抗肿瘤甾体皂苷的合成和构效关系研究
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摘要
为了对甾体皂苷,特别是呋甾烷皂苷和胆甾烷皂苷类化合物进行构效关系研究,本文以天然呋甾烷皂苷icogenin和胆甾烷皂苷OSW-1为先导化合物,设计合成了一系列天然产物的衍生物。本论文所涉及的工作共分为以下三部分:
一、Icogenin衍生物的设计合成
为了研究天然产物icogenin中3位糖链部分结构的变化对抗肿瘤细胞毒活性的影响,我们用鼠李二糖代替原来的三糖侧链,设计合成了一对二糖端基差向异构的icogenin衍生物,并对它们的抗肿瘤细胞毒活性进行了研究,通过与icogenin和一些典型的天然甾体皂苷化合物的细胞毒活性比较,进一步揭示了这一类化合物的细胞毒活性机理。
二、胆甾烷皂苷衍生物和呋甾烷皂苷衍生物的合成
以天然薯蓣皂苷元(diosgenin)为起始原料,采用一条非常简捷的合成路线,得到了三个胆甾烷皂苷衍生物。采用另外一条路线,得到了三个22位连单糖及二糖的呋甾烷皂苷衍生物。这一部分中得到的三个胆甾烷皂苷衍生物和三个22位连糖的呋甾烷皂苷衍生物的化学结构均通过~1H-NMR,~(13)C-NMR和LC-HRMS进行了结构确证。
三、15位羟基胆甾烷苷元的合成路线探索
同样以天然薯蓣皂苷元diosgenin为起始原料,对15位羟基胆甾烷苷元的合成路线进行了摸索,结果发现diosgenin中5,6-双键结构的存在使反应复杂化,因此设计用缺少5,6-双键的tigogenin代替diosgenin,采用相同的路线再进行合成。
For further structure-activity relationships(SAR) research of steroidal saponins, especially furostan and cholestan saponins,we used natural products icogenin and OSW-1 as the lead compounds,designed and synthesized a series of derivatives of natural products.All of the work in this paper can be divided into three parts:
1.The design and synthesis of icogenin derivatives
In order to study the role and contribution of the trisaccharide residue in icogenin,we employed the simplified disaccharide[α-L-Rhap-(1-2)-β-D-Glcp]and[α-L-Rhap-(1-2 )-α-D-Glcp]replacing the trisaccharide moiety of icogenin,synthesized a pair of epimeric icogenin derivatives.Through the cytotoxic activities research of these two derivatives,and activity comparison to icogenin and three typical steroidal saponins,we made progress in the research of cytotoxicity mechanism of these compounds.
2.The synthesis of cholestan saponin derivatives and furostan saponin derivatives Using natural product diosgenin as raw material,three cholestan derivatives were synthesized via a concise and efficient route.When another synthetic route was tried, three furostan derivatives were gotten.All of the chemical structure of the six compounds in this part were confirmed by ~1H-NMR,~(13)C-NMR and LC-HRMS.
3.The research for synthesis route of 15-hydroxy cholestan aglycone
When diosgenin was used to synthesize the target 15-hydroxy cholestan aglycone,5, 6-double bond in diosgenin caused great trouble.To avoid the affection of 5,6-double bond,we try to use tigogenin,which is lack of 5,6-double bond,to replace disogenin following the same synthetic route.
