7-[3-amino-4-O-(α-L-cladinosyl)-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl]daunorubicinone | 863502-91-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 蒽环类药物
• 英文名称: 7-[3-amino-4-O-(α-L-cladinosyl)-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl]daunorubicinone
• 英文别名: 4'-O-(α-L-cladinosyl)daunorubicin；(7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-[(2S,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
• CAS: 863502-91-4
• 化学式: C₃₅H₄₃NO₁₃
• 分子量: 685.725
• InChiKey: IBRPNLLRFAKHDZ-VJINFGKESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  49
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  214
• 氢给体数：
  5
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  7-[3-amino-4-O-(α-L-cladinosyl)-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl]daunorubicinone 在 triflic azide 、 potassium carbonate 、 copper(II) sulfate 作用下， 以 甲醇 为溶剂， 生成 7-[4-O-(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)-3-azido-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl]daunorubicinone
  参考文献：
  名称：

  Syntheses and Biological Activities of 3‘-Azido Disaccharide Analogues of Daunorubicin against Drug-Resistant Leukemia

  摘要：

  Anthracyclines, such as daunorubicin (DNR) and doxorubicin (Dox), are widely used for cancer therapy but are limited by drug resistance and cardiotoxicity. To overcome drug resistance, we synthesized a novel class of disaccharide analogues of DNR against drug-resistant leukemia. In these disaccharide analogues (1-6) the first (inner) sugar in the carbohydrate chain is a 3-azido-2,3,6-trideoxy-L-lyxo-alpha-hexopyranose; the second (outer) sugars that are linked via alpha(1 -> 4) to the first sugar are a series of uncommon sugars. Their cytotoxicities were examined in drug-sensitive leukemia cells K562 and doxorubicin-resistant K562/Dox cells by MTS assay. In drug-sensitive cells, compounds 1-6 were found to be active against leukemia K562 cells with IC50 in the nanomolar range (200-1100 nM), while compounds 2-5 with 2,6-dideoxy sugars showed better activity than compounds 1 and 6 with 2,3,6-trideoxy sugars. In doxorubicin-resistant K562/Dox cells, compounds 1, 3, and 5 exhibited much better activities (with IC50 between 0.29 and 2.0 mu M) than DNR (with IC50 > 5 mu M). Compound 3 emerged as the most active compound, showing at least 17-fold higher activity against drug-resistant cells than parent compound DNR. The IC50 values of compound 3 in both drug-sensitive and drug-resistant cells are identical, which indicates that compound 3 completely overcomes drug resistance. Structure-activity relationship (SAR) studies showed that the substitution and orientation of the 3-OH group in the second sugar significantly influence its activity against drug-resistant leukemia. These results suggest that sugar modifications of anthracyclines change their activity and overcome drug resistance.

  DOI：

  10.1021/jm050916m
• 作为产物：
  描述：

  柔红霉素 盐酸盐 在 吡啶 、 sodium hydroxide 、 六氟磷酸银 、 4 A molecular sieve 、 2,4,6-三叔丁基嘧啶 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 3.25h， 生成 7-[3-amino-4-O-(α-L-cladinosyl)-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl]daunorubicinone
  参考文献：
  名称：

  Syntheses and Biological Activities of 3‘-Azido Disaccharide Analogues of Daunorubicin against Drug-Resistant Leukemia

  摘要：

  Anthracyclines, such as daunorubicin (DNR) and doxorubicin (Dox), are widely used for cancer therapy but are limited by drug resistance and cardiotoxicity. To overcome drug resistance, we synthesized a novel class of disaccharide analogues of DNR against drug-resistant leukemia. In these disaccharide analogues (1-6) the first (inner) sugar in the carbohydrate chain is a 3-azido-2,3,6-trideoxy-L-lyxo-alpha-hexopyranose; the second (outer) sugars that are linked via alpha(1 -> 4) to the first sugar are a series of uncommon sugars. Their cytotoxicities were examined in drug-sensitive leukemia cells K562 and doxorubicin-resistant K562/Dox cells by MTS assay. In drug-sensitive cells, compounds 1-6 were found to be active against leukemia K562 cells with IC50 in the nanomolar range (200-1100 nM), while compounds 2-5 with 2,6-dideoxy sugars showed better activity than compounds 1 and 6 with 2,3,6-trideoxy sugars. In doxorubicin-resistant K562/Dox cells, compounds 1, 3, and 5 exhibited much better activities (with IC50 between 0.29 and 2.0 mu M) than DNR (with IC50 > 5 mu M). Compound 3 emerged as the most active compound, showing at least 17-fold higher activity against drug-resistant cells than parent compound DNR. The IC50 values of compound 3 in both drug-sensitive and drug-resistant cells are identical, which indicates that compound 3 completely overcomes drug resistance. Structure-activity relationship (SAR) studies showed that the substitution and orientation of the 3-OH group in the second sugar significantly influence its activity against drug-resistant leukemia. These results suggest that sugar modifications of anthracyclines change their activity and overcome drug resistance.

