CN108864130A - Enmein衍生物及其制备方法和应用 - Google Patents
Enmein衍生物及其制备方法和应用 Download PDFInfo
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- MQOJPNKACWKUGI-CDKPERABSA-N Enmein Chemical class C1C[C@H]2[C@@]34CO[C@@H](O)[C@@H]3C(C)(C)[C@@H](O)C[C@@H]4OC(=O)[C@]22C(=O)C(=C)[C@H]1C2 MQOJPNKACWKUGI-CDKPERABSA-N 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- MQOJPNKACWKUGI-UHFFFAOYSA-N Eumein Natural products C1CC2C34COC(O)C3C(C)(C)C(O)CC4OC(=O)C22C(=O)C(=C)C1C2 MQOJPNKACWKUGI-UHFFFAOYSA-N 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 239000012043 crude product Substances 0.000 claims description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
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- 238000010898 silica gel chromatography Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
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- OELMAFBLFOKZJD-CALCHBBNSA-N (3r,5s)-1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-diol Chemical compound C1=C(O)C(OC)=CC(CC[C@H](O)C[C@H](O)CCC=2C=C(OC)C(O)=CC=2)=C1 OELMAFBLFOKZJD-CALCHBBNSA-N 0.000 description 1
- ONDHYPAKCLRYFM-UHFFFAOYSA-N 1-(3,4-diethoxyphenyl)-6,7-diethoxy-1,4-dihydroisochromen-3-one Chemical compound C1=C(OCC)C(OCC)=CC=C1C1C2=CC(OCC)=C(OCC)C=C2CC(=O)O1 ONDHYPAKCLRYFM-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- 208000000197 Acute Cholecystitis Diseases 0.000 description 1
- GISOTBQTOFYOAF-UHFFFAOYSA-N CC(C)(C(CC(C1(CO2)C(CCC(C3)C4=C)(C33C4=O)C=C)OC3=O)[O](C)=C)C1(C)[IH]C2[O](C)=C Chemical compound CC(C)(C(CC(C1(CO2)C(CCC(C3)C4=C)(C33C4=O)C=C)OC3=O)[O](C)=C)C1(C)[IH]C2[O](C)=C GISOTBQTOFYOAF-UHFFFAOYSA-N 0.000 description 1
- YYAOGNGQIOAWRN-ZHACJKMWSA-N CC/C=C/C(OC(OC1)[IH]C(C)(C(C)(C)C(CC2O3)C(C)=C)C12C(C)(CCC(C1)C(C2=O)=C)C12C3=O)=O Chemical compound CC/C=C/C(OC(OC1)[IH]C(C)(C(C)(C)C(CC2O3)C(C)=C)C12C(C)(CCC(C1)C(C2=O)=C)C12C3=O)=O YYAOGNGQIOAWRN-ZHACJKMWSA-N 0.000 description 1
- 206010008614 Cholecystitis acute Diseases 0.000 description 1
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- 241000196324 Embryophyta Species 0.000 description 1
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- 244000071493 Iris tectorum Species 0.000 description 1
