12-(N_α-tert-butoxycarbonyl-L-alaninoylamino)dodecanoic acid methyl ester | 391610-89-2

• 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: 12-(N_α-tert-butoxycarbonyl-L-alaninoylamino)dodecanoic acid methyl ester
• 英文别名: methyl 12-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]dodecanoate
• CAS: 391610-89-2
• 化学式: C₂₁H₄₀N₂O₅
• 分子量: 400.559
• InChiKey: JOYHYVUTUUNIJJ-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  28
• 可旋转键数：
  17
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  93.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  12-(N_α-tert-butoxycarbonyl-L-alaninoylamino)dodecanoic acid methyl ester 在 4-二甲氨基吡啶 、 sodium hydroxide 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 5.17h， 生成 8-O-(12-[N_α-tert-butoxycarbonyl-L-alaninoylamino]dodecanoyl)-8-O-debutanoylthapsigargin
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of Thapsigargin Analogues for Targeting Apoptosis to Prostatic Cancer Cells

  摘要：

  A series of thapsigargin (TG) analogues, containing an amino acid applicable for conjugation to a peptide specifically cleaved by prostate-specific antigen (PSA), has been prepared to develop the drug-moiety of prodrugs for treatment of prostatic cancer. The analogues were synthesized by converting TG into O-8-debutanoylthapsigargin (DBTG) and esterifying O-8 of DBTG with various amino acid linkers. The compounds were evaluated for their ability to elevate the cytosolic Ca2+ concentration ([Ca2+](i)) in TSU-Pr1 cells, their ability to inhibit the rabbit skeletal muscle SERCA pump, and their ability to induce apoptosis in TSU-Pr1 human prostatic cancer cells. The activity of analogues, in which DBTG were esterified with w-amino acids [HOOC-(CH2)(n),NH2, n = 5-7, 10, 11], increased with the linker length. Analogues with 3-[4-(L-leucinoylamino)phenyl]propanoyl, 6-(L-leucinoylamino)hexanoyl, and 12-(L-serinoylamino)dodecanoyl were considerably less active than TG, and analogues with 12-(L-alaninoylamino)dodecanoyl and 12-(L-phenylalaninoylamino)dodecanoyl were almost as active as TG. The 12-(L-leucinoylamino)dodecanoyl gave an analogue equipotent with TG, making this compound promising as the drug-moiety of a PSA sensitive prodrug of TG.

  DOI：

  10.1021/jm010985a
• 作为产物：
  描述：

  12-氨基十二酸 在 氯化亚砜 、 N,N-二异丙基乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 12-(N_α-tert-butoxycarbonyl-L-alaninoylamino)dodecanoic acid methyl ester
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of Thapsigargin Analogues for Targeting Apoptosis to Prostatic Cancer Cells

  摘要：

  A series of thapsigargin (TG) analogues, containing an amino acid applicable for conjugation to a peptide specifically cleaved by prostate-specific antigen (PSA), has been prepared to develop the drug-moiety of prodrugs for treatment of prostatic cancer. The analogues were synthesized by converting TG into O-8-debutanoylthapsigargin (DBTG) and esterifying O-8 of DBTG with various amino acid linkers. The compounds were evaluated for their ability to elevate the cytosolic Ca2+ concentration ([Ca2+](i)) in TSU-Pr1 cells, their ability to inhibit the rabbit skeletal muscle SERCA pump, and their ability to induce apoptosis in TSU-Pr1 human prostatic cancer cells. The activity of analogues, in which DBTG were esterified with w-amino acids [HOOC-(CH2)(n),NH2, n = 5-7, 10, 11], increased with the linker length. Analogues with 3-[4-(L-leucinoylamino)phenyl]propanoyl, 6-(L-leucinoylamino)hexanoyl, and 12-(L-serinoylamino)dodecanoyl were considerably less active than TG, and analogues with 12-(L-alaninoylamino)dodecanoyl and 12-(L-phenylalaninoylamino)dodecanoyl were almost as active as TG. The 12-(L-leucinoylamino)dodecanoyl gave an analogue equipotent with TG, making this compound promising as the drug-moiety of a PSA sensitive prodrug of TG.

  DOI：

  10.1021/jm010985a

文献信息

• Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure–Activity Relationship and Binding Mode Analysis
  作者：Radka Houštecká、Martin Hadzima、Jindřich Fanfrlík、Jiří Brynda、Lenka Pallová、Iva Hánová、Helena Mertlíková-Kaiserová、Martin Lepšík、Martin Horn、Martin Smrčina、Pavel Majer、Michael Mareš

  DOI：10.1021/acs.jmedchem.9b01351

  日期：2020.2.27

  optimization, mapping of subsite interactions, and profiling of inhibitor selectivity. Furthermore, we solved high-resolution crystal structures of three macrocyclic inhibitors with low nanomolar or subnanomolar potency in complex with CatD and determined their binding mode using quantum chemical calculations. The study provides a new structural template and functional profile that can be exploited for design

  人组织蛋白酶D（CatD）是一种胃蛋白酶家族的天冬氨酸蛋白酶，在肿瘤的进展和转移中起着重要的作用。在这里，我们报告了仿生抑制剂CatD的发展，作为调节该治疗靶标的新型工具。我们设计了一个大环支架来模拟CatD活性位点中抑肽酶抑素A（一种微生物寡肽抑制剂）的最小假二肽结合基序的空间构象。使用30多种大环拟肽抑制剂的库进行支架优化，亚位点相互作用的作图以及抑制剂选择性的分析。此外，我们与CatD配合使用了三种具有低纳摩尔或亚纳摩尔能力的大环抑制剂的高分辨率晶体结构，并通过量子化学计算确定了它们的结合模式。