一、Icogenin衍生物的设计合成
为了研究天然产物icogenin中3位糖链部分结构的变化对抗肿瘤细胞毒活性的影响,我们用鼠李二糖代替原来的三糖侧链,设计合成了一对二糖端基差向异构的icogenin衍生物,并对它们的抗肿瘤细胞毒活性进行了研究,通过与icogenin和一些典型的天然甾体皂苷化合物的细胞毒活性比较,进一步揭示了这一类化合物的细胞毒活性机理。
二、胆甾烷皂苷衍生物和呋甾烷皂苷衍生物的合成
以天然薯蓣皂苷元(diosgenin)为起始原料,采用一条非常简捷的合成路线,得到了三个胆甾烷皂苷衍生物。采用另外一条路线,得到了三个22位连单糖及二糖的呋甾烷皂苷衍生物。这一部分中得到的三个胆甾烷皂苷衍生物和三个22位连糖的呋甾烷皂苷衍生物的化学结构均通过~1H-NMR,~(13)C-NMR和LC-HRMS进行了结构确证。
三、15位羟基胆甾烷苷元的合成路线探索
同样以天然薯蓣皂苷元diosgenin为起始原料,对15位羟基胆甾烷苷元的合成路线进行了摸索,结果发现diosgenin中5,6-双键结构的存在使反应复杂化,因此设计用缺少5,6-双键的tigogenin代替diosgenin,采用相同的路线再进行合成。
For further structure-activity relationships(SAR) research of steroidal saponins, especially furostan and cholestan saponins,we used natural products icogenin and OSW-1 as the lead compounds,designed and synthesized a series of derivatives of natural products.All of the work in this paper can be divided into three parts:
1.The design and synthesis of icogenin derivatives
In order to study the role and contribution of the trisaccharide residue in icogenin,we employed the simplified disaccharide[α-L-Rhap-(1-2)-β-D-Glcp]and[α-L-Rhap-(1-2 )-α-D-Glcp]replacing the trisaccharide moiety of icogenin,synthesized a pair of epimeric icogenin derivatives.Through the cytotoxic activities research of these two derivatives,and activity comparison to icogenin and three typical steroidal saponins,we made progress in the research of cytotoxicity mechanism of these compounds.
2.The synthesis of cholestan saponin derivatives and furostan saponin derivatives Using natural product diosgenin as raw material,three cholestan derivatives were synthesized via a concise and efficient route.When another synthetic route was tried, three furostan derivatives were gotten.All of the chemical structure of the six compounds in this part were confirmed by ~1H-NMR,~(13)C-NMR and LC-HRMS.
3.The research for synthesis route of 15-hydroxy cholestan aglycone
When diosgenin was used to synthesize the target 15-hydroxy cholestan aglycone,5, 6-double bond in diosgenin caused great trouble.To avoid the affection of 5,6-double bond,we try to use tigogenin,which is lack of 5,6-double bond,to replace disogenin following the same synthetic route.
引文
1.Tsuyoshi I;Hidetsugu T;Toshihiro N.Steroidal Oligoglycosides from Solanum nigrum.Chem.Pharm.Bull.2000,48(7),1062-1064.
2.Shen-xiang Q;Xing-cong L;Yan-san X;et al.Isolation and Characterization of Cytotoxic Saponin Chloromaloside A from Chlorophytum malayense.Planta Med.2000,66(6),587-590.
3.徐暾海,徐雅娟,刘大有等.虎眼万年青的化学成分[J].药学学报,2000,35(1):32-36.
4.Akihito Y;Yoshihiro M;Yutaka.Steroidal saponins from Dracaena surculosa.J Nat Prod.2000,63,1239-1243.
5.Yi-Xin X;Hai-Sheng;Hua-Qing L;et al.Three new saponins from Tribulus terrestris.Planta Med.2000,66(6),545-550.
6.Akihito Y;Yoshihiro M;Minpei K;et al.A new steroidal saponin from the leaves of Agave americana.Planta Med.2000,66(4),393-396.
7.Vincken J.P;Heng L;De Groot A;et al.Saponins,classification and ovvurrence in the plant kingdom.Phytochemistry.2007,68(3),275-297.
8.Chang,L.C.;Tsai,T.R.;Wang,J.J.;et al.Biochem.Biophys.Res.Commun.1998,242,21.
9.Popovich,D.G.;Kitts,D.D.Arch.Biochem.Biophys.2002,406,1.
10.Liang,C.H.;Liu,L.F.;Shiu,L.Y.;et al.Biochem.Biophys.Res.Commun.2004,322,751.
11.Hernadez,J.C.;leon,F.;Quintana,J.;et al.Bioorg.Med.Chem.2004,12,4423.
