CN101671376A - 紫草素乙酰糖及其制备方法和用途 - Google Patents
紫草素乙酰糖及其制备方法和用途 Download PDFInfo
- Publication number
- CN101671376A CN101671376A CN 200910152938 CN200910152938A CN101671376A CN 101671376 A CN101671376 A CN 101671376A CN 200910152938 CN200910152938 CN 200910152938 CN 200910152938 A CN200910152938 A CN 200910152938A CN 101671376 A CN101671376 A CN 101671376A
- Authority
- CN
- China
- Prior art keywords
- alkannin
- ethanoyl
- naphthoquinones
- dihydroxyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 title claims abstract description 51
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 title claims abstract description 49
- HXBYBCASAVUYKF-GVYWOMJSSA-N (4r,5s,6r,7r)-4,5,6,7,8-pentahydroxyoctane-2,3-dione Chemical compound CC(=O)C(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO HXBYBCASAVUYKF-GVYWOMJSSA-N 0.000 title claims abstract description 31
- 239000004229 Alkannin Substances 0.000 title claims abstract description 30
- 235000019232 alkannin Nutrition 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002808 molecular sieve Substances 0.000 claims abstract description 6
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 5
- 241001071917 Lithospermum Species 0.000 claims description 17
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
- 230000000259 anti-tumor effect Effects 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- SRBFZHDQGSBBOR-QMKXCQHVSA-N alpha-L-arabinopyranose Chemical compound O[C@H]1CO[C@@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-QMKXCQHVSA-N 0.000 claims description 6
- -1 carbon aldoses Chemical class 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 150000002016 disaccharides Chemical class 0.000 claims description 4
- 229960002246 beta-d-glucopyranose Drugs 0.000 claims description 3
- 239000000835 fiber Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- 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 abstract description 9
- 239000008103 glucose Substances 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 206010059866 Drug resistance Diseases 0.000 abstract 3
- 206010028980 Neoplasm Diseases 0.000 abstract 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
- 150000001875 compounds Chemical class 0.000 description 20
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 8
- 229960001031 glucose Drugs 0.000 description 8
- 229910015900 BF3 Inorganic materials 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 238000006386 neutralization reaction Methods 0.000 description 5
- SRBFZHDQGSBBOR-SOOFDHNKSA-N D-ribopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@@H]1O SRBFZHDQGSBBOR-SOOFDHNKSA-N 0.000 description 4
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 3
