半乳凝素-3潜在抑制剂—1-O-烯丙基-4-O-{3-脱氧-3-[4-苄胺羰基-1H-(1,2,3)三氮唑-1-基]-β-D-吡喃半乳糖基}-2-脱氧-2-乙酰氨基-β-D-吡喃葡萄糖的合成

半乳凝素-3潜在抑制剂—1-O-烯丙基-4-O-{3-脱氧-3-[4-苄胺羰基-1H-(1,2,3)三氮唑-1-基]-β-D-吡喃半乳糖基}-2-脱氧-2-乙酰氨基-β-D-吡喃葡萄糖的合成

李晨, 孟祥豹, 金小锋, 李中军, 李庆^*

北京大学药学院; 天然药物及仿生药物国家重点实验室, 北京 100191

收稿日期:2008-04-06 修回日期:2008-08-10 出版日期:2008-09-15 发布日期:2008-09-15
通讯作者: 李庆*

Synthesis of allyl 4-O-{3-deoxy-3-[4-benzylaminocarbonyl-1H-(1,2,3)-triazol-1-yl]-β-D-galactopyranosyl}-2-deoxy-2-acetamido-β-D-glucopyranoside as a potential inhibitor of galectin-3

Chen Li, Xiang-Bao Meng, Xiao-Feng Jin, Zhong-Jun Li, Qing Li^*

The State Key Laboratory of Natural and Biomimetic drugs;
School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

Received:2008-04-06 Revised:2008-08-10 Online:2008-09-15 Published:2008-09-15
Contact: Qing Li*

摘要/Abstract

摘要：

以乳糖为原料设计合成了半乳凝素-3的潜在抑制剂—1-O-烯丙基-4-O-{3-脱氧-3-[4-苄胺羰基-1H-(1, 2, 3)三氮唑-1-基]-β-D-吡喃半乳糖基}-2-脱氧-2-乙酰氨基-β-D-吡喃葡萄糖。乳糖2-位的改造采用了叠氮-碘糖基化法, 在乙酰氨基引入的同时立体选择性地构建了β-氨基乳糖苷; 通过两次构型翻转在3'-位引入叠氮基, 然后采用Click反应构建出三氮唑羧基, 再与苄胺反应便得到目标物。对乳糖的上述改造旨在提高其对半乳凝素-3的亲和活性。

关键词: 半乳凝素-3, 半乳凝素-3, 半乳凝素-3, 抑制剂, 抑制剂, 抑制剂, 叠氮-碘糖基化法, 叠氮-碘糖基化法, 叠氮-碘糖基化法, N-乙酰基乳糖胺衍生物, N-乙酰基乳糖胺衍生物, N-乙酰基乳糖胺衍生物, , ,

Abstract: Allyl 4-O-{3-deoxy-3-[4-benzylaminocarbonyl-1H-(1,2,3)-triazol-1-yl]-β-D-galactopyranosyl}-2-deoxy-2-acetamido-β-D-glucopyranoside, a potential inhibitor of galectin-3, was designed and synthesized using lactose as staring material. The modifications of lactose included in introducing of N-acetamino group at the C-2 position through an azidoiodoglycosylation meanwhile constructing the β-aminolactoside stereoselectively and replacing 3'-OH with substituent 1,2,3-triazolyl group to enhance the affinity toward galectin-3.

Key words: Galectin-3, Galectin-3, Inhibitor, Inhibitor, Azidoiodoglycosylation, Azidoiodoglycosylation, N-acetyllactosamine derivatives, N-acetyllactosamine derivatives, ,

中图分类号:

R916.41

Supporting: Foundation items: National Natural Science Foundation of China (Grant No. 20732001 and 90713004).
^*Corresponding author. Tel.: 86-10-82801714

李晨, 孟祥豹, 金小锋, 李中军, 李庆^*. 半乳凝素-3潜在抑制剂—1-O-烯丙基-4-O-{3-脱氧-3-[4-苄胺羰基-1H-(1,2,3)三氮唑-1-基]-β-D-吡喃半乳糖基}-2-脱氧-2-乙酰氨基-β-D-吡喃葡萄糖的合成

[J]. .

