CN111556746A - 青蒿酸糖缀合物化合物、其制备和使用方法 - Google Patents
青蒿酸糖缀合物化合物、其制备和使用方法 Download PDFInfo
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- CN111556746A CN111556746A CN201980007346.5A CN201980007346A CN111556746A CN 111556746 A CN111556746 A CN 111556746A CN 201980007346 A CN201980007346 A CN 201980007346A CN 111556746 A CN111556746 A CN 111556746A
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- Prior art keywords
- azide
- compound
- methyl
- acid
- formula
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- PLQMEXSCSAIXGB-SAXRGWBVSA-N (+)-artemisinic acid Chemical compound C1=C(C)CC[C@H]2[C@H](C)CC[C@@H](C(=C)C(O)=O)[C@H]21 PLQMEXSCSAIXGB-SAXRGWBVSA-N 0.000 title claims abstract description 108
- PLQMEXSCSAIXGB-UHFFFAOYSA-N artemisininic acid Natural products C1=C(C)CCC2C(C)CCC(C(=C)C(O)=O)C21 PLQMEXSCSAIXGB-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 150000001875 compounds Chemical class 0.000 title claims abstract description 53
- LZMOBPWDHUQTKL-RWMBFGLXSA-N artemisinic acid Natural products CC1=C[C@@H]2[C@@H](CCC[C@H]2C(=C)C(=O)O)CC1 LZMOBPWDHUQTKL-RWMBFGLXSA-N 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 claims abstract description 9
- -1 acetoxymethyl Chemical group 0.000 claims description 103
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 22
- 239000011541 reaction mixture Substances 0.000 claims description 22
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 claims description 20
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 17
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 claims description 14
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Chemical group OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 14
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Chemical group NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims description 14
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 13
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Chemical group CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims description 13
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Chemical group CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 150000001540 azides Chemical class 0.000 claims description 10
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 9
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical group O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 8
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical group OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 239000008101 lactose Chemical group 0.000 claims description 8
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 claims description 8
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 claims description 8
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Chemical group OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 7
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical group N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 claims description 7
- MSWZFWKMSRAUBD-CBPJZXOFSA-N 2-amino-2-deoxy-D-mannopyranose Chemical group N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-CBPJZXOFSA-N 0.000 claims description 7