- YFHNDHXQDJQEEE-UHFFFAOYSA-N acetic acid;hydrazine Chemical compound NN.CC(O)=O YFHNDHXQDJQEEE-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- JMELRMJNKRXCFL-UHFFFAOYSA-N 5,8-dihydronaphthalene-1,2-dione Chemical class C1(C(C=CC=2CC=CCC12)=O)=O JMELRMJNKRXCFL-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 150000001323 aldoses Chemical class 0.000 description 2
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 229960004249 sodium acetate Drugs 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products 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 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 235000004256 Buglossoides arvense Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose Chemical compound 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-CUHNMECISA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products 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 description 1
- 241000118841 Lithospermum incisum Species 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products 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 description 1
- 238000002835 absorbance Methods 0.000 description 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-PQMKYFCFSA-N alpha-D-mannose Chemical compound OC[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-PQMKYFCFSA-N 0.000 description 1
- SRBFZHDQGSBBOR-LECHCGJUSA-N alpha-D-xylose Chemical compound O[C@@H]1CO[C@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-LECHCGJUSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound 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 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000348 glycosyl donor Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- WNFXUXZJJKTDOZ-UHFFFAOYSA-N shikonin acetate Natural products C1=CC(O)=C2C(=O)C(C(OC(C)=O)CC=C(C)C)=CC(=O)C2=C1O WNFXUXZJJKTDOZ-UHFFFAOYSA-N 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960003487 xylose Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明公开了一种紫草素乙酰糖及其制备方法和用途。它是在二氯甲烷溶剂中加入1摩尔的1-三氯乙酰胺基乙酰糖和1~2摩尔的紫草素,在4分子筛、三氟化硼乙醚存在下反应,反应温度为-20~-40℃,得到紫草素乙酰糖。紫草素乙酰糖用于具有抗肿瘤活性以及耐药性的药物。本发明经过四步反应简单高效地制备紫草素乙酰糖,并对紫草素乙酰糖进行抗肿瘤活性和耐药性进行考察,发现其对肿瘤细胞株具有强烈的抑制作用,并证明具有很好的耐药性,是具有前途的抗肿瘤药物。
Description
技术领域
本发明涉及化合物及其制备方法,尤其涉及一种紫草素乙酰糖及其制备方法和用途。
背景技术
5,8-二氢萘醌类化合物已被美国国家癌症研究所确定为具有抗肿瘤活性的物质,紫草素(SH)是该类化合物的典型代表。紫草素具有广泛的生物活性包括:抗菌、抗艾滋病、促进烧伤伤口愈合、抗肿瘤等,备受研究者的关注。近年来对对紫草素的研究主要关注于以下的方面:紫草素的新药效研究,紫草素的全合成和对紫草素改性衍生化等研究。
抗肿瘤活性较弱且水溶性不佳等因素使得紫草素不能成为很好的抗肿瘤药物,为此很多研究者对紫草素进行了修饰,合成了多类紫草素衍生物。研究表明5,8-二氢萘醌结构是紫草素抗肿瘤活性的关键,因此绝大部分的紫草衍生物都是1’-位羟基进行修饰的,这类衍生物比紫草素本身具有更好的抗肿瘤活性,如1’-O-乙酰紫草素,1’-O-呋喃甲酰紫草素,1’-O-异戊酰紫草素,侧链氮原子取代的紫草素类似物。