12.Haddad,M.;Laurens,V.;Lacaille-Dubois,M.A.Bioorg.Med.Chem.2004,12,4725.
13.Becker,E.B.;Bonni,A.Prog.Neurobiol.2004,72,1.
14.Yu,J.;Zhang,L.Curr.Opin.Oncol.2004,16,19.
15.Trouillas,P.;Corbiere,C.;Liagre,B.;Duroux,J.L.;Beneytout,J.L.Bioorg.Med.Chem.2005,13,1141-1149.
16.Hernandez,J.C.;Franciso,L.;Brouard,I.;Torres,F.;Rubio,S.;Quintana,J.;Esterez,F.;Bermejo,J.Bioorg.Med.Chem.2008,16,2063-2076.
17.a).Marker,R.E.;Wagner,R.B.;Ulshafer,P.R.;Wittbecker,E.L.;Goldsmith,D.P.J.;Ruof,C.H.J.Am.Chem.Soc.1947,69,2167.
b).Marker,R.E.;Lopez,J.J.Am.Chem.Soc.1947,69,2389.
18. Schreiber, K.; Ripperger, H. Tetrahedron Lett. 1966, 5997.
19. Kawasaki, T.; Komori, T.; Miyahara, K.; Nohara, T.; Hosokawa, I.; Mihashi, K. Chem. Pharm. Bull. 1974, 22, 2164-2175.
20. Hu, K.; Yao, X. S.; Kobayashi, H.; Iwasaki, S. Planta. Med. 1996, 62, 573.
21. Hou, S. J.; Xu, P.; Liang, Z.; Yu, D. Q.; Lei, P. S. Bioorg. Med. Chem. Lett. 2006, 16, 2454-2458.
22. Kobayashi, M.; Kanda, F.; Damarla, S. R.; Rao, D. V.; Rao, C. B. Chem. Pharm. Bull. 1990, 38(9), 2400-2403.
23. Kawashima, K.; Mimaki, Y.; Sashida, Y. Chem. Pharm. Bull. 1991, 39(10), 2761-2763.
24. Kubo, S.; Mimaki, Y.; Terao, M.; Sashida, Y.; Nikaida, T.; Ohmoto, T. Phytochemistry. 1992,31,3969.
25. Guo C.; Fuchs P. L. Tetrahedron Lett. 1998, 39, 1099-1102.
26. Mimaki, Y.; Kuroda, M.; Kameyama, A.; Sashida, Y.; Hirano, T.; Oka, K.; Maekawa, R.; Wada, T.; Sugita, K.; Beutler, J. A. Bioorg. & Med. Chem. Lett. 1997, 7, 633.
27. (a). Jeong, J. U.; Sutton, S.; Kim, S.; Fuchs, P. L. J. Am. Chem. Soc. 1995, 117, 10157; (b). Drogemuller, M.; Jautelat, R.; Winterfeldt, E. Angew. Chem. Int. Ed. Engl.1996, 35, 1572;(c). Guo, C.; Bhandaru, S.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118, 10672.
28. Muller, IM.; Dirsch,VM.; Rudy, A. Molecular Pharmacology. 2005, 67(5), 1684.
29. Zhou, Y.; Garcia-Prieto, C.; Carney, D. A. et al. J Nat Cancer Inst. 2005, 97, 1781-1785.
30. Mimaki, Y.; Kuroda, M.; Sashida, Y.; Yamori, T.; Tsuruo, T. Helv. Chim. Acta. 2000, 83, 2698.
31. Mimaki, Y.; Yokosuka, A.; Sahida, Y et al. Cytotoxic activities and structure-cytotoxic relationships of steroidal saponin. Biol Pharm Bull. 2001, 24(11), 1286-1289.
32. Li, M.; Han, X.; Yu, B. Synthesis of monoethylated dioscin derivatives and their antitumor activities. Carbohydr Res. 2003, 338(2), 117-121.