- YVECGMZCTULTIS-HSUXUTPPSA-N D-galactal Chemical group OC[C@H]1OC=C[C@@H](O)[C@H]1O YVECGMZCTULTIS-HSUXUTPPSA-N 0.000 claims description 7
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical group OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 7
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical group O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims description 7
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 7
- PNNNRSAQSRJVSB-BXKVDMCESA-N aldehydo-L-rhamnose Chemical group C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O PNNNRSAQSRJVSB-BXKVDMCESA-N 0.000 claims description 7
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 claims description 7
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Chemical group OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 7
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical group N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 claims description 7
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical group OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- YVECGMZCTULTIS-PBXRRBTRSA-N glucal Chemical group OC[C@H]1OC=C[C@@H](O)[C@@H]1O YVECGMZCTULTIS-PBXRRBTRSA-N 0.000 claims description 7
- 235000000346 sugar Nutrition 0.000 claims description 7
- SHZGCJCMOBCMKK-SVZMEOIVSA-N D-fucopyranose Chemical compound C[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O SHZGCJCMOBCMKK-SVZMEOIVSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- 206010017533 Fungal infection Diseases 0.000 claims description 5
- 239000007821 HATU Substances 0.000 claims description 5
- 208000031888 Mycoses Diseases 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- YABZBTUZPWUEKP-MVNLRXSJSA-N (2s,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;azide Chemical compound [N-]=[N+]=[N-].OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O YABZBTUZPWUEKP-MVNLRXSJSA-N 0.000 claims description 3
- VSGLZXLDOTWWBF-JFNONXLTSA-N (3R,4R,5R,6S)-2-azido-6-methyloxane-3,4,5-triol Chemical compound C[C@@H]1OC(N=[N+]=[N-])[C@H](O)[C@H](O)[C@H]1O VSGLZXLDOTWWBF-JFNONXLTSA-N 0.000 claims description 3
- KSRDTSABQYNYMP-GASJEMHNSA-N (3r,4s,5s,6r)-2-azido-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OC[C@H]1OC(N=[N+]=[N-])[C@H](O)[C@@H](O)[C@@H]1O KSRDTSABQYNYMP-GASJEMHNSA-N 0.000 claims description 3
- QIGSLIHQXWSYFF-JMWSHJPJSA-N [N-]=[N+]=[N-].O1C=C[C@@H](O)[C@H](O)[C@H]1CO Chemical compound [N-]=[N+]=[N-].O1C=C[C@@H](O)[C@H](O)[C@H]1CO QIGSLIHQXWSYFF-JMWSHJPJSA-N 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- KSRDTSABQYNYMP-SVZMEOIVSA-N diazonio-[(3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]azanide Chemical compound OC[C@H]1OC(N=[N+]=[N-])[C@H](O)[C@@H](O)[C@H]1O KSRDTSABQYNYMP-SVZMEOIVSA-N 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- FJOYNMRZUBUGGP-QKKXKWKRSA-N C1([C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO)N=[N+]=[N-] Chemical compound C1([C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO)N=[N+]=[N-] FJOYNMRZUBUGGP-QKKXKWKRSA-N 0.000 claims description 2