1.V.P.Papageorgiou,A.N.Assimopoulou,E.A.Couladouros,D.Hepworth,K.C.Nicolaou.Angew.Chem.Int.Ed.1999,38,270.
2.W.J.Wang,J.Y.Bai,D.P.Liu,L.M..Xue,X.Y.Zhu.Yaoxue Xuebao,1994,29,161
3.Q.Lu,W.J.Liu,J.Ding,J.C.Cai,W.H.Duan.Bioorg.Med.Chem Lett.2002,12,1375.
4.F.Yang,Y.Chen,W.H.Duan,C.Zhang,H.Zhu,J.Ding.Int.J.Cancer.2006,119,1184.
为了寻找活性更好的紫草素衍生物,我们设计了紫草素乙酰糖的衍生物,并发现这一类化合物比紫草素具有更好的抗肿瘤活性,同时具备良好的耐药性,且未见有文献报道。
发明内容
本发明的目的是克服现有技术的不足,提供一种紫草素乙酰糖及其制备方法和用途。
紫草素乙酰糖的通式如下:
其中R为乙酰基保护的五碳醛糖、乙酰基保护的六碳醛糖或乙酰基保护的醛二糖。
所述的紫草素乙酰糖为:
5(a)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖、
5(b)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6-四-O-乙酰基-β-D-吡喃甘露糖、
5(c)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6-四-O-乙酰基-β-D-吡喃半乳糖、
5(d)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4-三-O-乙酰基-β-L-吡喃鼠李糖、
5(e)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4-三-O-乙酰基-β-D-吡喃木糖、
5(f)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,5-三-O-乙酰基-β-D-呋喃核糖、
5(g)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,5-三-O-乙酰基-β-D-呋喃阿拉伯糖、
5(h)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,5-三-O-乙酰基-β-L-呋喃阿拉伯糖、
5(i)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6,2’,3’,4’,6’-七-O-乙酰基-β-麦芽糖、
5(j)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6,2’,3’,4’,6’-七-O-乙酰基-β-纤维二糖或5(k)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6,2’,3’,4’,6’-七-O-乙酰基-β-乳糖。
紫草素乙酰糖用于具有抗肿瘤活性以及耐药性的药物。
本发明经过四步反应简单高效地制备紫草素乙酰糖,并对紫草素乙酰糖进行抗肿瘤活性和耐药性进行考察,发现其对肿瘤细胞株具有强烈的抑制作用,并证明具有很好的耐药性,是具有前途的抗肿瘤药物。
具体实施方式
本发明选取自然界中常见的醛糖作为糖基供体,包含单糖(五碳糖,六碳糖)和二糖。合成并优选的化合物的结构式如下:
紫草素乙酰糖的衍生物的制备方法的反应式如下:
醛糖1(a~k)在醋酸酐和醋酸钠的作用下乙酰化,醋酸酐为1的10倍摩尔量,醋酸钠为1的等摩尔量,反应温度控制在80℃,反应时间4小时,反应过程TLC跟踪。反应完成后冷却到室温,反应液倒入到冰冷的饱和碳酸氢钠溶液中和剩余的醋酸酐,继续搅拌1.5小时后加入适宜的萃取剂萃取,如二氯甲烷等,通过柱层析纯化,得到全乙酰糖2(a~k)。
全乙酰糖2(a~e,i~k)再经由醋酸肼在室温条件下反应4小时,四氢呋喃作为溶剂,醋酸肼用量为2(a~e,i~k)的1.1倍摩尔量。反应结束后减压蒸除溶剂,加入二氯甲烷溶解,水洗,干燥并旋干得到端氧脱乙酰基保护的3(a~e,i~k)。全乙酰糖2(f~h)在等摩尔的甲醇钠下脱端乙酰基,溶剂为四氢呋喃,反应温度控制在0℃,反应时间约30分钟,反应进程用TLC检测跟踪。反应结束后加入乙酸中和,并减压蒸除溶剂,加入二氯甲烷溶解,水洗两次,干燥,旋干得到3(f~h)。往1-羟基乙酰糖3(a~k)的二氯甲烷溶液中加入5倍摩尔量的碳酸钾和4倍摩尔量的三氯乙腈,室温下搅拌过夜。反应结束后过滤,滤液旋干,经柱层析分离得到α-乙酰糖三氯乙酰亚胺酯4(a~k)。
在氮气保护下,4(a~k)和1~2倍摩尔的紫草素等中加入新活化的分子筛,在-20~-40℃下滴加入溶于二氯甲烷0.1倍摩尔量的三氟化硼乙醚溶液,约30分钟滴加完毕,继续反应1小时,反应过程用TLC跟踪。反应结束后加入三乙胺,中和反应中的三氟化硼,而后用乙酸使溶液由深蓝色变为红色。然后过滤,滤液旋干,柱层析分离得到β-紫草素乙酰糖5(a~k)。
本发明制备的β-紫草素乙酰糖化合物在细胞毒实验中发现对肿瘤细胞株具有强烈的抑制作用,并证明具有很好的耐药性,是具有前途的抗肿瘤药物。
抗肿瘤活性测定:
MCF-7,HL60和K562细胞使用添加10%胎牛血清的RPMI-1640培养液,MCF-7/ADR,HL60/ADR和K562/ADR细胞使用添加10%胎牛血清和1ug/mL阿霉素的RPMI-1640培养液,培养于含5%CO2的饱和湿度37℃恒温培养箱中。所有的化合物用DMSO溶解制成浓度为20mM的储备液,使用前用新鲜培养基稀释成相应的浓度。3000/孔的MCF-7和MCF-7/ADR细胞接种于96孔板24小时后,用不同浓度的化合物处理,每个浓度3复孔,HL60和HL60/ADR,K562和K562/ADR的种板密度分别为8000和3000/孔,种板后直接用化合物处理。恒温箱中培养72小时后,每孔加20uL的5mg/mL的MTT(过滤除菌,遮光,4℃保存),37℃孵育4小时后,倾倒培养板内液体,每孔加入150uLDMSO,以溶解MTT形成的蓝紫色甲簪结晶,在570nm波长下用酶标仪检测吸光度值,计算不同化合物对各细胞的生长抑制率。
