(S)-1-(吡啶-3-羰基)-吡咯烷-2-羧酸叔丁酯 | 184646-28-4

• 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
• 中文名称: (S)-1-(吡啶-3-羰基)-吡咯烷-2-羧酸叔丁酯
• 英文名称: tert-butyl (2S)-1-(pyridine-3-carbonyl)pyrrolidine-2-carboxylate
• CAS: 184646-28-4
• 化学式: C₁₅H₂₀N₂O₃
• 分子量: 276.335
• InChiKey: DGDHKKWMOSORSS-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  59.5
• 氢给体数：
  0
• 氢受体数：
  4

上下游信息

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  1-(3-吡啶基羰基)-L-脯氨酸	N-(Pyridine-3-carbonyl)-L-proline	59834-37-6	C11H12N2O3	220.228
  ——	(2,3,4,5,6-pentafluorophenyl) (2S)-1-(pyridine-3-carbonyl)pyrrolidine-2-carboxylate	184646-09-1	C17H11F5N2O3	386.278
  ——	nicotinoyl-Pro-Tyr-Lys(Boc) cholesteryl ester	214596-55-1	C58H85N5O8	980.342
  ——	nicotinoyl-Pro-Ala-Tyr-Lys(Boc) cholesteryl ester	214596-57-3	C61H90N6O9	1051.42
  ——	nicotinoyl-Pro-Pro-Tyr-Lys(Boc) cholesteryl ester	214596-56-2	C63H92N6O9	1077.46

反应信息

• 作为反应物：
  描述：

  (S)-1-(吡啶-3-羰基)-吡咯烷-2-羧酸叔丁酯 在 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 96.5h， 生成 nicotinoyl-Pro-Tyr-Lys(Boc) cholesteryl ester
  参考文献：
  名称：

  Strategies To Target Kyotorphin Analogues to the Brain

  摘要：

  The design, synthesis, and pharmacological evaluation of brain-targeted chemical delivery systems (CDS) for a kyotorphin analogue (Tyr-Lys) are described. The brain-targeted compound contains the active peptide in a packaged, disguised form, flanked between the lipophilic cholesteryl ester on the C-terminus and the 1,4-dihydrotrigonellyl redox targetor, attached to the N-terminus through strategically selected L-amino acid(s) spacer. It was found that for successful brain targeting, the epsilon-amine of Lys needs to be also converted to a Lipophilic function. Through sequential enzymatic bioactivation, the Tyr-Lys dipeptide is released in a sustained manner, producing significant and prolonged analgesic activity as demonstrated by the rat tail latency test. An alternate strategy was also employed. Lys was replaced by a redox amino acid pair, Nys(+) <-> Nys, the nicotinamide <-> 1,4-dihydronicotinamide analogues of Lys (Nys(+) is 2-amino-6-(3-carbamoyl-1-pyridiniumyl)hexanoic acid). The Nys form is lipophilic and facilitates delivery in addition to the C- and N-terminal lipophilic functions, Enzymatic oxidation to Nys(+) provides the lock-in, followed by removal;of the lipophilic groups, releasing Tyr-Nys(+) from the brain-targeted analogue (BTRA). Nys(+) was shown to be an effective substitution for Arg or Lys. The activities of the CDS and BTRA, respectively,were antagonized by naloxone, supporting the designed brain-targeted processes. The mst potent compound is the two-proline spacer containing CDS (CDS-PP), followed by the BTRA.

  DOI：

  10.1021/jm970715l
• 作为产物：
  描述：

  L-脯氨酸叔丁酯盐酸盐 、 氯化烟碱盐酸盐 在 TEA 作用下， 以 二氯甲烷 为溶剂， 生成 (S)-1-(吡啶-3-羰基)-吡咯烷-2-羧酸叔丁酯
  参考文献：
  名称：

  Brain-Targeted Delivery of a Leucine-enkephalin Analogue by Retrometabolic Design