33. Kashiw, M. J.; Tassotto, M. L.; Th'ng, J.; Jiang, Z. H. Bioorg. & Med. Chem. 2008, 16,3209-3217.
34. Biao, Y.; Jianchun L.; Jianbo, Z.; Yongzheng, H. Tetrahedron Lett. 2001, 42, 77-79.
35. Cheng, M. S.; Wang, Q. L.; Tian Q. J. Org. Chem. 2003, 68, 3658-3662.
36. Hou, S. J.; X u, P.; Liang, Z.; Yu, D. Q.; Lei, P. S.; Zou, C. C. Chin. Chem. Lett. 2006, 17(2), 183-186.
37.Hou,S.J.;Xu,P.;Liang,Z.;Yu,D.Q.;Lei,P.S.Bioorg.Med.Chem.Lett.2006,16,2454-2458.
38.Deng,S.J.;Yu,B.;Lou,Y.;Hui,Y.Z.J.Org.Chem.1999,64,202-208.
39.Xu,Q.H.;Peng,X.W.;Tian,W.S.Tetrahedron Lett.2003,44,9375-9377.
40.Deng,L.H.;Wu,H.;Yu,B.;Jiang,M.R.;Wu,J.R.Bioorg.& Med.Chem.2004,14,2781-2785.
41.Shi,B.F.;Tang,P.P.;Hu,X.Y.;Liu,J.O.;Yu,B.J.Org.Chem.2005,70,10354-10367
42.(a).Watanabe,Y.;Sanada,S.;Tada,A.;Shoji,J.Chem.Pharm.Bull.,1977,25,3049-3055;
(b).Huffod,C.D.;Liu,S.;Clark,A.M.J.Nat.Prod.1988,51,94-98;
(c).Cai,J.;Liu,M.;Wang,Z.;Ju,Y.Biol.Pharm.Bull.,2002,25(2),193-196.
43.Mimaki,Y.;Yokosuka,A.;Kuroda,M.;Sashida,Y.Biol.Pharm.Bul.2001,24,1286-1289.
44.Kaufmann,S.;Rosenkranz,G.J.Am.Chem.Soc.1948,70,3502-3504.
45.Deng,S.J.;Yu,B.;Hui,Y.Z.;Yu,H.;Han,X.W.Carbohydr.Res.1999,317,53-62.
46.Tschesche,R.;Pandey,V.B.Phytochemistry.1978,17,1781-1782.
47.Mimaki,Y.;Takaashi,Y.;Kuroda,M.;Sashida,Y.;Nikaido,T.Phytochemistry.1996,42,1609-1615.
48.Wojtkielewicz,A.;Dlugosz,M.;Maj,J.et al.J.Med.Chem.2007,50,3667-3673.
49.Dale,J.A.;Mosher,H.S.J.Am.Chem.Soc.1973,95,512.
50.Ohtani,I.;Kusumi T.;Ishitsuka,M.O.;Kakisawa,H.Tetrahedron Lett.1989,30,3147.
51.Takaashi,Y.;Mimaki,Y.;Kameyama,A.et al.Chem.Pharm.Bull.1995,43(7),1180-1185.
52.Amann,A.;Qurisson,G.;Luu,B.Synthesis Communications.1987,1002-1005.
53.Williams,J.R.;Gong,H.;Hoff,N.;Olubodun,O.I.;Carroll,P.J.Organic Letters.2004,6(2),269-271.
2.Shen-xiang Q;Xing-cong L;Yan-san X;et al.Isolation and Characterization of Cytotoxic Saponin Chloromaloside A from Chlorophytum malayense.Planta Med.2000,66(6),587-590.
3.徐暾海,徐雅娟,刘大有等.虎眼万年青的化学成分[J].药学学报,2000,35(1):32-36.
4.Akihito Y;Yoshihiro M;Yutaka.Steroidal saponins from Dracaena surculosa.J Nat Prod.2000,63,1239-1243.
5.Yi-Xin X;Hai-Sheng;Hua-Qing L;et al.Three new saponins from Tribulus terrestris.Planta Med.2000,66(6),545-550.
6.Akihito Y;Yoshihiro M;Minpei K;et al.A new steroidal saponin from the leaves of Agave americana.Planta Med.2000,66(4),393-396.