- 241001533433 Isodon serra Species 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
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- 239000004480 active ingredient Substances 0.000 description 1
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- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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Abstract
本发明公开了一种Enmein衍生物及其制备方法和应用,属于药物化学技术领域。一种结构通式如下所示的Enmein衍生物及其药学上可接受的盐:
Description
技术领域
本发明属于药物化学技术领域,具体涉及一种Enmein衍生物及其制备方法和应用。
背景技术
溪黄草[Rabdosia Serra(Maxim.)Hara]系唇形科(Labiatae)香茶菜属(Isodon)植物,在民间,溪黄草作为草药被广泛使用,它全株入药,味苦性凉,具有清热利湿、退黄祛湿、凉血散瘀等功效,主要用于治疗急性黄疸型肝炎、急性胆囊炎、湿热痢疾、肠炎、跌打瘀肿和养生保健等,具有较好的药用价值。Enmein是溪黄草中含量较多的二萜类化合物,是其中的活性成份。相关研究表明,Enmein具有多种生物活性,如免疫活性、抗癌活性、抑菌作用等。然而,Enmein溶解度低,溶出速度也慢,口服不容易被吸收。
Enmein分子中有一个六元内酯环和一个α-亚甲基环五酮结构,为Enmein的活性中心。这两个结构不太稳定,剧烈的反应环境容易破坏其结构,有可能使它们活性减弱或消失,因此,关于此化合物的衍生物的研究较少。
发明内容
本发明解决的技术问题是提供了一种Enmein衍生物及其制备方法,该Enmein衍生物能够用于制备抗癌药物。
本发明为解决上述技术问题采用如下技术方案,一种结构式如下所示的Enmein衍生物及其药学上可接受的盐:
本发明所述的Enmein衍生物的制备方法,其特征在于:
Enmein 6位羟基成酯修饰的具体步骤为:将Enmein、有机溶剂和三乙胺依次加入到反应容器中,将反应容器置于低温反应仪中于-5~5℃搅拌混合均匀,再滴加酸酐类化合物或酰氯类化合物对应有机溶剂的溶液,滴完后于0℃~室温搅拌反应,反应完全后加水终止反应,用乙酸乙酯萃取3次,再依次用稀酸溶液洗,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析分离得到目标化合物3~8,所述酸酐类化合物为丁二酸酐、戊二酸酐或乙酸酐,所述酰氯类化合物为苯甲酰氯、肉桂酰氯或二苯氧基磷酰氯,所述有机溶剂为乙腈或四氢呋喃;
Enmein 6位羟基成醚修饰的具体步骤为:将Enmein和醇类化合物依次加入到反应容器中,再加入浓盐酸,将反应容器置于磁力搅拌器上于室温搅拌反应,然后加乙酸乙酯萃取2次,再依次水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析分离得到目标化合物9~14,所述醇类化合物为甲醇、乙醇、异丙醇、苯甲醇、丙炔醇或环丙甲醇。
本发明所述的Enmein衍生物及其药学上可接受的盐在制备抗癌药物中的应用。
本发明所述的Enmein衍生物及其药学上可接受的盐在制备抑制人肝癌细胞HepG2或/和人髓性白血病细胞K562增殖药物中的应用。
本发明以自然界来源丰富的Enmein单体化合物为前体化合物,采用简单温和的合成条件,在保持原有活性中心前体下进行分子结构修饰,引入不同的基团,合成系列Enmein衍生物,合成过程简单且容易控制,通过细胞毒活性测试表明该Enmein衍生物具有较好的抗癌细胞活性。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明,但不应该将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
Enmein丁二酸单酯(3)的合成
将Enmein 117.2mg(0.32mmol),乙腈5mL,三乙胺0.44mL(3.2mmol),依次加入到100mL圆底烧瓶中,置于低温反应仪中搅拌,调节温度0℃左右,另取丁二酸酐128.2mg(1.28mmol),用少量乙腈溶解,将后者缓慢滴入前者,滴完后置于室温搅拌反应12h,加少量水终止反应,用乙酸乙酯20mL萃取3次,依次用稀酸溶液洗,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析(氯仿:甲醇20:1)分离得到目标化合物,产率43.6%。