表1
a耐药因子=IC50耐药细胞株/IC50敏感细胞株
如上表所示,这类紫草素衍生物具有强烈的细胞毒活性且具有良好的耐药性。
实施例1
1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖
将1.80g(10mmol)葡萄糖和1.07g(13mmol)无水醋酸钠加入到单口烧瓶中,加入9.4mL(100mmol)醋酸酐,反应温度控制在80~90℃,反应时间约4小时,反应过程用TLC跟踪。反应完成后冷却到室温,反应液倒入到冰冷的饱和碳酸氢钠溶液中,中和剩余的醋酸酐,继续搅拌1.5小时后加入适宜的萃取剂萃取,如二氯甲烷等,然后分离并通过柱层析纯化,得到3.62g(收率92.8%)1,2,3,4,6-五-O-乙酰葡萄糖。
将1.95g(5mmol)五乙酰葡萄糖溶于20mL四氢呋喃,加入0.506g(5.5mmol)醋酸肼在室温条件下搅拌4小时。反应结束后减压蒸除四氢呋喃,加入40mL二氯甲烷溶解,水洗两次,干燥并旋干得到1.49g(收率85.6%)2,3,4,6-四-O-乙酰葡萄糖。将1.04g(3mmol)2,3,4,6-四-O-乙酰葡萄糖溶于40mL无水二氯甲烷,并加入2.07g(15mmol)碳酸钾和1.2mL(12mmol)三氯乙腈,室温下搅拌过夜。反应结束后过滤,滤液旋干,经柱层析分离得到1.20g(收率81.2%)2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯。
在氮气保护下,往0.288g(1mmol)紫草素和0.493g(1mmol)2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯中加入20mL无水二氯甲烷,而后加入0.1g新活化的分子筛,在-40℃下滴加入溶于5mL二氯甲烷的0.0141g(0.1mmol)三氟化硼乙醚溶液,约30分钟滴加完毕,继续在此温度下反应1小时,反应过程用TLC跟踪。反应结束后加入0.1g(1mmol)三乙胺中和反应体系中剩余的三氟化硼,而后用0.06g(1mmol)乙酸使溶液由深蓝色变为红色。过滤,滤液旋干,柱层析分离得到0.53g(85.8%)标题化合物。
1H NMR(400MHz,CDCl3):δ12.49(s,1H),12.41(s,1H),7.12(m,3H),5.13(m,1H),5.00(m,3H),4.86(m,1H),4.60(d,J=8.0Hz,1H),3.95(m,1H),35.3(m,1H),2.45(m,1H),2.26(m,1H),2.00(s,3H),1.95(s,3H),1.94(s,3H),1.85(s,3H),1.62(s,3H),1.49(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ180.4,179.2,170.3,170.2,169.3,169.1,165.3,164.8,149.7,135.2,133.6,132.3,131.7,118.1,111.8,111.5,100.8,75.6,72.6,71.8,71.4,68.2,61.5,33.7,25.7,20.6,20.5,20.4,20.3,17.9ppm
实施例2
1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6-四-O-乙酰基-β-D-吡喃甘露糖
操作同实施例1,只是将葡萄糖换成甘露糖,得到具体如下结构的标题化合物。
1H NMR(400MHz,CDCl3):δ12.57(s,1H),12.46(s,1H),7.18(m,3H),5.30(m,2H),5.23(t,J=10Hz,1H),5.12(t,J=6.8Hz,1H),5.04(m,2H),4.14(dd,J=5.6,12.0Hz,1H),3.89(dd,J=1.6,12.4Hz,1H),3.83(m,1H),2.51(m,1H),2.45(m,1H),2.14(s,3H),2.02(s,3H),2.00(s,3H),1.94(s,3H),1.67(s,3H),1.58(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ177.9,176.4,170.4,169.9,169.7,169.7,167.8,167.3,148.9,136.6,133.1,132.7,132.1,117.4,111.7,111.5,97.5,73.2,69.4,69.3,68.9,66.0,62.4,33.5,25.7,20.8,20.7,20.6,20.4,18.0ppm;
实施例3
1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6-四-O-乙酰基-β-D-吡喃半乳糖
操作同实施例1,只是把葡萄糖换成半乳糖,得到具体如下结构的标题化合物。
1H NMR(400MHz,CDCl3):δ12.58(s,1H),12.51(s,1H),7.21(m,3H),5.36(d,J=3.2Hz,1H),5.27(dd,J=10.4,8.0Hz,1H),5.14(t,J=6.8Hz,1H),5.02(dd,J=3.2,6.4Hz,1H),4.97(dd,J=4.0,6.8Hz,1H),4.62(d,J=7.6Hz,1H),3.99(d,J=6.4Hz,1H),3.83(t,J=6.4Hz,1H),2.52(m,1H),2.35(m,1H),2.17(s,3H),2.09(s,3H),2.00(s,3H),1.92(s,3H),1.69(s,3H),1.56(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ180.4,179.2,170.1,170.0,169.1,165.1,164.6,149.5,135.1,133.6,132.1,131.6,117.9,111.6,111.4,101.1,75.3,70.7,70.6,68.7,66.7,61.0,33.4,25.7,20.6,20.5,20.4,20.3,17.8ppm;
实施例4