7.Vincken J.P;Heng L;De Groot A;et al.Saponins,classification and ovvurrence in the plant kingdom.Phytochemistry.2007,68(3),275-297.
8.Chang,L.C.;Tsai,T.R.;Wang,J.J.;et al.Biochem.Biophys.Res.Commun.1998,242,21.
9.Popovich,D.G.;Kitts,D.D.Arch.Biochem.Biophys.2002,406,1.
10.Liang,C.H.;Liu,L.F.;Shiu,L.Y.;et al.Biochem.Biophys.Res.Commun.2004,322,751.
11.Hernadez,J.C.;leon,F.;Quintana,J.;et al.Bioorg.Med.Chem.2004,12,4423.
12.Haddad,M.;Laurens,V.;Lacaille-Dubois,M.A.Bioorg.Med.Chem.2004,12,4725.
13.Becker,E.B.;Bonni,A.Prog.Neurobiol.2004,72,1.
14.Yu,J.;Zhang,L.Curr.Opin.Oncol.2004,16,19.
15.Trouillas,P.;Corbiere,C.;Liagre,B.;Duroux,J.L.;Beneytout,J.L.Bioorg.Med.Chem.2005,13,1141-1149.
16.Hernandez,J.C.;Franciso,L.;Brouard,I.;Torres,F.;Rubio,S.;Quintana,J.;Esterez,F.;Bermejo,J.Bioorg.Med.Chem.2008,16,2063-2076.
17.a).Marker,R.E.;Wagner,R.B.;Ulshafer,P.R.;Wittbecker,E.L.;Goldsmith,D.P.J.;Ruof,C.H.J.Am.Chem.Soc.1947,69,2167.
b).Marker,R.E.;Lopez,J.J.Am.Chem.Soc.1947,69,2389.
18. Schreiber, K.; Ripperger, H. Tetrahedron Lett. 1966, 5997.
19. Kawasaki, T.; Komori, T.; Miyahara, K.; Nohara, T.; Hosokawa, I.; Mihashi, K. Chem. Pharm. Bull. 1974, 22, 2164-2175.
20. Hu, K.; Yao, X. S.; Kobayashi, H.; Iwasaki, S. Planta. Med. 1996, 62, 573.
21. Hou, S. J.; Xu, P.; Liang, Z.; Yu, D. Q.; Lei, P. S. Bioorg. Med. Chem. Lett. 2006, 16, 2454-2458.
22. Kobayashi, M.; Kanda, F.; Damarla, S. R.; Rao, D. V.; Rao, C. B. Chem. Pharm. Bull. 1990, 38(9), 2400-2403.
23. Kawashima, K.; Mimaki, Y.; Sashida, Y. Chem. Pharm. Bull. 1991, 39(10), 2761-2763.
24. Kubo, S.; Mimaki, Y.; Terao, M.; Sashida, Y.; Nikaida, T.; Ohmoto, T. Phytochemistry. 1992,31,3969.
25. Guo C.; Fuchs P. L. Tetrahedron Lett. 1998, 39, 1099-1102.
26. Mimaki, Y.; Kuroda, M.; Kameyama, A.; Sashida, Y.; Hirano, T.; Oka, K.; Maekawa, R.; Wada, T.; Sugita, K.; Beutler, J. A. Bioorg. & Med. Chem. Lett. 1997, 7, 633.
27. (a). Jeong, J. U.; Sutton, S.; Kim, S.; Fuchs, P. L. J. Am. Chem. Soc. 1995, 117, 10157; (b). Drogemuller, M.; Jautelat, R.; Winterfeldt, E. Angew. Chem. Int. Ed. Engl.1996, 35, 1572;(c). Guo, C.; Bhandaru, S.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118, 10672.
