O-(3,3-diacetoxypropyl)glycoladehyde

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: O-(3,3-diacetoxypropyl)glycoladehyde
• 英文别名: [1-Acetyloxy-3-(2-oxoethoxy)propyl] acetate
• 化学式: C₉H₁₄O₆
• 分子量: 218.207
• InChiKey: KSJZADFXAWCHGO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  15
• 可旋转键数：
  9
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  78.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  盐酸多柔比星 、 O-(3,3-diacetoxypropyl)glycoladehyde 在 sodium cyanoborohydride 作用下， 以 四氢呋喃 、 水 、 乙腈 为溶剂， 反应 1.0h， 生成 Acetic acid 1-acetoxy-3-(2-{(2S,3S,4S,6R)-3-hydroxy-2-methyl-6-[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxy-acetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-naphthacen-1-yloxy]-tetrahydro-pyran-4-ylamino}-ethoxy)-propyl ester
  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
• 作为产物：
  描述：

  Acetic acid 1-acetoxy-3-allyloxy-propyl ester 在 二甲基硫 、 臭氧 作用下， 生成 O-(3,3-diacetoxypropyl)glycoladehyde
  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

文献信息

• Anthracycline analogues bearing latent alkylating substituents
  申请人：Board of Regents

  公开号：US20010053845A1

  公开（公告）日：2001-12-20

  Compound having the structure 1 where anthracycline, N, R a , X, R b, n and m are as defined in the specification. The compound of the invention is activatable in vivo by esterases and spontaneous dehydration to form an aldehyde. The aldehyde may couple to nucleophiles of intracellular macromolecules. The compounds of the invention are cytotoxically effective in the inhibition of human myeloma cells.

  具有以下结构的化合物 1 其中蒽环类、N、R a X, R b, n 和 m 如说明书中所定义。本发明的化合物在体内可被酯酶激活并自发脱水形成醛。醛可与细胞内大分子的亲核物偶联。本发明的化合物在抑制人类骨髓瘤细胞方面具有细胞毒性。
• ANTHRACYCLINE ANALOGUES BEARING LATENT ALKYLATING SUBSTITUENTS
  申请人：BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM

  公开号：EP0555358B1

  公开（公告）日：1994-08-10
• US5196522A
  申请人：——

  公开号：US5196522A

  公开（公告）日：1993-03-23
• US6284737B1
  申请人：——

  公开号：US6284737B1

  公开（公告）日：2001-09-04
• US6433150B2
  申请人：——

  公开号：US6433150B2

  公开（公告）日：2002-08-13