1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4-三-O-乙酰基-β-L-吡喃鼠李糖
操作同实施例1,只是把葡萄糖换成鼠李糖,得到具体如下结构的标题化合物。
1H NMR(400MHz,CDCl3):δ12.60(s,1H),12.48(s,1H),7.19(s,2H),7.17(S,1H),5.26(m,2H),5.11(t,J=3.2Hz,1H),5.03(m,2H),4.93(s,1H),3.73(m,1H),2.47(m,2H),2.15(s,3H),2.04(s,3H),2.00(s,3H),1.67(s,3H),1.58(s,3H),1.03(d,J=3.2Hz,3H)ppm;
13C NMR(100MHz,CDCl3):δ178.4,176.9,169.8,169.8,169.7,167.1,166.6,149.1,136.2,132.7,132.4,132.1,117.4,111.6,111.4,97.4,73.1,70.6,69.5,68.8,67.1,33.2,25.5,20.7,20.6,20.6,17.8,17.1ppm;
实施例5
1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4-三-O-乙酰基-β-D-吡喃木糖
操作同实施例1,只是把葡萄糖换成木糖,得到具体如下结构的标题化合物。
1H NMR(400MHz,CDCl3):δ12.57(s,1H),12.48(s,1H),7.18(m,3H),5.12(m,2H),5.00(m,1H),4.93(m,2H),4.67(d,J=6.4Hz,1H),3.96(dd,J=11.6,4.4Hz),3.27(dd,J=10.4,9.6Hz,1H),2.52(m,1H),2.33(m,1H),2.09(s,3H),2.08(s,3H),2.03(s,3H),1.68(s,3H),1.56(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ180.5,179.2170.5,170.2,169.8,166.3,165.8,150.4,135.8,133.6,132.9,132.4,118.6,112.3,112.0,101.2,75.4,71.6,71.2,69.0,62.4,34.1,26.3,21.2,21.2,21.1,18.4ppm;
实施例6
1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6,2’,3’,4’,6’-七-O-乙酰基-β-麦芽糖
操作同实施例1,只是把葡萄糖换成麦芽糖,得到具体如下结构的标题化合物。
1H NMR(400MHz,CDCl3):δ12.59(s,1H),12.43(s,1H),7.17(m,3H),5.52(d,J=5.2Hz,1H),5.49(d,J=4Hz,1H),5.36(t,J=10.0Hz,1H),5.15(m,1H),5.03(t,J=6.0Hz,1H),4.98(s,2H),4.84(dd,J=4.0,10.4Hz,1H),4.22(m,4H),4.00(m 2H),3.80(t,J=6.4Hz,1H),3.58(d,J=8.4Hz,1H),2.36(m,1H),2.28(m,1H),2.09(s,3H),2.08(s,3H),2.06(s,3H),2.04(s,3H),2.02(s,3H),2.00(s,3H),1.98(s,3H),1.66(s,3H),1.56(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ176.7,175.1,170.5,170.3,170.1,169.4,169.2,169.1,168.5,150.8,135.5,133.5,133.1,131.4,121.9,118.9,111.8,111.4,96.9,94.7,73.0,72.2,70.2,69.7,68.6,68.2,68.1,67.6,63.7,61.7,35.1,25.6,21.4,20.7,20.6,20.5,20.7,17.9ppm;
实施例7
1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6,2’,3’,4’,6’-七-O-乙酰基-β-纤维二糖
操作同实施例1,只是把葡萄糖换成纤维二糖,得到具体如下结构的标题化合物。
1H NMR(400MHz,CDCl3):δ12.59(s,1H),12.41(s,1H),7.18(m,2H),7.02(s,1H),5.06(m,6H),4.93(m,1H),4.53(m,2H),4.38(m,2H),4.13(dd,J=4.8,11.6Hz,1H),4.05(d,J=12.4Hz,1H),3.82(t,J=9.2Hz,1H),3.66(d,J=8.8Hz,1H),3.54(dd,J=3.6,9.6Hz,1H),2.53(m,1H),2.40(m,1H),2.16(s,3H),2.12(s,3H),2.09(s,3H),2.02(s,6H),2.01(s,3H),1.98(s,3H),1.66(s,3H),1.51(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ175.9,175.0,170.4,170.1,169.7,169.6,169.5,169.2,169.1,168.9,148.2,135.0,133.7,133.3,131.9,118.3,111.8,111.5,100.7,99.0,76.3,73.7,72.9,72.7,72.6,71.9,71.6,71.5,67.8,61.6,61.5,34.2,25.6,20.8,20.7,20.6,20.5,17.9ppm;
实施例8
1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6,2’,3’,4’,6’-七-O-乙酰基-β-乳糖
操作同实施例1,只是把葡萄糖换成乳糖,得到具体如下结构的标题化合物。