  摘要：

  A brain-targeted chemical delivery system (CDS) based on retrometabolic drug design was applied to a Leu-enkephalin analogue, Tyr-D-Ala-Gly-Phe-D-Leu (DADLE). The molecular architecture of the peptide CDS disguises its peptide nature from neuropeptide-degrading enzymes and provides lipophilic, bioreversible functions for the penetration through the blood-brain barrier. These functions were provided by a targetor, a 1,4-dihydrotrigonellyl group, on the N-terminus and a bulky, lipophilic ester group on the C-terminus. A spacer amino acid residue was also inserted between the targetor and the parent peptide to assure the release of DADLE by specific enzymes. Four CDSs were synthesized by segment-coupling method that proved to be superior to sequential elongation in obtaining this type of peptide conjugates. Intravenous injection of the compounds produced a significant and long-lasting response in rats monitored by the tail-flick latency measurements. CDSs having the bulkier cholesteryl group showed a better efficacy than those having the smaller 1-adamantaneethyl ester. The spacer was the most important factor to manipulate the rate of DADLE release and, thus, the pharmacological activity; proline as a spacer produced more potent analgesia than alanine. The antinociceptive effect of the CDSs was naloxone-reversible and methylnaloxonium-irreversible, confirming that central opiate receptors were solely responsible for mediating analgesia induced by the peptide CDS that delivered, retained, and then released the peptide in the brain.

  DOI：

  10.1021/jm960356e

文献信息

• Brain-Targeted Delivery of a Leucine-enkephalin Analogue by Retrometabolic Design
  作者：Katalin Prokai-Tatrai、Laszlo Prokai、Nicholas Bodor

  DOI：10.1021/jm960356e

  日期：1996.1.1

  A brain-targeted chemical delivery system (CDS) based on retrometabolic drug design was applied to a Leu-enkephalin analogue, Tyr-D-Ala-Gly-Phe-D-Leu (DADLE). The molecular architecture of the peptide CDS disguises its peptide nature from neuropeptide-degrading enzymes and provides lipophilic, bioreversible functions for the penetration through the blood-brain barrier. These functions were provided by a targetor, a 1,4-dihydrotrigonellyl group, on the N-terminus and a bulky, lipophilic ester group on the C-terminus. A spacer amino acid residue was also inserted between the targetor and the parent peptide to assure the release of DADLE by specific enzymes. Four CDSs were synthesized by segment-coupling method that proved to be superior to sequential elongation in obtaining this type of peptide conjugates. Intravenous injection of the compounds produced a significant and long-lasting response in rats monitored by the tail-flick latency measurements. CDSs having the bulkier cholesteryl group showed a better efficacy than those having the smaller 1-adamantaneethyl ester. The spacer was the most important factor to manipulate the rate of DADLE release and, thus, the pharmacological activity; proline as a spacer produced more potent analgesia than alanine. The antinociceptive effect of the CDSs was naloxone-reversible and methylnaloxonium-irreversible, confirming that central opiate receptors were solely responsible for mediating analgesia induced by the peptide CDS that delivered, retained, and then released the peptide in the brain.
• Strategies To Target Kyotorphin Analogues to the Brain
  作者：Pei Chen、Nicholas Bodor、Whei-Mei Wu、Laszlo Prokai

  DOI：10.1021/jm970715l

  日期：1998.9.1

  The design, synthesis, and pharmacological evaluation of brain-targeted chemical delivery systems (CDS) for a kyotorphin analogue (Tyr-Lys) are described. The brain-targeted compound contains the active peptide in a packaged, disguised form, flanked between the lipophilic cholesteryl ester on the C-terminus and the 1,4-dihydrotrigonellyl redox targetor, attached to the N-terminus through strategically selected L-amino acid(s) spacer. It was found that for successful brain targeting, the epsilon-amine of Lys needs to be also converted to a Lipophilic function. Through sequential enzymatic bioactivation, the Tyr-Lys dipeptide is released in a sustained manner, producing significant and prolonged analgesic activity as demonstrated by the rat tail latency test. An alternate strategy was also employed. Lys was replaced by a redox amino acid pair, Nys(+) <-> Nys, the nicotinamide <-> 1,4-dihydronicotinamide analogues of Lys (Nys(+) is 2-amino-6-(3-carbamoyl-1-pyridiniumyl)hexanoic acid). The Nys form is lipophilic and facilitates delivery in addition to the C- and N-terminal lipophilic functions, Enzymatic oxidation to Nys(+) provides the lock-in, followed by removal;of the lipophilic groups, releasing Tyr-Nys(+) from the brain-targeted analogue (BTRA). Nys(+) was shown to be an effective substitution for Arg or Lys. The activities of the CDS and BTRA, respectively,were antagonized by naloxone, supporting the designed brain-targeted processes. The mst potent compound is the two-proline spacer containing CDS (CDS-PP), followed by the BTRA.