N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[(3S,3'R,3'aS,6'S,6aS,6bS,7'aR,9R,11aS,11bR)-3-hydroxy-3',6',10,11b-tetramethylspiro[2,3,4,6,6a,6b,7,8,11,11a-decahydro-1H-benzo[a]fluorene-9,2'-3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine]-4'-yl]-5-amino-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-amino-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]morpholine-4-carboxamide | 1029122-22-2

• 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: N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[(3S,3'R,3'aS,6'S,6aS,6bS,7'aR,9R,11aS,11bR)-3-hydroxy-3',6',10,11b-tetramethylspiro[2,3,4,6,6a,6b,7,8,11,11a-decahydro-1H-benzo[a]fluorene-9,2'-3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine]-4'-yl]-5-amino-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-amino-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]morpholine-4-carboxamide
• CAS: 1029122-22-2
• 化学式: C₆₁H₉₆N₁₂O₁₃
• 分子量: 1205.51
• InChiKey: XEARXQIPZLJRPP-AVYDATOOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  86
• 可旋转键数：
  25
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  375
• 氢给体数：
  12
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  在 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 以75%的产率得到N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[(3S,3'R,3'aS,6'S,6aS,6bS,7'aR,9R,11aS,11bR)-3-hydroxy-3',6',10,11b-tetramethylspiro[2,3,4,6,6a,6b,7,8,11,11a-decahydro-1H-benzo[a]fluorene-9,2'-3,3a,5,6,7,7a-hexahydrofuro[3,2-b]pyridine]-4'-yl]-5-amino-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-amino-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]morpholine-4-carboxamide
  参考文献：
  名称：

  Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer

  摘要：

  A promising agent for use in prostate cancer therapy is the Hedgehog (Hh) signaling pathway inhibitor, cyclopamine. This compound, however, has the potential for causing serious side effects in non-tumor tissues. To minimize these bystander toxicities, we have designed and synthesized two novel peptide-cyclopamine conjugates as prostate-specific antigen (PSA)-activated prodrugs for use against prostate cancer. These prodrugs were composed of cyclopamine coupled to one of two peptides (either HSSKLQ or SSKYQ) that can be selectively cleaved by PSA, converting the mature prodrug into an active Hedgehog inhibitor within the malignant cells. Of the two prodrugs, Mu-SSKYQ-Cyclopamine was rapidly hydrolyzed, with a half-life of 3.2 h, upon incubation with the PSA enzyme. Thus, modulating cyclopamine at the secondary amine with PSA-cleavable peptides is a promising strategy for developing prodrugs to target prostate cancer. (C) 2008 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2008.01.012

文献信息

• Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer
  作者：Srinivas K. Kumar、Indrajit Roy、Ravi K. Anchoori、Sarah Fazli、Anirban Maitra、Philip A. Beachy、Saeed R. Khan

  DOI：10.1016/j.bmc.2008.01.012

  日期：2008.3.15

  A promising agent for use in prostate cancer therapy is the Hedgehog (Hh) signaling pathway inhibitor, cyclopamine. This compound, however, has the potential for causing serious side effects in non-tumor tissues. To minimize these bystander toxicities, we have designed and synthesized two novel peptide-cyclopamine conjugates as prostate-specific antigen (PSA)-activated prodrugs for use against prostate cancer. These prodrugs were composed of cyclopamine coupled to one of two peptides (either HSSKLQ or SSKYQ) that can be selectively cleaved by PSA, converting the mature prodrug into an active Hedgehog inhibitor within the malignant cells. Of the two prodrugs, Mu-SSKYQ-Cyclopamine was rapidly hydrolyzed, with a half-life of 3.2 h, upon incubation with the PSA enzyme. Thus, modulating cyclopamine at the secondary amine with PSA-cleavable peptides is a promising strategy for developing prodrugs to target prostate cancer. (C) 2008 Published by Elsevier Ltd.