- RFSUNEUAIZKAJO-VRPWFDPXSA-N D-Fructose Chemical group OC[C@H]1OC(O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-VRPWFDPXSA-N 0.000 claims 1
- 125000002353 D-glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical group OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims 1
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
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Abstract
本发明涉及青蒿酸糖缀合物化合物。更具体地,本发明涉及式(I)的糖缀合物化合物和使用1,3‑偶极环加成化学从青蒿酸开始制备式(I)的青蒿酸糖缀合物化合物的方法。
Description
技术领域
本发明涉及青蒿酸糖缀合物(artemisinic acid glycoconjugate)化合物。更具体地,本发明涉及式(I)的糖缀合物化合物和使用1,3-偶极环加成(1,3-dipolarcycloaddition)化学从青蒿酸开始制备式(I)的青蒿酸糖缀合物化合物的方法。
本发明的背景技术和现有技术
青蒿素是传统中草药青蒿(Artemisia annua)的成分,该青蒿在中国用于控制发烧症状已有1000多年的历史。青蒿酸(AA)具有与青蒿素相似的化学结构(杜松烷型倍半萜烯),被广泛用作青蒿中青蒿素的生物合成途径的推测中间体研究。青蒿酸是合成青蒿素的假定生物起源前体。据报道,在青蒿的叶片中青蒿酸比青蒿素含量更高(Kawamoto H,AsadaY,Sekine H,Furuya T.Phytochemistry,1998,48,1329)。青蒿酸的生物转化产生了青蒿酸糖苷,其表现出对Hela细胞系的强活性(Zhu J,Chen L,Hu X,Song L,Wang M,Yu R,Pharmacogn Mag.2015,11,518)。
Juliana M.F.M.Schneider等人的标题为“Synthesis of New Family ofThiazoline and Thiazole Esters and Investigation of their Thermal Properties”文章,发表在Journal of the Brazilian Chemical Society,2014,Vol.25,No.8,1493-1503,报道了噻唑啉酯是通过由4-取代的苯腈和氨基酸L-半胱氨酸的环化反应,然后与选择的醇和酚进行酯化反应而获得的。
Henning S.G.Beckman发表于Organic Azides:Syntheses and Applications,2010,469-490的标题为“Azides in Carbohydrate Chemistry”的文章报道了通过叠氮化物-炔烃[3+2]环加成反应合成糖缀合物。铜(I)催化的叠氮化物-炔烃环加成反应(CuAAC)能够在非常温和的条件下,即使在生物学环境下,也可以区域选择性形成1,4-二取代的1,2,3-三唑。然而,铜催化剂的细胞毒性妨碍了其中细胞必须保持活力的应用。
现有技术中没有关于青蒿酸衍生物的有机合成的报道。现有技术仅报道了青蒿酸糖苷的生物合成。考虑到青蒿酸或其衍生物的生物学重要性,需要开发青蒿酸衍生物的有机合成。
发明目的
本发明的主要目的是提供式(I)的青蒿酸糖缀合物化合物。
本发明另一目的是提供制备式(I)的青蒿酸糖缀合物化合物的方法。
本发明另一目的是提供药物组合物,其包含式(I)的青蒿酸糖缀合物化合物和至少一种药学上可接受的载体。
本发明另一目的是提供式(I)的青蒿酸糖缀合物化合物作为抗癌剂、抗真菌剂、抗疟疾剂、退热剂、抗细菌剂或显像剂的用途。而且,本发明提供式(I)的青蒿酸糖缀合物化合物,其显示植化相克(allelopathy)作用或抗脂肪形成作用。
发明内容
因此,本发明提供式(I)的青蒿酸糖缀合物化合物;
其中,
X选自O或N;
Y选自各种被保护的或游离的糖如D-葡萄糖、D-半乳糖、L-鼠李糖、麦芽糖、D-葡萄烯糖、D-半乳醛、乳糖、阿拉伯糖、D-半乳糖胺、D-葡糖胺、D-甘露糖胺、D-甘露糖、D-木糖、D-岩藻糖等。
在优选的实施方案中,式(I)的青蒿酸糖缀合物化合物选自:
a)三乙酸(2R,3S,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(4);
b)三苯甲酸(2R,3S,4S,5R,6R)-2-((苯甲酰基氧基)甲基)-6-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(5);
c)三乙酸(2R,3R,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(6);
d)三乙酸(2R,3R,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯基酰胺基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(7);
e)三乙酸(2R,3S,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯基酰胺基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(8);
f)三苯甲酸(2R,3R,4S,5R,6R)-2-((苯甲酰基氧基)甲基)-6-(4-((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯基酰胺基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(9)和
g)三乙酸(2R,3R,4R,5S,6S)-2-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)-6-甲基四氢-2H-吡喃-3,4,5-三基酯(10)。
本发明还提供合成式(I)的化合物的方法,包括以下步骤:
a)将青蒿酸与炔丙醇或炔丙胺反应以分别得到丙烯酸酯(2)或丙烯酰胺(3),和
b)将步骤(a)的丙烯酸酯(2)或丙烯酰胺(3)与糖-叠氮化物进行1,3-偶极环加成,得到式(I)的化合物。
在一个实施方案中所述步骤(a)包括将青蒿酸、炔丙醇和4-二甲基氨基吡啶(DMAP)的反应混合物在溶剂中在温度0℃搅拌1至2小时的时间段,然后进一步将该反应混合物在25至30℃的温度范围搅拌10至12小时范围内的时间段,得到对应的丙烯酸酯化合物(2)。
在另一实施方案中所述步骤(a)包括将炔丙胺在25至30℃的温度范围添加至青蒿酸、(1-[二(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐){HATU}、N,N-二异丙基乙基胺(DIPEA)在溶剂中的反应混合物中,然后将该反应混合物在25至30℃的温度范围搅拌5至7小时范围的时间段,得到对应的丙烯酰胺化合物(3)。