1H NMR(400MHz,CDCl3):δ12.57(s,1H),12.42(s,1H),7.15(m,3H),5.57(d,J=5.2Hz,1H),5.45(m,1H),5.34(d,J=2.8Hz,1H),5.14(m,2H),5.06(dd,J=3.6,7.6Hz,1H),4.96(dd,J=3.6,10.4Hz,1H),4.56(d,J=8Hz,1H),4.26(dd,J=2.4,4.4Hz,1H),4.20(dd,J=2.0,12.0Hz,1H),4.07(m,3H),3.90(t,J=6.8Hz,1H),3.77(m,1H),3.60(d,J=9.6Hz,1H),2.36(m,1H),2.29(m,1H),2.15(s,3H),2.14(s,3H),2.08(s,3H),2.07(s,3H),2.02(s,3H),2.00(s,3H),1.94(s,3H),1.66(s,3H),1.58(s,3H),1.55(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ177.5,175.9,170.6,170.3,170.2,170.0,169.3,168.9,168.4,167.8,150.7,135.1,133.2,132.8,132.0,121.6,119.2,111.8,111.6,102.4,96.9,77.4,73.2,70.9,70.8,69.8,68.8,68.5,67.1,66.7,63.4,60.9,35.3,29.6,25.7,21.6,20.8,20.7,20.6,20.6,20.5,17.9ppm;
实施例9
1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,5-三-O-乙酰基-β-D-呋喃核糖
将1.50g(10mmol)核糖和1.07g(13mmol)无水醋酸钠加入到单口烧瓶中,加入9.4mL(100mmol)醋酸酐,反应温度控制在80~90℃,反应时间约4小时,反应过程用TLC跟踪。反应完成后冷却到室温,反应液倒入到冰冷的饱和碳酸氢钠溶液中中和剩余的醋酸酐,继续搅拌1.5小时后加入适宜的萃取剂萃取,如二氯甲烷等,然后分离并通过柱层析纯化,得到3.09g(收率97.2%)1,2,3,5-四-O-乙酰核糖。
将1.59g(5mmol)四乙酰核糖溶于20mL四氢呋喃,加入0.27g(5mmol)甲醇钠在冰浴下搅拌30分钟,过程用TLC跟踪。反应结束后加入0.32g(5.3mmol)乙酸,减压蒸除四氢呋喃,加入40mL二氯甲烷溶解,水洗两次,干燥并旋干得到1.12g(收率81.2%)2,3,5-三-O-乙酰核糖。将0.83g(3mmol)2,3,5-三-O-乙酰核糖溶于40mL无水二氯甲烷,并加入2.07g(15mmol)碳酸钾和1.2mL(12mmol)三氯乙腈,室温下搅拌过夜。反应结束后过滤,滤液旋干,经柱层析分离得到0.76g(收率60.2%)2,3,5-三-O-乙酰基-α-D-呋喃核糖三氯乙酰亚胺酯。
在氮气保护下,往0.576g(2mmol)紫草素和0.421g(1mmol)2,3,5-三-O-乙酰基-α-D-呋喃核糖三氯乙酰亚胺酯中加入20mL无水二氯甲烷,而后加入0.1g新活化的分子筛,在-20℃下滴加入溶于5mL二氯甲烷的0.0141g(0.1mmol)三氟化硼乙醚溶液,约30分钟滴加完毕,继续在此温度下反应1小时,反应过程用TLC跟踪。反应结束后加入0.1g(1mmol)三乙胺中和反应体系中剩余的三氟化硼,而后用0.06g(1mmol)乙酸使溶液由深蓝色变为红色。然后过滤,滤液旋干,柱层析分离得到0.42g(77%)标题化合物。
1H NMR(400MHz,CDCl3):δ12.59(s,1H),12.47(s,1H),7.19(m,2H),7.15(m,1H),5.44(t,J=3.2Hz,1H),5.13(m,1H),5.08(m,1H),5.05(m,1H),4.99(m,2H),3.81(dd,J=3.2,12.4Hz,1H),3.66(dd,J=5.6,12.4Hz,1H),2.53(m,1H),2.41(m,1H),2.12(s,3H),2.09(s,3H),2.07(s,3H),1.68(s,3H),1.57(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ179.2,177.8,169.8,169.7,169.5,166.5,166.0,149.5,135.8,132.7,132.6,132.2,117.9,111.8,111.5,98.5,74.0,68.4,66.5,66.4,61.6,33.5,25.7,20.8,20.8,20.7,18.0ppm;
实施例10
1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,5-三-O-乙酰基-β-D-呋喃阿拉伯糖
操作同实施例9,只是把核糖换成D-阿拉伯糖,得到具体如下结构的标题化合物。
1H NMR(400MHz,CDCl3):δ12.59(s,1H),12.43(s,1H),7.17(m,2H),7.04(s,1H),5.24(m,2H),5.16(m,2H),5.01(dd,J=3.2,8.8Hz,1H),4.35(d,J=6.4Hz,1H),4.04(dd,J=3.6,12.8Hz,1H),3.58(dd,J=1.6,12.8Hz,1H),2.57(m,1H),2.46(m,1H),2.16(s,3H),2.13(s,3H),2.03(s,3H),1.66(s,3H),1.50(s,3H)ppm;13C NMR(100MHz,CDCl3):δ176.4,175.6,170.3,170.0,169.4,169.1,168.6,148.3,135.2,133.5,133.1,132.1,118.1,111.8,111.5,98.9,72.9,70.0,69.3,67.3,62.8,34.3,25.7,21.0,20.8,20.6,18.0ppm;
实施例11
1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,5-三-O-乙酰基-β-L-呋喃阿拉伯糖
操作同实施例9,只是把核糖换成L-阿拉伯糖,得到具体如下结构的标题化合物。
