N-(5,5-diacetoxy-pent-1-yl)doxorubicin hydrochloride | 142632-21-1

• 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: N-(5,5-diacetoxy-pent-1-yl)doxorubicin hydrochloride
• CAS: 142632-21-1
• 化学式: C₃₆H₄₃NO₁₅*ClH
• 分子量: 766.196
• InChiKey: VRIXQRXJYLPDBG-UBKPELEHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.68
• 重原子数：
  53.0
• 可旋转键数：
  13.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  244.68
• 氢给体数：
  6.0
• 氢受体数：
  16.0

反应信息

• 作为反应物：
  描述：

  聚合甲醛 、 N-(5,5-diacetoxy-pent-1-yl)doxorubicin hydrochloride 在 sodium cyanoborohydride 作用下， 以 四氢呋喃 、 水 、 乙腈 为溶剂， 反应 24.0h， 生成 [1-acetyloxy-5-[[(2S,3S,4S,6R)-3-hydroxy-2-methyl-6-[[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1H-tetracen-1-yl]oxy]oxan-4-yl]-methylamino]pentyl] acetate
  参考文献：
  名称：

  Intensely Potent Doxorubicin Analogues:  Structure−Activity Relationship

  摘要：

  N-(5,5-Diacetoxypent-1-yl)doxorubicin (1b) is an intensely cytotoxic doxorubicin analogue that retains full potency against tumor cells that express elevated levels of P-glycoprotein and are resistant to doxorubicin. 1b was designed to be hydrolyzed in the presence of carboxylate esterases to N-(5-oxypent-1-yl)doxorubicin, an aldehyde capable of existing in equilibrium with a cyclic carbinolamine. To investigate the structural determinants of potency for 1b, we have prepared a series of chemically related compounds in which various omega-[bis(acetoxy)]alkyl or omega-[bis(acetoxy)]alkoxyalkyl groups are substituted at the 3'-amino position of the daunosamine sugar. These groups were selected to assess the effect of chain length, oxygen substitution, and carbinolamine ring size on analogue potency. The compounds were evaluated for their ability to inhibit the in vitro growth of the following cell lines: (a) Chinese hamster ovary (CHO) cells, (b) a CHO cell mutant 100-fold resistant to doxorubicin that expresses elevated levels of P-glycoprotein, (c) a murine ductal cell pancreatic adenocarcinoma (Pane 02), and (d) a murine mammary carcinoma (CA 755). The most potent members of the series were those that could form a straight chain aldehyde intermediate after esterase-mediated hydrolysis of the omega-bis(acetoxy) groups and give rise to 5- or 6-membered ring carbinolamines. Analogues capable of forming 7-, 8-, or 9-membered carbinolamines were markedly less active. The N-methyl derivative of 1b, which cannot give rise to a cyclic carbinolamine, was 2 orders of magnitude less potent than 1b. A branched chain analogue, If, which contained a tertiary carbon atom adjacent to the omega-bis(acetoxy) groups, was also substantially less active than its nonbranched counterpart, 1a. These findings suggest that the chain length of the 3'-amino substituents and the ability of the derived aldehydes to form 5- or 6-membered carbinolamines are critical determinants of biologic potency.

  DOI：

  10.1021/jm9706980