HRMS-ESI(m/z):calcd for C24H30O9[M+Na]+485.1793,found:485.1783;1H-NMR(400MHz,C5D5N,δ,ppm):6.58(1H,s,H-6α),6.07,5.41(2×1H,s,H2-17),5.70(1H,dd,J=4.0Hz,H1-1β),4.40and 4.34(2×1H,d,J=10.0,H2-20),3.75(1H,br d,J=4Hz,H-3α),1.02and 0.97(3H,s,Me-18,19),2.67,2.50(each 2H,m,H-2’3’);13C-NMR(100MHz,C5D5N,δ,ppm):75.2(C-1),24.2(C-2),73.2(C-3),31.6(C-4),55.7(C-5),108.1(C-6),171.6(C-7),56.3(C-8),48.7(C-9),50.0(C-10),19.9(C-11),41.5(C-12),35.6(C-13),34.2(C-14),200.3(C-15),149.6(C-16),118.3(C-17),33.4(C-18),23.5(C-19),74.3(C-20),171.3(C1’),29.8(C-2’),29.1(C-3’),171.7(C4’)。
实施例2
Enmein戊二酸单酯(4)的合成
将Enmein 138.2mg(0.38mmol),乙腈5mL,三乙胺0.52mL(3.75mmol),依次加入到100mL圆底烧瓶中,置于低温反应仪中搅拌,调节温度0℃左右,另取戊二酸酐172.4mg(1.51mmol),用少量乙腈溶解,将后者缓慢滴入前者,滴完后置于室温搅拌反应12h,加少量水终止反应,用乙酸乙酯20mL萃取3次,依次用稀酸溶液洗,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析(氯仿:甲醇20:1)分离得到目标化合物,产率62.7%。
HRMS-ESI(m/z):calcd for C25H32O9[M+Na]+499.1950,found:499.1944;1H-NMR(400MHz,C5D5N,δ,ppm):6.58(1H,s,H-6α),6.07,5.41(2×1H,s,H2-17),5.70(1H,dd,J=4.0Hz,H1-1β),4.40and 4.34(2×1H,d,J=10.0,H2-20),3.75(1H,br d,J=4Hz,H-3α),1.02and 0.97(3H,s,Me-18,19),2.67,2.50(each 2H,m,H-2’4’),1.95(2H,m,H-3’);13C-NMR(100MHz,C5D5N,δ,ppm):75.2(C-1),24.2(C-2),73.2(C-3),31.6(C-4),55.7(C-5),108.1(C-6),171.6(C-7),56.3(C-8),48.7(C-9),50.0(C-10),19.9(C-11),41.5(C-12),35.6(C-13),34.2(C-14),200.3(C-15),149.6(C-16),118.3(C-17),33.4(C-18),23.5(C-19),74.3(C-20),171.3(C1’),30.1(C-2’),29.1(C-3’),29.9(C-4’),174.7(C5’)。
实施例3
6-乙酰基Enmein(5)的合成
将Enmein 121.0mg(0.33mmol),四氢呋喃5mL,三乙胺0.45mL(3.25mmol),依次加入到100mL圆底烧瓶中,置于低温反应仪中搅拌,调节温度0℃左右,另取乙酸酐0.18mL(1.90mmol),用少量四氢呋喃溶解,将后者缓慢滴入前者,滴完后置于室温搅拌反应12h,加少量水终止反应,用乙酸乙酯25mL萃取2次,依次用稀酸溶液洗,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析(二氯甲烷:丙酮16:1)分离得到目标化合物,产率32.9%。
HRMS-ESI(m/z):calcd for C22H28O7[M+Na]+427.1738,found:427.1741;1H-NMR(400MHz,CDCl3,δ,ppm):6.16(1H,s,H-6α),6.08,5.50(2×1H,s,H2-17),4.90(1H,dd,J=8.0,4.0Hz,H1-1β),4.10and 4.01(2×1H,d,J=10.0,H2-20),3.68(1H,br d,J=4Hz,H-3α),1.13and 0.87(3H,s,Me-18,19),1.96(3H,COCH3);13C-NMR(100MHz,CDCl3,δ,ppm):75.3(C-1),30.9(C-2),74.0(C-3),35.9(C-4),51.1(C-5),102.3(C-6),172.2(C-7),57.1(C-8),46.6(C-9),50.1(C-10),19.9(C-11),32.8(C-12),35.3(C-13),29.5(C-14),200.6(C-15),150.2(C-16),117.4(C-17),28.3(C-18),23.2(C-19),72.6(C-20).169.6(CO),21.3(CH3)。
实施例4
6-苯甲酰基Enmein(6)的合成