1H NMR(400MHz,CDCl3):δ12.57(s,1H),12.50(s,1H),7.25(s,1H),7.19(m,2H),5.22(m,2H),5.12(t,J=6.8Hz,1H),5.09(dd,J=3.6,8.8Hz,1H),4.97(dd,J=4,5.6Hz,1H),4.61(d,J=6.4Hz,1H),3.86(dd,J=3.6,12.8Hz,1H),3.52(d,J=12.8Hz,1H),2.53(m,1H),2.36(m,1H),2.13(s,3H),2.10(s,3H),2.07(s,3H),1.68(s,3H),1.55(s,3H)ppm;
13C NMR(100MHz,CDCl3):δ180.5,179.1,170.3,170.1,169.3,165.4,164.9,150.0,135.4,133.4,132.2,131.8,118.1,111.8,111.6,100.5,74.6,69.8,69.2,67.2,62.7,33.5,25.8,20.9,20.8,20.7,18.0ppm;
Claims (4)
2.根据权利要求1所述的一种紫草素乙酰糖,,其特征在于所述的紫草素乙酰糖为:
5(a)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖、
5(b)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6-四-O-乙酰基-β-D-吡喃甘露糖、
5(c)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6-四-O-乙酰基-β-D-吡喃半乳糖、
5(d)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4-三-O-乙酰基-β-L-吡喃鼠李糖、
5(e)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4-三-O-乙酰基-β-D-吡喃木糖、
5(f)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,5-三-O-乙酰基-β-D-呋喃核糖、
5(g)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,5-三-O-乙酰基-β-D-呋喃阿拉伯糖、
5(h)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,5-三-O-乙酰基-β-L-呋喃阿拉伯糖、
5(i)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6,2’,3’,4’,6’-七-O-乙酰基-β-麦芽糖、
5(j)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6,2’,3’,4’,6’-七-O-乙酰基-β-纤维二糖或
5(k)1-(1-(5,8-二羟基-1,4-萘醌-2-基)-4-甲基-3-戊基)-2,3,4,6,2’,3’,4’,6’-七-O-乙酰基-β-乳糖。
4.根据权利要求3所述的一种紫草素乙酰糖的用途,其特征在于用于具有抗肿瘤活性以及耐药性的药物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 200910152938 CN101671376B (zh) | 2009-09-21 | 2009-09-21 | 紫草素乙酰糖及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 200910152938 CN101671376B (zh) | 2009-09-21 | 2009-09-21 | 紫草素乙酰糖及其制备方法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101671376A true CN101671376A (zh) | 2010-03-17 |
CN101671376B CN101671376B (zh) | 2013-04-17 |
Family
ID=42018818
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 200910152938 Expired - Fee Related CN101671376B (zh) | 2009-09-21 | 2009-09-21 | 紫草素乙酰糖及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101671376B (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102552296A (zh) * | 2010-12-30 | 2012-07-11 | 浙江大学 | 紫草素糖苷在制备丙酮酸激酶抑制剂中的应用 |
WO2016063896A1 (ja) * | 2014-10-21 | 2016-04-28 | サントリーホールディングス株式会社 | アスコルビン酸誘導体及びこの誘導体を用いた配糖体の製造方法 |
CN111925347A (zh) * | 2020-07-17 | 2020-11-13 | 江西中医药大学 | 从灰枝紫菀中分离的新二萜苷类化合物、制备及其保肝用途 |
CN113149973A (zh) * | 2021-04-26 | 2021-07-23 | 珠海润都制药股份有限公司 | 一种恩格列净的合成方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1283238C (zh) * | 2004-05-18 | 2006-11-08 | 浙江大学 | 紫草素在制备治疗肿瘤疾病药物中的用途 |
CN101392010B (zh) * | 2008-11-04 | 2011-05-04 | 南京大学 | 紫草宁糖类衍生物及其合成方法和应用 |
-
2009
- 2009-09-21 CN CN 200910152938 patent/CN101671376B/zh not_active Expired - Fee Related
