(2R,3R,4R,5R,6R)-5-amino-6-[(2R)-3-hexadecoxy-2-methoxypropoxy]-2-(hydroxymethyl)oxane-3,4-diol | 1449480-21-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2R,3R,4R,5R,6R)-5-amino-6-[(2R)-3-hexadecoxy-2-methoxypropoxy]-2-(hydroxymethyl)oxane-3,4-diol
• CAS: 1449480-21-0
• 化学式: C₂₆H₅₃NO₇
• 分子量: 491.709
• InChiKey: PMGMQSZUZOMTRF-JMLBKQIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  34
• 可旋转键数：
  22
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  124
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  phenyl 3,4,6-tri-O-acetyl-2-azido-2-deoxy-1-thiol-D-galactopyranoside 在 N-碘代丁二酰亚胺 、 palladium 10% on activated carbon 、 氢气 、 sodium methylate 、 silver trifluoromethanesulfonate 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 (2R,3R,4R,5R,6R)-5-amino-6-[(2R)-3-hexadecoxy-2-methoxypropoxy]-2-(hydroxymethyl)oxane-3,4-diol
  参考文献：
  名称：

  Cytotoxic properties of d-gluco-, d-galacto- and d-manno-configured 2-amino-2-deoxy-glycerolipids against epithelial cancer cell lines and BT-474 breast cancer stem cells

  摘要：

  Glycosylated antitumor ether lipids (GAELs) 6 and 7 containing a alpha- or beta-D-gluco-configured 2-amino-2-deoxy (2-NH2-Glc) sugar moiety linked to a glycerolipid aglycone kill cancer cell lines via a non-apoptotic mechanism that could be exploited to kill cancer stem cells. To test this hypothesis and develop novel potent GAEL analogs, we synthesized GAELS which contain D-galacto- and D-manno-configured 2-amino-2-deoxy sugar moieties (2-NH2-Gal or 2-NH2-Man) and investigated their cytotoxicity against human epithelial cancer cell lines and cancer stem cells derived from BT-474 breast cancer cells. Within the class of D-galacto-configured GAELs, we prepared both O- and S-glycosidic linkages as well as their corresponding alpha- and beta-anomers and screened against breast (BT-474, JIMT-1 and BT-549), pancreas (MiaPaCa2) and prostate cancer (DU145, PC3) cancer cell lines. The alpha-anomeric 2-NH2-Gal-based lipid 1 was the most active of all the compounds tested with CC50 values of 4.4-8 mu M and is the most active GAEL synthesized to date. The beta-anomer 2 was 4->5-fold less active than 1. Replacement of the alpha-O-glycosidic by an alpha-S-glycosidic linkage resulted in a 2-4-fold reduction in activity, while the beta-S-glycolipid 4 was inactive. In comparison, alpha-configured 2-NH2-Man-based glycerolipid 5 displayed very little activity with CC50 > 30 mu M. The effect of the most active GAELs, 1, 6, or 7, on cancer stem cell viability revealed that all three inhibited the formation of tumorspheres from BT-474 cancer stem cell lines, caused the disintegration of preformed tumorspheres and resulted in total loss of cell viability of the cancer stem cells at concentrations of 20 mu M. In contrast, the related antitumor ether lipid gold standard, edelfosine that is in clinical development was much less effective in preventing tumorsphere formation and affecting the viability of the cancer stem cells. Taken together our study demonstrates that alpha-GAEL anomers are more potent than their corresponding beta-anomers and that the nature of the CHO moiety as well as the glycosidic bond significantly affects activity. The study also showed that GAELs are effective in killing CSCs while the apoptosis-inducing edelfosine is not. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.03.057

文献信息

• Cytotoxic properties of d-gluco-, d-galacto- and d-manno-configured 2-amino-2-deoxy-glycerolipids against epithelial cancer cell lines and BT-474 breast cancer stem cells
  作者：Pranati Samadder、Yaozu Xu、Frank Schweizer、Gilbert Arthur

  DOI：10.1016/j.ejmech.2014.03.057

  日期：2014.5

  Glycosylated antitumor ether lipids (GAELs) 6 and 7 containing a alpha- or beta-D-gluco-configured 2-amino-2-deoxy (2-NH2-Glc) sugar moiety linked to a glycerolipid aglycone kill cancer cell lines via a non-apoptotic mechanism that could be exploited to kill cancer stem cells. To test this hypothesis and develop novel potent GAEL analogs, we synthesized GAELS which contain D-galacto- and D-manno-configured 2-amino-2-deoxy sugar moieties (2-NH2-Gal or 2-NH2-Man) and investigated their cytotoxicity against human epithelial cancer cell lines and cancer stem cells derived from BT-474 breast cancer cells. Within the class of D-galacto-configured GAELs, we prepared both O- and S-glycosidic linkages as well as their corresponding alpha- and beta-anomers and screened against breast (BT-474, JIMT-1 and BT-549), pancreas (MiaPaCa2) and prostate cancer (DU145, PC3) cancer cell lines. The alpha-anomeric 2-NH2-Gal-based lipid 1 was the most active of all the compounds tested with CC50 values of 4.4-8 mu M and is the most active GAEL synthesized to date. The beta-anomer 2 was 4->5-fold less active than 1. Replacement of the alpha-O-glycosidic by an alpha-S-glycosidic linkage resulted in a 2-4-fold reduction in activity, while the beta-S-glycolipid 4 was inactive. In comparison, alpha-configured 2-NH2-Man-based glycerolipid 5 displayed very little activity with CC50 > 30 mu M. The effect of the most active GAELs, 1, 6, or 7, on cancer stem cell viability revealed that all three inhibited the formation of tumorspheres from BT-474 cancer stem cell lines, caused the disintegration of preformed tumorspheres and resulted in total loss of cell viability of the cancer stem cells at concentrations of 20 mu M. In contrast, the related antitumor ether lipid gold standard, edelfosine that is in clinical development was much less effective in preventing tumorsphere formation and affecting the viability of the cancer stem cells. Taken together our study demonstrates that alpha-GAEL anomers are more potent than their corresponding beta-anomers and that the nature of the CHO moiety as well as the glycosidic bond significantly affects activity. The study also showed that GAELs are effective in killing CSCs while the apoptosis-inducing edelfosine is not. (C) 2014 Elsevier Masson SAS. All rights reserved.