在一个实施方案中所述步骤(b)包括将N,N-二异丙基乙基胺(DIPEA)和碘化亚铜(I)(CuI)添加至糖-叠氮化物和丙烯酸酯化合物2或丙烯酰胺化合物3在溶剂中的反应混合物,然后将该反应混合物在25至30℃的温度范围搅拌8至10小时范围的时间段,得到式(I)的化合物。
在一个实施方案中所述糖-叠氮化物为保护的或游离的糖叠氮化物,其选自D-葡萄糖、D-半乳糖、L-鼠李糖、麦芽糖、D-葡萄烯糖、D-半乳醛、乳糖、阿拉伯糖、D-半乳糖胺、D-葡糖胺、D-甘露糖胺、D-甘露糖、D-木糖或D-岩藻糖的叠氮化物。
在一个优选实施方案中所述糖-叠氮化物选自D-葡萄糖基叠氮化物,D-半乳糖基叠氮化物、L-鼠李糖基叠氮化物、麦芽糖基叠氮化物、D-葡萄烯糖叠氮化物、乳糖基(Lactosyl)叠氮化物和D-甘露糖叠氮化物。
在一个实施方案中用于步骤a和b的溶剂选自二氯甲烷、二甲基甲酰胺、四氢呋喃、氯仿或四氯化碳。
在另一实施方案中,本发明提供药物组合物,其包含式(I)的青蒿酸糖缀合物化合物和至少一种药学上可接受的载体。
在一个实施方案中,本发明提供药物组合物,其包含式(I)的化合物或其药学上可接受的盐和药学上可接受的载体,其用于预防和治疗癌症或真菌感染,包括将有效剂量的药物组合物给药于哺乳动物。
发明详述
现在将结合某些优选和任选的实施方案来详细描述本发明,从而可以更充分地理解和了解其各个方面。
鉴于以上,本发明提供式(I)的青蒿酸糖缀合物化合物和使用1,3-偶极环加成化学从青蒿酸开始对其合成的方法。
在一个实施方案中,本发明提供式(I)的青蒿酸糖缀合物化合物;
其中,
X选自O或N;
Y选自各种被保护的或游离的糖如D-葡萄糖、D-半乳糖、L-鼠李糖、麦芽糖、D-葡萄烯糖、D-半乳醛、乳糖、阿拉伯糖、D-半乳糖胺、D-葡糖胺、D-甘露糖胺、D-甘露糖、D-木糖、D-岩藻糖等。
在优选的实施方案中,式(I)的青蒿酸糖缀合物化合物选自
a)三乙酸(2R,3S,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(4);
b)三苯甲酸(2R,3S,4S,5R,6R)-2-((苯甲酰基氧基)甲基)-6-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(5);
c)三乙酸(2R,3R,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(6);
d)三乙酸(2R,3R,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯基酰胺基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(7);
e)三乙酸(2R,3S,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯基酰胺基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(8);或
f)三苯甲酸(2R,3R,4S,5R,6R)-2-((苯甲酰基氧基)甲基)-6-(4-((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯基酰胺基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(9)和
g)三乙酸(2R,3R,4R,5S,6S)-2-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)-6-甲基四氢-2H-吡喃-3,4,5-三基酯(10)。
本发明提供使用1,3-偶极环加成化学从青蒿酸开始制备12-O-青蒿酸糖缀合物和12-N-青蒿酸糖缀合物的方法。首先将青蒿酸炔丙基化且与多种糖叠氮化物进行1,3-偶极环加成反应,得到所需的标题化合物。
在本发明一个实施方案中,本发明提供合成式(I)的青蒿酸糖缀合物化合物的方法,包括以下步骤:
a)将青蒿酸与炔丙胺或炔丙醇反应,得到丙烯酸酯(2)或丙烯酰胺(3);和
b)将步骤(a)的丙烯酸酯(2)或丙烯酰胺(3)与糖-叠氮化物进行1,3-偶极环加成,得到式(I)的化合物。
在优选的实施方案中,步骤(a)包括将青蒿酸、炔丙醇和4-二甲基氨基吡啶(DMAP)在溶剂中的反应混合物在温度0℃搅拌1至2小时范围的时间段,然后在25至30℃的温度范围进一步搅拌该反应混合物10至12小时范围内的时间段,得到对应的丙烯酸酯化合物(2)。
在另一优选实施方案中,步骤(a)包括将炔丙胺在25至30℃的温度范围添加至青蒿酸、(1-[二(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐){HATU}、N,N-二异丙基乙基胺(DIPEA)在溶剂中的反应混合物中,然后将该反应混合物在25至30℃的温度范围搅拌5至7小时范围内的时间段,得到对应的丙烯酰胺化合物(3)。
在本发明一个实施方案中,步骤(b)包括将N,N-二异丙基乙基胺(DIPEA)和碘化亚铜(I)(CuI)添加至糖-叠氮化物和丙烯酸酯化合物2或丙烯酰胺化合物3在溶剂中的反应混合物,然后将该反应混合物在25至30℃的温度范围搅拌8至10小时范围的时间段,得到式(I)的化合物。
在优选的实施方案中,所述糖-叠氮化物选自各种被保护的或游离的糖叠氮化物如D-葡萄糖、D-半乳糖、L-鼠李糖、麦芽糖、D-葡萄烯糖、D-半乳醛、乳糖、阿拉伯糖、D-半乳糖胺、D-葡糖胺、D-甘露糖胺、D-甘露糖、D-木糖和D-岩藻糖。
在更优选实施方案中,糖-叠氮化物选自D-葡萄糖基叠氮化物,D-半乳糖基叠氮化物、L-鼠李糖基叠氮化物、麦芽糖基叠氮化物、D-葡萄烯糖叠氮化物、乳糖基叠氮化物和D-甘露糖叠氮化物。
在本发明一个实施方案中,反应步骤(a)和(b)在氩气氛进行。
步骤(a)或(b)的溶剂选自二氯甲烷、二甲基甲酰胺、四氢呋喃、氯仿或四氯化碳。
合成式(I)的化合物的方法如以下方案所示:
方案:1
试剂和条件:(i)炔丙醇,EDC.HCl(1.2当量),DMAP,(0.1当量),无水DCM,0℃至25℃,12h,94%;(ii)炔丙胺,HATU(1.2当量),DIPEA(1.2当量),无水DMF,6h,95%;(iii)糖-N3,CuI,DIPEA,无水DCM,25℃,8至10h。
方案1显示合成式(I)的化合物的方法,其中所述糖选自各种被保护的或游离的糖如D-葡萄糖、D-半乳糖、L-鼠李糖、麦芽糖、D-葡萄烯糖、D-半乳醛、乳糖、阿拉伯糖、D-半乳糖胺、D-葡糖胺、D-甘露糖胺、D-甘露糖、D-木糖、D-岩藻糖等。
在另一实施方案中,本发明提供药物组合物,其包含式(I)的青蒿酸糖缀合物化合物或其药学上可接受的盐和至少一种药学上可接受的载体。
载体通常在制备组合物时使用,且包括,但不限于,乳糖、右旋糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶(acacia rubber)、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油,等。