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102552296A (zh) * | 2010-12-30 | 2012-07-11 | 浙江大学 | 紫草素糖苷在制备丙酮酸激酶抑制剂中的应用 |
WO2016063896A1 (ja) * | 2014-10-21 | 2016-04-28 | サントリーホールディングス株式会社 | アスコルビン酸誘導体及びこの誘導体を用いた配糖体の製造方法 |
CN106795129A (zh) * | 2014-10-21 | 2017-05-31 | 三得利控股株式会社 | 抗坏血酸衍生物及使用了该衍生物的糖苷的制造方法 |
JPWO2016063896A1 (ja) * | 2014-10-21 | 2017-08-03 | サントリーホールディングス株式会社 | アスコルビン酸誘導体及びこの誘導体を用いた配糖体の製造方法 |
CN111925347A (zh) * | 2020-07-17 | 2020-11-13 | 江西中医药大学 | 从灰枝紫菀中分离的新二萜苷类化合物、制备及其保肝用途 |
CN113149973A (zh) * | 2021-04-26 | 2021-07-23 | 珠海润都制药股份有限公司 | 一种恩格列净的合成方法 |
Also Published As
Publication number | Publication date |
---|---|
CN101671376B (zh) | 2013-04-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8785405B2 (en) | Compounds for treating cancer and other diseases | |
EP2933250B1 (en) | Phenyl c-glucoside derivative containing deoxyglucose structure, preparation method and use thereof | |
CN102126934B (zh) | 对三联苯衍生物及其在制备抗肿瘤药物中的应用 | |
WO2007082475A1 (fr) | Nouveau composé diterpène ent-kaurène et ses dérivés, leur préparation et leur utilisation | |
CN101671376B (zh) | 紫草素乙酰糖及其制备方法和用途 | |
Xue-Jian et al. | Synthesis and hypoglycemic activity of esterified-derivatives of mangiferin | |
Lei et al. | Synthesis and anti-tumor activity of 14-O-derivatives of natural oridonin | |
CN115650980A (zh) | 一种氧化吲哚类化合物及其制备方法和应用 | |
CN107286207B (zh) | 一种龙胆二糖的合成方法 | |
Li et al. | Multi-gram scale synthesis of a bleomycin (BLM) carbohydrate moiety: exploring the antitumor beneficial effect of BLM disaccharide attached to 10-hydroxycamptothecine (10-HCPT) | |
CN105461681A (zh) | 具有抗肿瘤活性的krn7000类似物及合成方法 | |
CN102391352B (zh) | 救必应酸氨基酸衍生物及其在制备抗肿瘤的药物中的应用 | |
CN108610386B (zh) | 一种取代苄基或取代苯基β-D-己糖醛酸糖苷的制备方法 | |
Zhang et al. | Synthesis and antiviral evaluation of 6′-acylamido-6′-deoxy-α-d-mannoglycerolipids | |
CN111848537B (zh) | 一种绿原酸衍生物的合成方法及抗菌活性测定方法 | |
TWI378939B (en) | Bifunctional compound with monomeric sugars and n2s2 ligands, method for preparing and the use thereof | |
CN101671278B (zh) | 氨基甲酸紫草素酯及其制备方法和用途 | |
CN103374049A (zh) | 一种制备5,6,4’-三羟基黄酮-7-0-d-葡萄糖醛酸的方法 | |
Zhang et al. | Synthesis of 2-amino-2-deoxy-β-glycosyl-(1→ 5)-nucleosides and the interaction with RNA | |
CN109206389B (zh) | 异土木香内酯衍生物,其药物组合物及其用途 | |
ES2646628A2 (es) | Molécula de azúcar activa farmacéuticamente y su método de síntesis | |
Kumar et al. | Chemo-enzymatic route to bridged homolyxofuranosyl-pyrimidines | |
CN104098524A (zh) | 1-间甲氧基苯甲酰基-3-苯基-1,4-二氢-1,2,4,5-四嗪及制备和应用 | |
CN110003291B (zh) | 一种氟代糖基修饰的紫杉醇类化合物及其合成方法和应用 | |
CN102424696A (zh) | 紫草素氨基去氧糖苷类化合物及其在制备抗肿瘤药物中的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130417 Termination date: 20170921 |