将Enmein 100.9mg(0.28mmol),乙腈5mL,三乙胺0.39mL(2.77mmol),依次加入到100mL圆底烧瓶中,置于低温反应仪中搅拌,调节温度-5℃左右,另取苯甲酰氯0.19mL(1.66mmol),用少量乙腈溶解,将后者缓慢滴入前者,滴完后调节温度0℃搅拌反应4h,加少量水终止反应,用乙酸乙酯25mL萃取2次,依次用稀酸溶液洗,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析(正己烷:乙酸乙酯1:1)分离得到目标化合物,产率41.5%。
HRMS-ESI(m/z):calcd for C27H30O7[M+Na]+489.1884,found:489.1888;1H-NMR(400MHz,CDCl3,δ,ppm):6.44(1H,s,H-6α),6.08,5.52(2×1H,s,H2-17),4.94(1H,dd,J=10.0,8.00,H1-1β),4.14and 4.08(2×1H,d,J=10.0,H2-20),3.69(1H,br q,H-3α),1.03and 0.91(3H,s,Me-18,19),7.84(2H,m,H-3’,5’),7.52(1H,m,H-4’),7.36(2H,m,H-2’,5’);13C-NMR(100MHz,CDCl3,δ,ppm):75.3(C-1),30.9(C-2),74.0(C-3),35.9(C-4),51.1(C-5),102.3(C-6),172.2(C-7),57.1(C-8),46.6(C-9),50.1(C-10),19.9(C-11),32.8(C-12),35.3(C-13),29.5(C-14),200.6(C-15),150.2(C-16),117.4(C-17),28.3(C-18),23.2(C-19),72.6(C-20),165.0(CO-phenyl),133.3(C-1’),129.61(C-1’),128.3(C-2’,6’),129.33(C-3’,5’)。
实施例5
6-肉桂酰基Enmein(7)的合成
将Enmein 150.8mg(0.42mmol),四氢呋喃5mL,三乙胺0.7mL(5.05mmol),依次加入到100mL圆底烧瓶中,置于低温反应仪中搅拌,调节温度-5℃左右,另取肉桂酰氯290mg(1.74mmol),用少量乙腈溶解,将后者缓慢滴入前者,滴完后调节温度0℃搅拌反应4h,加少量水终止反应,用乙酸乙酯25mL萃取3次,依次用稀酸溶液洗,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析(二氯甲烷:丙酮16:1)分离得到目标化合物,产率16.8%。
HRMS-ESI(m/z):calcd for C29H32O7[M+Na]+515.2040,found:515.2031;1H-NMR(400MHz,CDCl3,δ,ppm):6.32(1H,s,H-6α),6.12,5.50(2×1H,s,H2-17),4.93(1H,dd,J=8.0,4.0,H1-1β),4.08and 4.01(2×1H,d,J=8.0,H2-20),3.70(1H,d,J=4.0,H-3α),1.03and 0.91(3H,s,Me-18,19),7.51(1H,d,J=16.0Hz,H-3’),7.43(2H,m,H-6’,8’),7.40(1H,m,H-4’),7.36(2H,m,H-5’,9’),6.27(1H,d,J=16.0Hz,H-2’);13C-NMR(100MHz,CDCl3,δ,ppm):75.3(C-1),30.9(C-2),74.0(C-3),35.9(C-4),51.1(C-5),102.3(C-6),172.2(C-7),57.1(C-8),46.6(C-9),50.1(C-10),19.9(C-11),32.8(C-12),35.3(C-13),29.5(C-14),200.6(C-15),150.2(C-16),117.7(C-17),28.3(C-18),23.2(C-19),72.6(C-20),165.2(C-1’),118.6(C-2’),145.3(C-3’),133.9(C-4’),130.6(C-7’),128.5(C-6’,8’),128.0(C-5’,9’)。
实施例6
6-二苯氧基磷酰基Enmein(8)的合成
将Enmein 206.4mg(0.57mmol),四氢呋喃5mL,三乙胺0.7mL(5.05mmol),依次加入到100mL圆底烧瓶中,置于低温反应仪中搅拌,调节温度-5℃左右,另取二苯氧基磷酰氯0.5mL(2.4mmol),用少量四氢呋喃溶解,将后者缓慢滴入前者,滴完后调节温度0℃搅拌反应4h,加少量水终止反应,用乙酸乙酯25mL萃取3次,依次用稀酸溶液洗,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析(二氯甲烷:丙酮16:1)分离得到目标化合物,产率5.1%。
