紫杉烷类化合物SINENXAN A的化学及结构修饰
摘要
SIA为我所生物合成法得到的新紫杉烷化合物。为了寻找具有细胞毒性的新型taxol类似物，对SIA进行了结构修饰。
本文经过6步反应(SIA→SI—21—5→SIS—09→SIS—12→SIS—26→SIS—45→SIS—53)完成了SIA分子中引入D环oxetane的工作。通过考察每步反应，提出了一条可望高收率得到目的物SIS—53的方法。
设计合成了10个母核中引入二氧呋喃环，14β—位或10β—位连有taxol／taxotere侧链的化合物，药理初筛显示一定的细胞毒性。并讨论了这类化合物的构效关系。
实验过程中对SIA及其衍生物的性质进行了较详细的号察，总结了反应规律。
以S—α—苯乙胺为手性诱导剂完成了taxol侧链的立体选择性合成。
本文共合成了86个化合物，其中25个已知物，61个为新紫杉烷化合物。
SIA is a new biosynthetic taxane. In order to search for new taxol analogues with cytotoxicity, SIA was studied and modified.A new taxoid with D—ring has been carried out by a reaction sequence of six steps. A more facile synthetic procedure has been put forward by studying and analyzing the features of the reactions involved.A number of new taxoids containing the tetrahydrofuran ring with a exocyclic double bound were esterified at C_(14) or C_(10) positions with taxol/taxotere side chain, preliminary pharmacological tests showed that all the compounds have cytotoxicity on KB, HCF8 cmd A2780. Meanwhile, the relationship between their structures and activity was discussed. The side chains of taxol and taxotere were synthesized stere-oselectively. Eighty—six compounds were synthesizd, sixty—one of which are new taxoids.
本文经过6步反应(SIA→SI—21—5→SIS—09→SIS—12→SIS—26→SIS—45→SIS—53)完成了SIA分子中引入D环oxetane的工作。通过考察每步反应，提出了一条可望高收率得到目的物SIS—53的方法。
设计合成了10个母核中引入二氧呋喃环，14β—位或10β—位连有taxol／taxotere侧链的化合物，药理初筛显示一定的细胞毒性。并讨论了这类化合物的构效关系。
实验过程中对SIA及其衍生物的性质进行了较详细的号察，总结了反应规律。
以S—α—苯乙胺为手性诱导剂完成了taxol侧链的立体选择性合成。
本文共合成了86个化合物，其中25个已知物，61个为新紫杉烷化合物。
SIA is a new biosynthetic taxane. In order to search for new taxol analogues with cytotoxicity, SIA was studied and modified.A new taxoid with D—ring has been carried out by a reaction sequence of six steps. A more facile synthetic procedure has been put forward by studying and analyzing the features of the reactions involved.A number of new taxoids containing the tetrahydrofuran ring with a exocyclic double bound were esterified at C_(14) or C_(10) positions with taxol/taxotere side chain, preliminary pharmacological tests showed that all the compounds have cytotoxicity on KB, HCF8 cmd A2780. Meanwhile, the relationship between their structures and activity was discussed. The side chains of taxol and taxotere were synthesized stere-oselectively. Eighty—six compounds were synthesizd, sixty—one of which are new taxoids.
引文
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2. Schiff P.B., Fant I., Horwitz S.B. et al Nature 1979, 277, 665—667
3. Parness J., Horwitz S. B. J. Cell. Biol 1981, 91, 479—487
4. Science/Technology Communication 1993, 1, 11, 25
5. Kingston D. G. I. Pharmac. Ther. 1991, 52, 1—34
6. Georg G. L, Cheruvallaoth Z. S., Himes R.H. Bioorg Med. Chem. Lett 1992, 2, 295—298
7. Mclaughlin J. L., Miller R. W., Dowell R.G. et al J. Nat. Prod. 1981, 44, 312—319
8. Kinsston D. G. I., Hawkins D.R., Ovington L.J. Nat. Prod 1982, 45, 466—470
9. Ettouati L., Ahond A., Convert O. et al Bull. See. Chem. 1988,4,749—755; 1989, 5, 687—694
10. Vidensek N., Lirn P., Campbell A. et al J. Nat. Prod 1990, 53, 1609—1610
11. Kelsey R.G., Vance N.C.J. Nat. Prod 1992, 55, 912—917
12. Wheeler N. C., Jech K., Masters S. et al J. Nat Prod 1992, 55, 430—440
13. Bormann S. Chem. Eng. News 1992, 70, 30—30
14. Denis J. N., Green A. E., Potier P. et al J. Am. Chem. Soc. 1989, 110, 5917—5919
15. HoltonR. A. CA. 1990, 114, 164568q
16. Science and Technology Communication 1994, 2, 21