  DOI：

  10.1021/jm050916m

文献信息

• WO2006/124720
  申请人：——

  公开号：——

  公开（公告）日：——
• Syntheses and Biological Activities of Disaccharide Daunorubicins
  作者：Guisheng Zhang、Lanyan Fang、Lizhi Zhu、Josephine E. Aimiuwu、Jie Shen、Hao Cheng、Mark T. Muller、Gun Eui Lee、Duxin Sun、Peng George Wang

  DOI：10.1021/jm050144u

  日期：2005.8.1

  Carbohydrate moiety is found in many anticancer nature products. To explore the carbohydrate moiety of daunorubicin in enhancing anticancer efficacy, several daunorubicin derivatives bearing disaccharide (1-8) have been synthesized. Their cytotoxicities were tested in leukemia K562 and colon cancer SW620 cells. Topoisomerase II (topo II) poisoning was performed with the in vivo complex of topoisomerase bioassay. In both cell lines, compounds with various terminal 2,6-dideoxy sugars (compounds 1, 3, 5, and 8) showed 30- to 60-fold higher anticancer activity than compounds with 2-deoxy- or 6-deoxy sugar (compounds 6 and 7). Compounds with an alpha-linkage between two sugar units (compound 3) showed 35-fold higher anticancer activity than compounds with a beta-linkage (compound 4). In addition, the anticancer activities of these compounds correlated with their ability to target topo II mediated genomic DNA damage in vivo. Compounds 1 and 3 with 2,6-dideoxy sugars produced more covalent topo-DNA complex than compounds with 2-deoxy sugar (6) and 6-deoxy sugar (7). Compounds with an alpha-configuration of terminal 2,6-dideoxy sugar (compounds 1 and 3) showed higher topo II poisoning than their counterparts with the beta-configuration (compounds 2 and 4). These results indicate that sugar moieties in daunorubicin play a significant role in its anticancer activity and topo II inhibition. The second sugar of disaccharide daunorubicin should possess 2,6-dideoxy with alpha-linkage to the first sugar to exhibit better anticancer activity.
• Syntheses and Biological Activities of 3‘-Azido Disaccharide Analogues of Daunorubicin against Drug-Resistant Leukemia
  作者：Guisheng Zhang、Lanyan Fang、Lizhi Zhu、Yanqiang Zhong、Peng George Wang、Duxin Sun

  DOI：10.1021/jm050916m

  日期：2006.3.1

  Anthracyclines, such as daunorubicin (DNR) and doxorubicin (Dox), are widely used for cancer therapy but are limited by drug resistance and cardiotoxicity. To overcome drug resistance, we synthesized a novel class of disaccharide analogues of DNR against drug-resistant leukemia. In these disaccharide analogues (1-6) the first (inner) sugar in the carbohydrate chain is a 3-azido-2,3,6-trideoxy-L-lyxo-alpha-hexopyranose; the second (outer) sugars that are linked via alpha(1 -> 4) to the first sugar are a series of uncommon sugars. Their cytotoxicities were examined in drug-sensitive leukemia cells K562 and doxorubicin-resistant K562/Dox cells by MTS assay. In drug-sensitive cells, compounds 1-6 were found to be active against leukemia K562 cells with IC50 in the nanomolar range (200-1100 nM), while compounds 2-5 with 2,6-dideoxy sugars showed better activity than compounds 1 and 6 with 2,3,6-trideoxy sugars. In doxorubicin-resistant K562/Dox cells, compounds 1, 3, and 5 exhibited much better activities (with IC50 between 0.29 and 2.0 mu M) than DNR (with IC50 > 5 mu M). Compound 3 emerged as the most active compound, showing at least 17-fold higher activity against drug-resistant cells than parent compound DNR. The IC50 values of compound 3 in both drug-sensitive and drug-resistant cells are identical, which indicates that compound 3 completely overcomes drug resistance. Structure-activity relationship (SAR) studies showed that the substitution and orientation of the 3-OH group in the second sugar significantly influence its activity against drug-resistant leukemia. These results suggest that sugar modifications of anthracyclines change their activity and overcome drug resistance.