28. Muller, IM.; Dirsch,VM.; Rudy, A. Molecular Pharmacology. 2005, 67(5), 1684.
29. Zhou, Y.; Garcia-Prieto, C.; Carney, D. A. et al. J Nat Cancer Inst. 2005, 97, 1781-1785.
30. Mimaki, Y.; Kuroda, M.; Sashida, Y.; Yamori, T.; Tsuruo, T. Helv. Chim. Acta. 2000, 83, 2698.
31. Mimaki, Y.; Yokosuka, A.; Sahida, Y et al. Cytotoxic activities and structure-cytotoxic relationships of steroidal saponin. Biol Pharm Bull. 2001, 24(11), 1286-1289.
32. Li, M.; Han, X.; Yu, B. Synthesis of monoethylated dioscin derivatives and their antitumor activities. Carbohydr Res. 2003, 338(2), 117-121.
33. Kashiw, M. J.; Tassotto, M. L.; Th'ng, J.; Jiang, Z. H. Bioorg. & Med. Chem. 2008, 16,3209-3217.
34. Biao, Y.; Jianchun L.; Jianbo, Z.; Yongzheng, H. Tetrahedron Lett. 2001, 42, 77-79.
35. Cheng, M. S.; Wang, Q. L.; Tian Q. J. Org. Chem. 2003, 68, 3658-3662.
36. Hou, S. J.; X u, P.; Liang, Z.; Yu, D. Q.; Lei, P. S.; Zou, C. C. Chin. Chem. Lett. 2006, 17(2), 183-186.
37.Hou,S.J.;Xu,P.;Liang,Z.;Yu,D.Q.;Lei,P.S.Bioorg.Med.Chem.Lett.2006,16,2454-2458.
38.Deng,S.J.;Yu,B.;Lou,Y.;Hui,Y.Z.J.Org.Chem.1999,64,202-208.
39.Xu,Q.H.;Peng,X.W.;Tian,W.S.Tetrahedron Lett.2003,44,9375-9377.
40.Deng,L.H.;Wu,H.;Yu,B.;Jiang,M.R.;Wu,J.R.Bioorg.& Med.Chem.2004,14,2781-2785.
41.Shi,B.F.;Tang,P.P.;Hu,X.Y.;Liu,J.O.;Yu,B.J.Org.Chem.2005,70,10354-10367
42.(a).Watanabe,Y.;Sanada,S.;Tada,A.;Shoji,J.Chem.Pharm.Bull.,1977,25,3049-3055;
(b).Huffod,C.D.;Liu,S.;Clark,A.M.J.Nat.Prod.1988,51,94-98;
(c).Cai,J.;Liu,M.;Wang,Z.;Ju,Y.Biol.Pharm.Bull.,2002,25(2),193-196.
43.Mimaki,Y.;Yokosuka,A.;Kuroda,M.;Sashida,Y.Biol.Pharm.Bul.2001,24,1286-1289.
44.Kaufmann,S.;Rosenkranz,G.J.Am.Chem.Soc.1948,70,3502-3504.
45.Deng,S.J.;Yu,B.;Hui,Y.Z.;Yu,H.;Han,X.W.Carbohydr.Res.1999,317,53-62.
46.Tschesche,R.;Pandey,V.B.Phytochemistry.1978,17,1781-1782.
47.Mimaki,Y.;Takaashi,Y.;Kuroda,M.;Sashida,Y.;Nikaido,T.Phytochemistry.1996,42,1609-1615.
48.Wojtkielewicz,A.;Dlugosz,M.;Maj,J.et al.J.Med.Chem.2007,50,3667-3673.
49.Dale,J.A.;Mosher,H.S.J.Am.Chem.Soc.1973,95,512.
50.Ohtani,I.;Kusumi T.;Ishitsuka,M.O.;Kakisawa,H.Tetrahedron Lett.1989,30,3147.
51.Takaashi,Y.;Mimaki,Y.;Kameyama,A.et al.Chem.Pharm.Bull.1995,43(7),1180-1185.
52.Amann,A.;Qurisson,G.;Luu,B.Synthesis Communications.1987,1002-1005.
53.Williams,J.R.;Gong,H.;Hoff,N.;Olubodun,O.I.;Carroll,P.J.Organic Letters.2004,6(2),269-271.