MEN 10755 | 211100-13-9

• 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: MEN 10755
• 英文别名: 7-[(2,6-dideoxy-4-O-[3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)]-α-L-lyxohexopyranosyl]-4-demethoxydoxorubicinone；Sabarubicin；(7S,9S)-7-[(2R,4S,5S,6S)-5-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-8,10-dihydro-7H-tetracene-5,12-dione
• CAS: 211100-13-9
• 化学式: C₃₂H₃₇NO₁₃
• 分子量: 643.645
• InChiKey: VQHRZZISQVWPLK-UIRGBLDSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  46
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  236
• 氢给体数：
  7
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  MEN 10755ol 在 sodium tetrahydroborate 作用下， 生成 MEN 10755
  参考文献：
  名称：

  Impairment of myocardial contractility by anticancer anthracyclines: role of secondary alcohol metabolites and evidence of reduced toxicity by a novel disaccharide analogue

  摘要：

  蒽环类抗癌药物多柔比星（DOX）会导致心肌毒性。其侧链羰基通过酶促还原作用转化为次级醇代谢物，而该代谢物被认为与心脏毒性相关。因此，我们监测了暴露于DOX或两种生成较少次级醇代谢物的类似物（表柔比星EPI和新型二糖基蒽环类化合物MEN 10755）的雄性大鼠右心室条的负性变时作用（定义为对舒张后收缩的抑制作用）。 30μM EPI的摄取率高于DOX，但由于其对羰基还原具有抗性，导致形成相同数量的醇代谢物。MEN 10755表现出摄取受损，因此形成了最低水平的醇代谢物。相应地，DOX和EPI抑制了舒张后收缩约40–50%，而MEN 10755抑制了约6%。 100μM EPI表现出与DOX相等的摄取率，但形成了约50%的醇代谢物减少。100μM MEN 10755仍然表现出最低摄取率，并形成了较EPI约60%的醇代谢物减少。在这些条件下，DOX对舒张后收缩的抑制作用为88%。EPI和MEN 10755的抑制作用分别为DOX的约18%（P<0.05）和约80%（P<0.001）。 30–100μM DOX、EPI或MEN 10755的负性变时作用与细胞中醇代谢物的水平（r=0.88，P<0.0001）和羰基蒽环类药物的水平（r=0.79，P<0.0001）相关。然而，多重比较显示，醇代谢物在抑制收缩性方面的效果比羰基蒽环类药物高出约20–40倍。因此，通过化学手段（如侧链缬氨酸酯化）增加MEN 10755的摄取和转化为醇代谢物（而不是保留为羰基形式），可以增强其负性变时作用。 这些结果表明，次级醇代谢物是心脏毒性的关键介导因素。减少摄取并限制向醇代谢物转化的形成，可能会使MEN 10755比DOX和EPI更具心脏耐受性。 英国药理学杂志 (2001) 134, 1271–1278; doi:10.1038/sj.bjp.0704369

  DOI：

  10.1038/sj.bjp.0704369

文献信息

• Method of using a COX-2 inhibitor and a topoisomerase II inhibitor as a combination therapy in the treatment of neoplasia
  申请人：Pharmacia Corporation

  公开号：US20030225150A1

  公开（公告）日：2003-12-04

  The present invention provides compositions and methods to treat, prevent or inhibit a neoplasia or a neoplasia-related disorder in a mammal using a combination of a COX-2 inhibitor and a topoisomerase II inhibitor.

  本发明提供了使用 COX-2 抑制剂和拓扑异构酶 II 抑制剂组合治疗、预防或抑制哺乳动物肿瘤或肿瘤相关疾病的组合物和方法。
• Method of using a cox-2 inhibitor and a topoisomerase II inhibitor as a combination therapy in the treatment of neoplasia
  申请人：Masferrer L Jaime

  公开号：US20060105961A1

  公开（公告）日：2006-05-18

  The present invention provides compositions and methods to treat, prevent or inhibit a neoplasia or a neoplasia-related disorder in a mammal using a combination of a COX-2 inhibitor and a topoisomerase II inhibitor.