Chen Li, Xiang-Bao Meng, Xiao-Feng Jin, Zhong-Jun Li, Qing Li^*. Synthesis of allyl 4-O-{3-deoxy-3-[4-benzylaminocarbonyl-1H-(1,2,3)-triazol-1-yl]-β-D-galactopyranosyl}-2-deoxy-2-acetamido-β-D-glucopyranoside as a potential inhibitor of galectin-3[J]. .

参考文献

[1] a) Barondes, S.H.; Cooper, D.N.W.; Gitt, M.A.; Leffler, H. J. Biol. Chem. 1994, 269, 20807-20810. b) Perillo, N.L.; Marcus, M.E.; Baum, L.G. J. Mol. Med. 1998, 76, 402-412. c) Leffler, H. Results Probl. Cell Differ. 2001, 33, 57-83.
[2] a) Liu, F.T.; Clin. Immunol. 2000, 97, 79-88. b) Lowe, J.B. Cell. 2001, 104, 809-812. c) Hirashima, M. Int. Arch. Allergy. Immunol. 2000, 122, 6-9. d) Almkvist, J.; Faldt, J.; Dahlgren, C.; Leffler, H.; Karlsson, A. Infect. Immun. 2001, 69, 832-837.
[3] Demetriou, M.; Granovsky, M.; Quaggin, S.; Dennis, J.W. Nature. 2001, 409, 733-739.
[4] a) Glinsky, V.V.; Glinsky, G.V.; Rittenhouse-Olson, K.; Huflejt, M.E.; Glinskii, O.V.; Deutscher, S.L.; Quinn, T.P. Cancer Res. 2001, 61, 4851-4857. b) Nangia-Makker, P.; Baccarini, S.; Raz, A. Cancer Metastasis Rev. 2000, 19, 51-57. c) Glinsky, V.V.; Huflejt, M.E.; Glinsky, G.V.; Deutscher, S.L.; Quinn, T.P. Cancer Res. 2000, 60, 2584-2588. d) Honjo, Y.; Nangia-Makker, P.; Inohara, H.; Raz, A. Clin. Cancer Res. 2001, 7, 661-668. e) Kim, H.R.; Lin, H.M.; Biliran, H.; Raz, A. Cancer Res. 1999, 59, 4148-4154. f) Nangia-Makker, P.; Honjo, Y.; Sarvis, R.; Akahani, S.; Hogan, V.; Pienta, K.J.; Raz, A. Am. J. Pathol. 2000, 156, 899-909.
[5] Sörme, P.; Qian, Y.; Nyholm, P.G.; Leffler, H.; Nilsson, U.J. ChemBioChem. 2002, 3, 183-189.
[6] Sörme, P.; Pascal, A.; Barbro, K.K.; Leffler, H.; James, M.R.; Nilsson, U.J. J. Am. Chem. Soc. 2005, 127, 1737-1743.
[7] Bader, A.S.; Leffler, H.; Nilsson, U.J. Bioorg. Med. Chem. Lett. 2005, 15, 3344-3346.
[8] Cumpstey, I.; Salomonsson, E.; Sundin, A.; Leffler, H.; Nilsson, U.J. ChemBioChem. 2007, 8, 1389-1398.
[9] Paulsen, H. Angew. Chem. (Int. Ed. Engl.) 1982, 21, 155-173.
[10] Giuseppe, B.; Cinzia, C.; Felicia D.A.; Giacomo, L.M. Tetrahedron. 1997, 53, 3417-3424.
[11] Lafont, D.; Boullanger, P.; Carvalho, F.; Vottero, P. Carbohydr. Res. 1997, 297, 117-126.
[12] Zimmer, H.; Singh, G. Angew. Chem. 1963, 75, 574.
[13] Liakatos, A.; Kiefel, M.J.; Itzstein, M.V. Org. Lett. 2003, 5, 4365-4368.
[14] Liakatos, A.; Kiefel, M.J.; Fleming, F.; Coulson, B.; Itzstein, M.V. Bioorg. Med. Chem. 2006, 14, 739-757.
[15] Rich, J.R.; Bundle, D.R. Org. Lett. 2004, 6, 897-900.
[16] Jansson, K.; Ahlfors, S.; Frejd, T.; Kihlberg, J.; Magnusson, G.; Dahmen, J.; Noori, G.; Stenvall, K. J. Org. Chem. 1988, 53, 5629-5647.