该组合物可以另外包含稳定性改进材料、粘度改进或调节材料、溶解度改进材料、增甜剂、染料、适口性改进材料、渗透压可变盐、缓冲液溶液、抗氧化剂等。
本发明的药物组合物可以口服、舌下、皮下、肌内、静脉内、透皮、局部或直肠给药,所述活性成分可以单独或与另一种活性成分组合向动物和人类以单位给药形式给药,作为与常规药物载体的混合物给药。合适的单位给药形式包括口服形式,例如片剂、凝胶胶囊、粉剂、颗粒剂和口服混悬剂或溶液、舌下和颊给药形式、气雾剂、植入物、皮下、透皮、局部、腹膜内、肌内、静脉内、皮下、透皮、鞘内和鼻内给药形式以及直肠给药形式。
优选地,药物组合物包含对于能够被注射的制剂而言是药学上可接受的载体。这些可以特别是等渗的无菌盐水溶液(磷酸二氢钠或磷酸氢二钠、氯化钠、氯化钾、氯化钙或氯化镁等、或此类盐的混合物),或干燥的,尤其是冻干的组合物,其根据情况,在添加无菌水或生理盐水后,可配制注射溶液。
包含本发明作为游离碱或药学上可接受的盐的化合物的溶液可以在水中适当地与表面活性剂例如羟丙基纤维素混合而制备。分散体也可以在甘油、液体聚乙二醇及其混合物和油中制备。在常规的储存和使用条件下,这些制剂含有防腐剂以防止微生物的生长。例如,对于在水溶液中的肠胃外给药,如果需要,应当适当地缓冲溶液,并且首先用足够的盐水或葡萄糖使液体稀释剂等渗。
在本发明中,药学上可接受的盐可以包括药学上可接受的酸加成盐。药学上可接受的酸加成盐可得自无机酸,例如盐酸、硝酸、硫酸、氢溴酸、氢碘酸、亚硝酸或亚磷酸,以及无毒有机酸,例如脂族一元和二元羧酸、苯基取代的链烷酸、羟基链烷酸和链烷二酸、芳族酸以及脂族和芳族硫酸。
在另一实施方案中,本发明提供药物组合物,其包含式(I)的化合物或其药学上可接受的盐,其用于预防和治疗癌症或真菌感染,包括将有效剂量的药物组合物给药于哺乳动物。
此外,本发明提供了一种治疗癌症或真菌感染的方法,其特征在于对哺乳动物施用有效剂量的药物组合物。
通常,本发明的药物组合物以单位剂量的形式给药,该单位剂量形式包含其有效成分的量为约1mg至约500mg。本发明药物组合物的每日总剂量为约1mg至约500mg,优选约1mg至约300mg的范围。然而,在综合考虑患者的情况以及考虑所施用药物的活性的情况下,可以施用超出该范围的特定剂量。在特定情况下施用的最佳剂量必须通过实验确定。
本发明的化合物可以以一定剂量一次或多次施用。优选地,每日剂量每天给药一次或两次。本发明的化合物可以单独施用或与药学上可接受的载体和赋形剂联合施用。可以将本发明的药物组合物配制在本领域已知的赋形剂以及药学上可接受的载体和稀释剂中。为了方便起见,该制剂可以通过药学领域已知的方法采取单位剂量的形式。
本发明的药物组合物可以与一种或多种其他治疗上有用的材料结合使用,例如其他抗癌或抗疟疾药物。
在本发明一个实施方案中提供式(I)的青蒿酸糖缀合物化合物作为抗癌剂、抗真菌剂、抗疟疾剂、退热剂、抗细菌剂或显像剂的用途。而且,本发明提供式(I)的青蒿酸糖缀合物化合物,其显示植化相克作用或抗脂肪形成作用。
在另一实施方案中,本发明以IC50值提供化合物(I)对MCF-7(乳腺癌细胞系)的抗癌活性的研究。
在优选的实施方案中,化合物三乙酸(2R,3R,4R,5S,6S)-2-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)-6-甲基四氢-2H-吡喃-3,4,5-三基酯(10)显示对MCF-7(乳腺癌细胞系)的抗癌活性,其IC50值为42+/-4μM。
制备了许多式(I)化合物且研究这些化合物对MCF7(乳腺癌细胞系)的抗癌活性。抗癌活性的结果总结在下表1。
表1:糖缀合物对MCF7(乳腺癌细胞系)的体外抗癌活性。
化合物编码 | 化合物 | IC50μmol |
KTK-PA-1 | >100 | |
KTK-PA-2 | 7 | >100 |
KTK-PA-3 | 8 | >100 |
KTK-PA-4 | 9 | >100 |
KTK-PA-5 | >100 | |
KTK-PA-6 | >100 | |
KTK-PA-7 | >100 | |
KTK-PA-8 | >100 | |
KTK-PA-9 | >100 | |
KTK-PA-10 | >100 | |
KTK-PA-11 | >100 | |
KTK-PA-12 | >100 | |
KTK-AA-1 | >100 | |
KTK-AA-2 | 4 | >100 |
KTK-AA-3 | >100 | |
KTK-AA-4 | 6 | >100 |
KTK-AA-5 | >100 | |
KTK-AA-6 | 5 | >100 |
KTK-AA-7 | 10 | 42±2 |
KTK-AA-8 | >100 | |
KTK-AA-9 | >100 | |
KTK-AA-10 | >100 | |
KTK-AA-11 | >100 | |
KTK-AA-12 | >100 | |
KTK-AA-青蒿酸 | 1 | >100 |
从表1中观察到,化合物10显示出比青蒿酸出乎意料的抗癌活性提高,与青蒿酸相比,IC50值低50%以上,因此提供了对乳腺癌细胞系非常有效的抗癌活性。
此外,式(I)化合物的库正在针对多种药理活性针对更多的细胞系进行筛选和测试。
在一个实施方案中,本发明提供了一种用于治疗癌症或真菌感染的方法,其中所述方法包括向受试者施用治疗有效量的式(I)的青蒿酸糖缀合物化合物或其药学上可接受的盐。
实施例
通过举例说明的方式给出以下实施例,因此不应解释为限制本发明的范围。
实施例1:合成2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酸丙-2-炔-1-基酯(2):
将青蒿酸(AA)(325mg,1当量)、炔丙醇(80μL,1当量)和DMAP(17mg,0.1当量)在无水DCM(5mL)中的溶液冷却至0℃,然后用EDC.HCl(1.2当量)处理。反应混合物在相同温度(0℃)搅拌2h,然后在25℃搅拌10h。反应完成后(TLC),将反应混合物真空浓缩,将残余物溶于EtOAc和水。收集有机层且用饱和NH4Cl溶液洗涤,用Na2SO4干燥。将溶剂真空浓缩且进行快速色谱法,得到化合物2(354mg),产率94%。
1H NMR(氯仿-d,500MHz):δ=6.35(s,1H),5.49(s,1H),4.97(br.s,1H),4.78-4.68(m,2H),2.73-2.69(m,1H),2.50-2.57(m,1H),2.47-2.46(m,1H),1.94-1.83(m,2H),1.78-1.67(m,2H),1.58(s,3H),1.55-1.49(s,1H),1.45-1.30(m,4H),1.10-1.02(m,1H),0.89(d,J=5.7Hz,3H)。13C NMR(氯仿-d,126MHz):δ=166.3,142.6,134.9,125.2,120.2,77.8,74.8,52.1,42.3,41.3,37.9,35.2,27.5,26.4,25.9,25.5,23.7,19.7。HRMS(ESI)m/z,实测值:295.1661[M+Na]+(C18H24O2Na的计算值,295.1669)。
实施例2:合成2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)-N-(丙-2-炔-1-基)丙烯酰胺(3):