  本发明提供了使用 COX-2 抑制剂和拓扑异构酶 II 抑制剂组合治疗、预防或抑制哺乳动物肿瘤或肿瘤相关疾病的组合物和方法。
• Impairment of myocardial contractility by anticancer anthracyclines: role of secondary alcohol metabolites and evidence of reduced toxicity by a novel disaccharide analogue
  作者：Giorgio Minotti、Massimo Parlani、Emanuela Salvatorelli、Pierantonio Menna、Amalia Cipollone、Fabio Animati、Carlo A Maggi、Stefano Manzini

  DOI：10.1038/sj.bjp.0704369

  日期：2001.11

  The anticancer anthracycline doxorubicin (DOX) causes cardiotoxicity. Enzymatic reduction of a side chain carbonyl group converts DOX to a secondary alcohol metabolite that has been implicated in cardiotoxicity. We therefore monitored negative inotropism, assessed as inhibition of post‐rest contractions, in rat right ventricle strips exposed to DOX or to analogues forming fewer amounts of their alcohol metabolites (epirubicin, EPI, and the novel disaccharide anthracycline MEN 10755). Thirty μM EPI exhibited higher uptake than equimolar DOX, but formed comparable amounts of alcohol metabolite due to its resistance to carbonyl reduction. MEN 10755 exhibited also an impaired uptake, and consequently formed the lowest levels of alcohol metabolite. Accordingly, DOX and EPI inhibited post‐rest contractions by ∼40 – 50%, whereas MEN 10755 inhibited by ∼6%. One hundred μM EPI exhibited the same uptake as equimolar DOX, but formed ∼50% less alcohol metabolite. One hundred μM MEN 10755 still exhibited the lowest uptake, forming ∼60% less alcohol metabolite than EPI. Under these conditions DOX inhibited post‐rest contractions by 88%. EPI and MEN 10755 were ∼18% (P<0.05) or ∼80% (P<0.001) less inhibitory than DOX, respectively. The negative inotropism of 30 – 100 μM DOX, EPI, or MEN 10755 correlated with cellular levels of both alcohol metabolites (r=0.88, P<0.0001) and carbonyl anthracyclines (r=0.79, P<0.0001). Nonetheless, multiple comparisons showed that alcohol metabolites were ∼20 – 40 times more effective than carbonyl anthracyclines in inhibiting contractility. The negative inotropism of MEN 10755 was therefore increased by chemical procedures, like side chain valeryl esterification, that facilitated its uptake and conversion to alcohol metabolite but not its retention in a carbonyl form. These results demonstrate that secondary alcohol metabolites are important mediators of cardiotoxicity. A combination of reduced uptake and limited conversion to alcohol metabolite formation might therefore render MEN 10755 more cardiac tolerable than DOX and EPI. British Journal of Pharmacology (2001) 134, 1271–1278; doi:10.1038/sj.bjp.0704369

  蒽环类抗癌药物多柔比星（DOX）会导致心肌毒性。其侧链羰基通过酶促还原作用转化为次级醇代谢物，而该代谢物被认为与心脏毒性相关。因此，我们监测了暴露于DOX或两种生成较少次级醇代谢物的类似物（表柔比星EPI和新型二糖基蒽环类化合物MEN 10755）的雄性大鼠右心室条的负性变时作用（定义为对舒张后收缩的抑制作用）。 30μM EPI的摄取率高于DOX，但由于其对羰基还原具有抗性，导致形成相同数量的醇代谢物。MEN 10755表现出摄取受损，因此形成了最低水平的醇代谢物。相应地，DOX和EPI抑制了舒张后收缩约40–50%，而MEN 10755抑制了约6%。 100μM EPI表现出与DOX相等的摄取率，但形成了约50%的醇代谢物减少。100μM MEN 10755仍然表现出最低摄取率，并形成了较EPI约60%的醇代谢物减少。在这些条件下，DOX对舒张后收缩的抑制作用为88%。EPI和MEN 10755的抑制作用分别为DOX的约18%（P<0.05）和约80%（P<0.001）。 30–100μM DOX、EPI或MEN 10755的负性变时作用与细胞中醇代谢物的水平（r=0.88，P<0.0001）和羰基蒽环类药物的水平（r=0.79，P<0.0001）相关。然而，多重比较显示，醇代谢物在抑制收缩性方面的效果比羰基蒽环类药物高出约20–40倍。因此，通过化学手段（如侧链缬氨酸酯化）增加MEN 10755的摄取和转化为醇代谢物（而不是保留为羰基形式），可以增强其负性变时作用。 这些结果表明，次级醇代谢物是心脏毒性的关键介导因素。减少摄取并限制向醇代谢物转化的形成，可能会使MEN 10755比DOX和EPI更具心脏耐受性。 英国药理学杂志 (2001) 134, 1271–1278; doi:10.1038/sj.bjp.0704369