HRMS-ESI(m/z):calcd for C32H35O9P[M+Na]+617.1917,found:617.1917;1H-NMR(400MHz,CDCl3,δ,ppm):7.25-7.43(10H,m,Ph),6.08,5.39(2×1H,s,H2-17),5.50(1H,s,H-6α),4.61(2H,ABd,H2-20),3.08(1H,br q,H-3α),1.13(3H,s,Me-18),1.01(3H,s,Me-19);13C-NMR(100MHz,CDCl3,δ,ppm):77.2(C-1),29.7(C-2),71.7(C-3),32.0(C-4),49.9(C-5),101.8(C-6),171.2(C-7),56.3(C-8),45.5(C-9),49.1(C-10),19.1(C-11),32.3(C-12),34.8(C-13),29.2(C-14),199.9(C-15),150.0(C-16),118.6(C-17),27.7(C-18),22.8(C-19),74.6(C-20),130.1,130.0(C-1’,1”),125.7(C-4’,4”),120.0,119.9,119.7,119.7(C-2’,2”,3’,3”);31P-NMR(162MHz,CDCl3,δ,ppm):-12.85。
实施例7
6-甲氧基Enmein(9)的合成
将Enmein 161.5mg(0.45mmol),甲醇5mL,依次加入到100mL圆底烧瓶中,加少量浓盐酸,置于磁力搅拌器上,室温搅拌反应72h,加乙酸乙酯25mL萃取2次,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析(二氯甲烷:丙酮12:1)分离得到目标化合物,产率90.8%。
HRMS-ESI(m/z):calcd for C21H28O6[M+Na]+399.1778,found:399.1783;1H-NMR(400MHz,CDCl3,δ,ppm):6.06,5.47(2×1H,s,H2-17),4.88(1H,dd,J=8.0,4.0,H1-1β),4.80(1H,s,H-6α),4.04and 3.91(2×1H,d,J=10.0,H2-20),3.66(1H,d,J=4.0,H-3α),1.02and 0.95(3H,s,Me-18,19),3.25(3H,s,OCH3);13C-NMR(100MHz,CDCl3,δ,ppm);75.1(C-1),30.9(C-2),74.0(C-3),35.9(C-4),51.1(C-5),102.3(C-6),172.2(C-7),57.1(C-8),46.6(C-9),50.1(C-10),19.9(C-11),32.8(C-12),35.3(C-13),29.5(C-14),200.6(C-15),151.4(C-16),117.4(C-17),28.3(C-18),23.2(C-19),72.7(C-20),54.7(OCH3)。
实施例8
6-乙氧基Enmein(10)的合成
将Enmein 102.1mg(0.28mmol),乙醇5mL,依次加入到100mL圆底烧瓶中,加少量浓盐酸,置于磁力搅拌器上,室温搅拌反应72h,加乙酸乙酯25mL萃取2次,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析(二氯甲烷:丙酮12:1)分离得到目标化合物,产率52.5%。
HRMS-ESI(m/z):calcd for C22H30O6[M+Na]+413.1935,found:413.1934;1H-NMR(400MHz,CDCl3,δ,ppm);6.04,5.46(2×1H,s,H2-17),4.88(1H,dd,J=8.0,4.00,H1-1β),4.91(1H,s,H-6α),4.10and 4.00(2×1H,d,J=8.0Hz,H2-20),1.02and 0.95(3H,s,Me-18,19),3.28(2H,m,OCH2),1.09(3H,t,J=CH3-CH2);13C-NMR(100MHz,CDCl3,δ,ppm):75.6(C-1),30.9(C-2),74.1(C-3),35.9(C-4),51.1(C-5),102.3(C-6),172.2(C-7),57.1(C-8),46.6(C-9),50.1(C-10),19.9(C-11),32.8(C-12),35.3(C-13),29.5(C-14),200.6(C-15),151.4(C-16),117.4(C-17),28.3(C-18),23.2(C-19),72.8(C-20),62.0(C-1’),15.1(C-2’)。
实施例9
6-异丙氧基Enmein(11)的合成
将Enmein 188.5mg(0.52mmol),异丙醇5mL,依次加入到100mL圆底烧瓶中,加少量浓盐酸,置于磁力搅拌器上,室温搅拌反应72h,加乙酸乙酯25mL萃取2次,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析(正己烷:乙酸乙酯2:1)分离得到目标化合物,产率94.5%。
