浓度为横坐标,以细胞抑制率为纵坐标绘制5株癌细胞的细胞抑制率图,每次实验均设有顺铂和甲啶铂为2个阳性化合物,以浓度为横坐标,细胞存活率为纵坐标绘制细胞生长曲线图,使用两点法计算得到化合物的IC50值;半数抑制率IC50值结果见表1;
表1细胞活性研究数据
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