17. Nicolaou K. C., Dai WM., Ouy R. K. , Augew. Chem. Int. Ed. Engl 1994, 33, 15—44
18. Blume E. J. Natl Cancer Inst 1991, 83, 1054—1056
19. Stlerle A., Strobel G., Stierle D. Science 1993, 260, 24—26
20. Stone R. Science 1993, 260, 154—155
21, Kitagawa I., Tsujii S., Fujioku H. et al Chem. Pharm. Bull 1984, 32, 1294—1302
22. Magee T.V., Bornmarn W.G.J. Org: Chem. 1992, 57, 3274—3276
23. Wender P. A., Tebbe M.J. Synthesis 1991, 1089—1094
24. Nieolaou K. C., Liu J.J., llwang C.K.J. Chem. Soc. Chem. Commun 1992, 118—1120
25. Holton R. A. et al. J. Am. Chem. Soc. 1984, 106, 5731—5732
26. Winkler J. D. , Hey J. P., Williard P. G. J. Am. Chem. Soc 1986, 108, 6425—6427
27. Nicolaou K.C., Yang. Z. et al Nature 1994, 367, 630
28. Holton R.A. etal J. Am. Chem. Soc. 1994, 116, 1597—1599
29. Kingston, D.G.I. Tibtech 1994, 12, 222—227
30. Deutsch H. M., Glinski J. A., Hernandes M. J. Med. Chem. 1989, 32, 788—792
31. Mathew A. E., Mejfllano R., Stella V.J.J. Med. Chem. 1992, 35, 145—151
32. Nieolaou K. C., Claiborne C. F., Nantermet P.G.J. Am. Chem. Soc. 1994, 116, 1591—1592
33. Denis J.N., Greene A.E., Serra A. et al J. Org. Chem 1986, 51, 40—50
34. Deng L., Jacobsen E.N.J. Org. Chem. 1992, 57, 4320—4323
35. Denis J. N., Gorrea A., Greene A.E.J. Org. Chem 1991, 56, 6939—42
36. Ojima I., Habus I., Zhao. M. et al Tetrahedron 1992, 48, 6985—7012
37. WagleD. R., Garai C., Chiang J. et al J. Org. Chem. 1988, 53, 4227—4236
38. Moore H.W., Hayhes G., Srinivasacha K. J. Org. Chem. 1985, 50, 4231—4238
39. Palomo C., Arrieta A., Cossio F.P. et al Tetrahedron Lett 1990, 31, 6429—6432
40. Cooper R. D. G., Daugherty B. W. Boyd D. B. Pure & Appl. Chem 1987, 59, 485—492
41. Georg G. I., Mashava P. M., Akgun E. et al Tetrahedron Lett 1991, 32, 3151—3154
42. Vogel's Textbook of Practical Organic Chemistry P458
43. Kunz H., Sager W., Pfrcnglc W. et at Tetrahedron Lett 1988, 29, 4397 —4490
44. Bourzat J. D., Commercon A. Tetrahedron Lett 1993, 34, 6044—6052
45. Akashi K. , Palermo R. E., Sharpless K. B. J. Org. Chem. 1978, 43, 2063
46．王东辉，刘瑞武实验未发表
47. Berkowitz W. F., Amarasekara A.S. Tetrahedron Lett 1985, 26, 3663
48. Lin J., Nikaido M., Clark G. J. Org. Chem 1987, 52, 3745—3752
49. Wender P. A., Rawlins B. Tetrahedron 1992, 48, 7033—7048
50. Corey E.J., Venkateswariu J. Am. Chem. Soc. 1972, 94, 6190—91
51. Corey E.J., Snider B.B.J. Am. Chem. Soc. 1972, 94, 2549
52. Newton R. P., Reynolds D.P. Tetrahedron Lett 1971, 3981
53. Corey E.J., Cho H., Riicker C.et al Tetra_hedron Lett 1981, 22, 3455—3458
54. Martin Schroder Chem. Rew. 1980, 80, 187—213
55. Cope A., Fenton S. W., Spencer C.F.J. Am. Chem. Soc. 1952, 74, 5884
56. Milas. N.A., SussmanS., Mason H.S.J. Am. Chem. Soc. 1939, 61, 1844
57. Sharpless K. B., Akashik J. Am. Chem. Soc 1976, 98, 1986
58. Van pheenen V., KeLly R.C. Cha., DY. Tetrahedron Lett 1976, 1973
59. John S. M., IstvanMarko., Shar pless. K.B.J. Am. Chem. Soc. 1989, 111, 1123—1125
60. Rosemhein L., Speiser D., Haim. A. Inorg. Chem. 1974, 13, 1571
61. Marzilli L.G., Hanson B.E., Kistenmacher T. J. Inorg. Chem. 1976, 15, 1661
62. Nielson A.J., Griffith W. P. J. Histochem. Cytochem. 1978, 26, 138
63. Nielson A.J., Griffith W. P. J. Chem. Soc. Dalton Trans, 1978, 1501
64. Sharpless K.B., Akashi K. J. Am. Chem. Soc. 1976, 98, 1986
65. Akashi K., Palermo R. E., Sharpless K. B. J. Org. Chem. 1978, 43, 2063
66. Nicolaou K. C., Christopher F. C., Philippe G. N. J. Am. Chem. Soc. 1994, 116, 1591—1592