在25℃在氩气氛向青蒿酸(1),(100mg,1equiv)、HATU(191mg,1.2当量)和DIPEA(87μL,1.2当量)在DMF(10mL)中的溶液中添加炔丙胺(32μL,1.2当量)。将混合物搅拌6h。反应完成后(TLC),真空去除溶剂且所得油性残余物用DCM(15mL)稀释且用水萃取。合并的DCM层用Na2SO4干燥,过滤且浓缩。粗产物通过快速色谱法纯化,得到化合物3(109mg),产率95%。
1H NMR(500MHz,CDCl3)δ=6.29(brs,1H),5.63(s,1H),5.15(s,1H),4.96(s,1H),4.16-4.11(m,1H),4.03-3.98(m,1H),2.74(d,J=12.6Hz,1H),2.42(s,1H),2.23(t,J=2.7Hz,1H),2.15(s,1H),1.90-1.85(m,2H),1.75–1.66(m,2H),1.57(s,3H),1.56-1.49(m,1H),1.44-1.37(m,3H),1.29-1.23(m,1H),0.86(d,J=5.3Hz,3H)。13C NMR(125MHz,CDCl3)δ=169.5,148.7,135.1,120.2,116.6,79.6,71.6,42.6,41.2,37.7,35.0,29.4,27.5,26.4,25.4,25.3,23.7,19.7.HRMS(ESI):m/z[M+H]+,C18H26ON的计算值:272.2009,实测值:272.2004。
实施例3:合成青蒿酸糖缀合物的一般步骤:
在氩气氛向多种糖-叠氮化物(1当量)和化合物2(1当量)或化合物3(1当量)在无水DCM(5mL)中的搅拌溶液中,添加DIPEA(1当量)和CuI(0.5当量)。溶液在25℃搅拌8至10h。反应完成后(TLC),反应混合物用DCM(10mL)稀释且用水洗涤,DCM层用无水Na2SO4干燥,真空浓缩。粗残余物进行快速色谱法,得到多种青蒿酸糖缀合物,产率优异(85-98%)。
I.三乙酸(2R,3S,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(4)
在氩气氛向多种半乳糖基叠氮化物(1当量)和化合物2(1当量)在无水DCM(5mL)中的搅拌溶液中,添加DIPEA(1当量)和CuI(0.5当量)。溶液在25℃搅拌10h。反应完成后(TLC),反应混合物用DCM(10mL)稀释且用水洗涤,DCM层用无水Na2SO4干燥,真空浓缩。粗残余物进行快速色谱法,得到青蒿酸糖缀合物,产率优异(94%)。
1H NMR(400MHz,CDCl3):δ=7.90(s,1H),6.30(s,1H),5.84(d,J=9.2Hz,1H),5.54-5.49(m,2H),5.44(s,1H),5.33-5.30(m,1H),5.26-5.17(m,2H),4.94(br.s.,1H),4.24-4.16(m,2H),4.12-4.08(m,2H),2.67(d,J=11.0Hz,1H),2.51(br.s.,1H),2.19(s,3H),2.00(s,3H),1.97(s,3H),1.89-1.87(m,1H),1.82(s,3H),1.72-1.64(m,2H),1.54(br.s.,3H),1.38-1.28(m,3H),1.26-1.19(m,3H),0.85(d,J=4.9Hz,3H);13C NMR(100MHz,CDCl3):δ=170.3,170.0,169.8,168.9,166.9,143.6,142.7,134.8,125.2,122.5,120.2,86.2,74.0,70.7,67.8,66.9,61.2,60.3,57.5,42.3,41.3,37.9,35.2,27.5,26.3,25.9,25.5,23.6,20.6,20.4,20.1,19.7;HRMS(ESI):m/z[M+H]+,C32H44O11N3的计算值:646.3699,实测值:646.2970。
II.三苯甲酸(2R,3S,4S,5R,6R)-2-((苯甲酰基氧基)甲基)-6-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(5)
1H NMR(400MHz,CDCl3):δ=8.14-8.12(m,3H),8.02–8.00(m,2H),7.81–7.77(m,4H),7.70–7.66(m,1H),7.58-7.54(m,3H),7.47-7.40(m,4H),7.32-7.24(m,4H),6.32-6.18(m,4H),5.91-5.88(m,1H),5.47(br s,1H),5.39(d,J=12.8Hz,1H),5.24(d,J=12.8Hz,1H),5.01(br.s.,1H),4.72-4.64(m,2H),4.53–4.49(m,1H),2.74–2.71(m,1H),2.58(br.s.,1H),1.90–1.69(m,5H),1.59(br.s.,3H),1.55–1.50(m,1H),1.43-1.36(m,4H),0.89(d,J=4.5Hz,3H);13C NMR(100MHz,CDCl3):δ=167.0,166.0,165.4,165.3,164.8,142.8,134.9,133.9,133.7,133.5,133.4,129.9,129.8,129.7,129.1,128.9,128.8,128.5,128.4,128.1,125.1,120.3,86.5,74.7,71.7,68.8,68.0,62.0,57.6,42.3,41.4,38.0,35.2,27.6,26.4,25.9,25.6,23.7,19.7;HRMS(ESI)m/z:[M+Na]+,C52H51O11N3Na的计算值:916.3416,实测值:916.3408。
III.三乙酸(2R,3R,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(6)
1H NMR(500MHz,CDCl3):δ=7.84(s,1H),6.27(s,1H),5.89-5.87(m,1H),5.42-5.39(m,3H),5.28-5.18(m,3H),4.92(br.s.,1H),4.28-4.24(m,1H),4.12-4.09(m,1H),4.02–3.99(m,1H),2.65(d,J=11.8Hz,1H),2.49(br.s.,1H),2.03(s,3H),2.01(s,3H),1.97(s,3H),1.83-1.80(m,4H),1.71-1.63(m,3H),1.52(br.s.,3H),1.37-1.27(m,4H),1.18-1.23(m,2H),0.83(d,J=5.7Hz,3H);13C NMR(125MHz,CDCl3):δ=170.5,169.9,169.3,168.7,166.9,143.7,142.7,134.8,125.1,122.2,120.2,85.6,75.1,72.6,70.3,67.7,61.5,57.5,42.3,41.3,37.9,35.2,29.6,27.5,26.3,25.8,25.5,23.6,20.6,20.5,20.0,19.7;HRMS(ESI)m/z:[M+Na]+,C32H43O11N3Na的计算值:668.2790,实测值:668.2880。