HRMS-ESI(m/z):calcd for C23H32O6[M+Na]+427.2091,found:427.2092;1H-NMR(400MHz,CDCl3,δ,ppm):6.06,5.47(2×1H,s,H2-17),5.05(1H,s,H-6α),4.88(1H,dd,J=8.0,4.0,H1-1β),4.04and 3.91(2×1H,d,J=10.0,H2-20),3.66(1H,d,J=4.0,H-3α),1.06and 0.95(3H,s,Me-18,19),3.82(1H,m,OCH),1.05(3H,d,J=4.0Hz,H-2’),1.02(3H,d,J=4.0Hz,H-2’);13C-NMR(100MHz,CDCl3,δ,ppm):75.8(C-1),30.9(C-2),73.9(C-3),35.9(C-4),51.1(C-5),102.3(C-6),172.2(C-7),57.1(C-8),46.6(C-9),50.1(C-10),19.9(C-11),32.8(C-12),35.3(C-13),29.5(C-14),200.0(C-15),150.4(C-16),118.5(C-17),28.3(C-18),23.4(C-19),72.8(C-20),67.1(C-1’),23.0(C-2’),21.1(C-3’)。
实施例10
6-苯甲氧基Enmein(12)的合成
将Enmein 100.1mg(0.28mmol),苯甲醇3mL,依次加入到100mL圆底烧瓶中,加少量浓盐酸,置于磁力搅拌器上,室温搅拌反应72h,加乙酸乙酯25mL萃取2次,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析(第一次:石油醚:乙酸乙酯20:1,第二次起:二氯甲烷:丙酮16:1)分离得到目标化合物,产率80.5%。
HRMS-ESI(m/z):calcd for C27H32O6[M+Na]+475.2091,found:475.2090;1H-NMR(400MHz,CDCl3,δ,ppm):6.08,5.47(2×1H,s,H2-17),5.07(1H,s,H-6α),4.90(1H,dd,J=8.0,4.0Hz,H1-1β),4.10and 3.97(2×1H,d,J=10.0Hz,H2-20),3.66(1H,d,J=4.0,H-3α),1.02and 0.99(each 3H,s,Me-18,19),4.67and 4.29(2×1H,d,J=8.0Hz,O-CH2-Phenyl),7.24(4H,m,phenyl),7.14(1H,m,H-Phenyl);13C-NMR(100MHz,CDCl3,δ,ppm):78.2(C-1),24.2(C-2),73.9(C-3),31.6(C-4),54.8(C-5),104.1(C-6),171.6(C-7),55.3(C-8),47.3(C-9),49.0(C-10),19.9(C-11),41.9(C-12),37.6(C-13),34.6(C-14),199.9(C-15),149.7(C-16),118.2(C-17),33.4(C-18),23.5(C-19),74.1(C-20),68.5(O-CH2-Pheny),137.90(C1’-phenyl),128.32(C3’,C5’phenyl),127.89(C2’,C6’-phenyl),127.52(C4’-phenyl)。
实施例11
6-丙炔氧基Enmein(13)的合成
将Enmein 102.2mg(0.28mmol),丙炔醇3mL,依次加入到100mL圆底烧瓶中,加少量浓盐酸,置于磁力搅拌器上,室温搅拌反应72h,加乙酸乙酯25mL萃取2次,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析(正己烷:乙酸乙酯2:1)得到目标化合物,产率91.6%。
HRMS-ESI(m/z):calcd for C23H28O6[M+Na]+423.1778,found:423.1786;1H-NMR(400MHz,CDCl3,δ,ppm):6.04and 5.48(2×1H,s,H2-17),5.23(1H,dd,J=10.0,8.00Hz,H1-1β),4.77(1H,s,H-6α),4.02和3.91(2×1H,d,J=10.0Hz,H2-20),3.66(1H,d,J=4.0,H-3α),1.02and 0.99(each 3H,s,Me-18,19),4.07(2H,s,H-propynyl),2.24(1H,s,H-propynyl);13C-NMR(100MHz,CDCl3,δ,ppm):78.4(C-1),24.2(C-2),73.9(C-3),31.6(C-4),54.8(C-5),105.6(C-6),171.6(C-7),55.3(C-8),47.3(C-9),49.0(C-10),19.9(C-11),41.9(C-12),37.6(C-13),34.6(C-14),199.9(C-15),149.6(C-16),118.4(C-17),33.4(C-18),23.3(C-19),74.3(C-20),79.6(C-1’-propynyl),66.5(C-2’-propynyl)。
实施例12
6-环丙甲氧基Enmein(14)的合成
将Enmein 149.1mg(0.41mmol),环丙甲醇3mL,依次加入到100mL圆底烧瓶中,加少量浓盐酸,置于磁力搅拌器上,室温搅拌反应72h,加乙酸乙酯25mL萃取2次,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析(正己烷:乙酸乙酯2:1)分离得到目标化合物,产率77.5%。