IV.三乙酸(2R,3R,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯基酰胺基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(7)
1H NMR(500MHz,CDCl3)δ=7.81(s,1H),6.81(m,1H),5.86(d,J=8.8Hz,1H),5.59(s,1H),5.43-5.38(m,2H),5.21(t,J=9.5Hz,1H),5.13-5.10(m,1H),4.98(br.s.,1H),4.59(dd,J=15.3,6.1Hz,1H),4.48(dd,J=15.3,5.7Hz,1H),4.26(dd,J=12.6,5.0Hz,1H),4.14-4.06(m,1H),4.03–4.00(m,1H),2.77-2.72(m,1H),2.44(br.s.,1H),2.05(s,3H),2.03(s,3H),1.99(s,3H),1.91-1.86(m,2H),1.81(s,3H),1.76-1.72(m,1H),1.68-1.66(m,1H),1.56(s,3H),1.40-1.37(m,3H),1.25-1.22(m,2H),0.85(d,J=5.7Hz,3H);13CNMR(125MHz,CDCl3)δ=170.5,169.9,169.3,168.7,148.8,145.6,135.1,121.0,120.3,116.4,85.7,75.0,72.6,70.5,67.7,61.5,42.5,41.2,37.8,35.0,34.9,27.5,26.4,25.5,25.2,23.7,20.6,20.5,20.4,20.1,19.7;HRMS(ESI)m/z:[M+H]+,C32H45O10N4的计算值:645.3130,实测值:645.3109。
V.三乙酸(2R,3S,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯基酰胺基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(8)
1H NMR(500MHz,CDCl3)δ=7.86(s,1H),6.82-6.81(m,1H),5.83(d,J=9.2Hz,1H),5.60(s,1H),5.52-5.48(m,2H),5.26(dd,J=10.3,3.0Hz,1H),5.12(s,1H),4.97(br.s.,1H),4.66(dd,J=15.3,6.3Hz,1H),4.39(dd,J=15.3,5.3Hz,1H),4.25(t,6.5Hz,1H),4.20-4.16(m,1H),4.13-4.06(m,1H),2.77-2.72(m,1H),2.43(br.s.,1H),2.20(s,3H),2.01(s,3H),1.98(s,3H),1.89-1.85(m,2H),1.83(s,3H),1.73–1.65(m,2H),1.55(s,3H),1.42-1.37(m,3H),1.28-1.22(m,2H),0.85(d,J=5.3Hz,3H);13C NMR(125MHz,CDCl3)δ=170.3,170.1,169.8,168.9,148.7,145.2,135.0,121.2,120.3,116.5,86.2,74.0,70.7,68.0,66.9,61.2,42.5,41.2,37.8,35.0,34.8,27.5,26.4,25.4,25.3,23.7,20.6,20.6,20.5,20.1,19.7;HRMS(ESI)m/z:[M+H]+,C32H45O10N4的计算值:645.3130,实测值:645.3113。
VI.三苯甲酸(2R,3R,4S,5R,6R)-2-((苯甲酰基氧基)甲基)-6-(4-((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯基酰胺基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(9)
1H NMR(400MHz,CDCl3)δ=8.01-7.98(m,3H),7.93–7.91(m,2H),7.82–7.80(m,2H),7.76-7.74(m,2H),7.53–7.48(m,2H),7.43–7.33(m,6H),7.29-7.25(m,4H),6.68(s,1H),6.29(d,J=9.2Hz,1H),6.15(t,J=9.5Hz,1H),5.99–5.94(m,1H),5.89–5.84(m,1H),5.54(s,1H),5.08(s,1H),5.01(s,1H),4.64-4.63(m,2H),4.52–4.49(m,3H),2.79–2.78(m,2H),2.49(s,1H),2.03(s,1H),1.91-1.85(m,2H),1.70–1.67(m,1H),1.59(s,3H),1.40(m,2H),1.26-1.23(m,2H),0.88(d,J=4.9Hz,3H);13C NMR(100MHz,CDCl3)δ=169.9,166.1,165.6,165.1,164.6,148.8,135.1,133.7,133.6,133.5,133.3,129.9,129.8,129.7,129.3,128.5,128.4,128.3,128.0,121.1,120.3,116.4,86.1,75.5,73.0,71.2,68.9,62.8,42.6,41.2,38.6,37.8,35.0,27.6,26.4,25.4,25.3,23.7,19.7;HRMS(ESI)m/z:[M+H]+,C52H53O10N4的计算值:893.3756,实测值:893.3749。
VII.三乙酸(2R,3R,4R,5S,6S)-2-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)-6-甲基四氢-2H-吡喃-3,4,5-三基酯(10)
无色固体;产率:90%,m.p.:89-92℃;Rf=0.40(40%EtOAc-石油醚);快速色谱法用25%EtOAc-石油醚洗脱;[α]D26=+26.62(c 1.7,CHCl3);1H NMR(500MHz,CDCl3):δ=7.84(s,1H),6.30-6.27(m,1H),6.14(s,1H),5.95-5.80(m,1H),5.66-5.65(m,1H),5.45-5.43(m,1H),5.34-5.29(m,1H),5.23-5.20(m,1H),5.18-5.15(m,1H),4.92(s,1H),3.86-3.81(m,1H),2.69-2.64(m,1H),2.49(brs,1H),2.14(s,1H),2.06(s,3H),2.03-2.01(m,4H),1.95(s,3H),1.91-1.82(m,2H),1.74-1.65(m,2H),1.55(s,3H),1.39-1.38(m,2H),1.32(d,J=6.5Hz,3H),1.22-1.20(m,2H),0.86(d,J=5.3Hz,3H);13C NMR(125MHz,CDCl3):δ=169.8,169.8,169.1,167.0,143.6,142.9,142.7,142.7,134.9,125.2,125.1,124.0,123.1,120.1,120.1,84.6,83.8,73.9,70.7,70.0,69.6,69.2,68.8,68.4,60.3,57.6,57.5,42.3,41.4,41.3,37.9,35.2,27.5,26.3,25.8,25.5,23.6,20.7,20.5,20.5,20.3,19.7,17.5,17.1,14.1;HRMS(ESI)m/z:C30H42O9N3[M+H]+的计算值:588.2916,实测值:588.2903。
实施例4:对MCF-7(乳腺癌细胞系)的抗癌活性的研究
方法
化合物溶于DMSO(Sigma)以制备50mM浓储液。所有进一步的稀释也是在DMSO中进行的。在处理过程中,DMSO的终浓度保持在<0.02%。
抗体
抗胱天蛋白酶9和抗胱天蛋白酶3抗体购自Cell Signaling且抗α微管蛋白抗体购自Sigma,山羊抗兔HRP缀合的二抗购自Bio-Rad,且山羊抗小鼠HRP缀合的二抗购自CellSignaling。
细胞培养
在NCCS(提供细胞系的国家资源)维护的乳腺癌细胞系MCF7中,在DMEM(GIBCO)、RPMI中的MBA-MB-231(GIBCO)(其具有10%FBS、100U/mL青霉素和100μg/mL链霉素)和DMEM/F12中的MCF10A(Gibco)(其含有马血清(10%最终)、EGF(20ng/ml)、氢化可的松(0.5mg/ml)、霍乱毒素(100ng/ml)、胰岛素(10μg/ml)和青霉素/链霉素混合物(1ml/100ml))中在37℃在潮湿、5%CO2调节培养箱中生长。
通过细胞毒性测试测定的生长抑制
使用MTT(3-(4,5-二甲基噻唑-2-基)-2-5-二苯基四唑鎓溴化物)测定法测定化合物的细胞毒性作用。将细胞接种在96孔板中(每孔4X 103)。接种24小时后,将细胞以不同浓度(0–100μM)的各个化合物进行一式三份的暴露48小时。然后,添加MTT溶液(对于96孔板的每个孔为20μL 5mg/mL储备液),并在5%CO2潮湿培养箱中进一步培养3.5小时。然后将含有MTT溶液的培养基替换为MTT溶剂(异丙醇,HCl和Triton X-100),在室温下轻轻摇动孵育15分钟,以完全溶解甲瓒。使用Thermo Scientific Multiskan G0 Elisa读板仪在570nm处测量吸光度,并通过常规方法计算IC50。所有实验至少一式三份进行,并且计算活细胞的百分比作为相对于对照的平均值。
表1显示抗癌活性的结果。
本发明的优点:
本发明提供了式(I)的新型青蒿酸糖缀合物,其用作抗癌剂/抗疟剂或显像剂。从青蒿酸开始,通过简单、环境友好和经济的方法合成了许多新的12-O-青蒿酸糖缀合物和12-N-青蒿酸糖缀合物。
Claims (10)
2.权利要求1所述的式(I)的化合物,其中所述式(I)的化合物选自
a)三乙酸(2R,3S,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(4);
b)三苯甲酸(2R,3S,4S,5R,6R)-2-((苯甲酰基氧基)甲基)-6-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(5);
c)三乙酸(2R,3R,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(6);
d)三乙酸(2R,3R,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯基酰胺基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(7);
e)三乙酸(2R,3S,4S,5R,6R)-2-(乙酰氧基甲基)-6-(4-((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯基酰胺基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(8);
f)三苯甲酸(2R,3R,4S,5R,6R)-2-((苯甲酰基氧基)甲基)-6-(4-((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯基酰胺基)甲基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4,5-三基酯(9)和
g)三乙酸(2R,3R,4R,5S,6S)-2-(4-(((2-((1R,4R,4aS,8aR)-4,7-二甲基-1,2,3,4,4a,5,6,8a-八氢萘-1-基)丙烯酰基)氧基)甲基)-1H-1,2,3-三唑-1-基)-6-甲基四氢-2H-吡喃-3,4,5-三基酯(10)。
3.合成式(I)的化合物的方法,包括以下步骤:
a)将青蒿酸与炔丙醇或炔丙胺反应以分别得到丙烯酸酯(2)或丙烯酰胺(3),和
b)将步骤(a)的丙烯酸酯(2)或丙烯酰胺(3)与糖-叠氮化物进行1,3-偶极环加成,得到式(I)的化合物。
4.权利要求3所述的方法,其中所述步骤(a)包括将青蒿酸、炔丙醇和4-二甲基氨基吡啶(DMAP)的反应混合物在溶剂中在温度0℃搅拌1至2小时的时间段,然后进一步将该反应混合物在25至30℃的温度范围搅拌10至12小时范围内的时间段,得到对应的丙烯酸酯化合物(2)。
5.权利要求3所述的方法,其中所述步骤(a)包括将炔丙胺在25至30℃的温度范围添加至青蒿酸、(1-[二(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐){HATU}、N,N-二异丙基乙基胺(DIPEA)在溶剂中的反应混合物中,然后将该反应混合物在25至30℃的温度范围搅拌5至7小时范围的时间段,得到对应的丙烯酰胺化合物(3)。
6.权利要求3所述的方法,其中所述步骤(b)包括将N,N-二异丙基乙基胺(DIPEA)和碘化亚铜(I)(CuI)添加至糖-叠氮化物和丙烯酸酯化合物2或丙烯酰胺化合物3在溶剂中的反应混合物,然后将该反应混合物在25至30℃的温度范围搅拌8至10小时范围的时间段,得到式(I)的化合物。
7.权利要求6所述的方法,其中所述糖-叠氮化物为被保护的或游离的糖叠氮化物,其选自以下物质的叠氮化物:D-葡萄糖、D-半乳糖、L-鼠李糖、麦芽糖、D-葡萄烯糖、D-半乳醛、乳糖、阿拉伯糖、D-半乳糖胺、D-葡糖胺、D-甘露糖胺、D-甘露糖、D-木糖或D-岩藻糖。
8.权利要求7所述的方法,其中所述糖-叠氮化物选自D-葡萄糖基叠氮化物,D-半乳糖基叠氮化物、L-鼠李糖基叠氮化物、麦芽糖基叠氮化物、D-葡萄烯糖叠氮化物、乳糖基叠氮化物和D-甘露糖叠氮化物。
9.权利要求3所述的方法,其中用于步骤a和b的溶剂选自二氯甲烷、二甲基甲酰胺、四氢呋喃、氯仿或四氯化碳。
10.药物组合物,其包含式(I)的化合物或其药学上可接受的盐和药学上可接受的载体,其用于预防和治疗癌症或真菌感染,包括将有效剂量的药物组合物给药于哺乳动物。
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