HRMS-ESI(m/z):calcd for C24H32O6[M+Na]+439.2091,found:439.2098;1H-NMR(400MHz,CDCl3,δ,ppm):6.07,5.47(2×1H,s,H2-17),4.88(1H,dd,J=8.0,4.00,H1-1β),4.96(1H,s,H-6α),4.03and 3.91(2×1H,d,J=8.0Hz,H2-20),3.66(1H,d,J=4.0,H-3α),1.02and 0.95(3H,s,Me-18,19),3.28(2H,m,OCH),1.09(1H,m,H-2’),0.35(2H,m,H-3’),0.15(2H,m,H-3’);13C-NMR(100MHz,CDCl3,δ,ppm):75.8(C-1),30.9(C-2),74.1(C-3),35.9(C-4),51.1(C-5),102.3(C-6),172.2(C-7),57.1(C-8),46.6(C-9),50.1(C-10),19.9(C-11),32.8(C-12),35.3(C-13),29.5(C-14),200.6(C-15),151.4(C-16),117.4(C-17),28.3(C-18),23.2(C-19),72.8(C-20),70.8(C-1’),10.6(C-2),2.8(C3’,4’)。
实施例13
Enmein及其衍生物的抗癌细胞活性测定
实验设备与试剂:
仪器:高压灭菌锅:LDZX-50KBS,上海申安医疗器械厂;超低温冰箱:900SERIES,Thermo Scientific;全波长多功能读数仪(SpectraMax I3,美国MD公司);CO2恒温培养箱:Labserv CO-150,Thermo Fisher Scientific;
试剂:DMEM高糖培养基(Hyclone公司);胎牛血清(Gibco公司);CCK8(cellcounting kit-8)(碧云天生物技术研究所);96孔板(corning公司);
细胞株:人肝癌HepG2,人髓性白血病细胞K562细胞株购于中国科学院上海细胞库,新乡医学院药学院实验室传代培养,采用含10wt%胎牛血清的DMEM高糖培养基,37℃、体积分数为5%CO2条件下常规培养。
实验方法:
CCK8检测细胞增殖抑制率,取对数生长期的HepG2、K562细胞,加0.25wt%胰酶制成细胞悬液,细胞浓度3×104/mL,接种于96孔板,每孔100μL,空白孔加100μL DMEM高糖培养基,置于37℃、体积分数为5%CO2培养箱培养24h,实验组更换新的含不同浓度被测样品的培养基,每个浓度4个复孔,对照组则换含等体积溶剂的培养基,继续培养48h,每孔加入CCK8 10μl继续培养1h,酶标仪450nm波长下检测各孔吸光度A值,按下列公式计算抑制率:细胞增殖抑制率=[1-(A给药组-A空白孔)/(A阴性对照组-A空白孔)]×100﹪,并计算半数抑制浓度(IC50)。
实验结果:
CCK8检测HepG2、K562细胞增殖抑制率,计算各化合物对HepG2、K562半数抑制浓度(IC50),结果见表1。
表1 Enmein及其衍生物对HepG2、K562半数抑制浓度(IC50)
以上显示和描述了本发明的基本原理,主要特征和优点,在不脱离本发明精神和范围的前提下,本发明还有各种变化和改进,这些变化和改进都要求落入本发明的保护范围之内。
Claims (4)
1.一种结构式如下所示的Enmein衍生物及其药学上可接受的盐:
2.一种权利要求1所述的Enmein衍生物的制备方法,其特征在于:
Enmein 6位羟基成酯修饰的具体步骤为:将Enmein、有机溶剂和三乙胺依次加入到反应容器中,将反应容器置于低温反应仪中于-5~5℃搅拌混合均匀,再滴加酸酐类化合物或酰氯类化合物对应有机溶剂的溶液,滴完后于0℃~室温搅拌反应,反应完全后加水终止反应,用乙酸乙酯萃取3次,再依次用稀酸溶液洗,水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析分离得到目标化合物3~8,所述酸酐类化合物为丁二酸酐、戊二酸酐或乙酸酐,所述酰氯类化合物为苯甲酰氯、肉桂酰氯或二苯氧基磷酰氯,所述有机溶剂为乙腈或四氢呋喃;
Enmein 6位羟基成醚修饰的具体步骤为:将Enmein和醇类化合物依次加入到反应容器中,再加入浓盐酸,将反应容器置于磁力搅拌器上于室温搅拌反应,然后加乙酸乙酯萃取2次,再依次水洗,分离有机层,无水硫酸镁干燥,浓缩得粗品,将粗品硅胶柱层析分离得到目标化合物9~14,所述醇类化合物为甲醇、乙醇、异丙醇、苯甲醇、丙炔醇或环丙甲醇。
3.权利要求1所述的Enmein衍生物及其药学上可接受的盐在制备抗癌药物中的应用。
4.权利要求1所述的Enmein衍生物及其药学上可接受的盐在制备抑制人肝癌细胞HepG2或/和人髓性白血病细胞K562增殖药物中的应用。
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