Boc-D-Trp(N-propyl)-OH | 168471-25-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: Boc-D-Trp(N-propyl)-OH
• 英文别名: (R)-2-(tert-butoxycarbonylamino)-3-(1-propyl-1H-indol-3-yl)propanoic acid；(2R)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(1-propylindol-3-yl)propanoic acid
• CAS: 168471-25-8
• 化学式: C₁₉H₂₆N₂O₄
• 分子量: 346.426
• InChiKey: NPCAMEFIFAARMW-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  25
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  80.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  Boc-D-Trp(N-propyl)-OH 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成
  参考文献：
  名称：

  Pentapeptides for the treatment of small cell lung cancer: Optimisation by N ind -alkyl modification of the tryptophan side chain

  摘要：

  The pentapeptide, tert-Prenyl4th-NH2 (DMePhe-DTrp-Phe-DTrp(N-tert-prenyl)-Leu-NH2), has recently been reported by our group to exhibit properties of substance P (SP) antagonist G against small cell lung cancer (SCLC). In this study, we undertook a systematic structure activity investigation to optimise this lead compound to improve its in vitro anti-tumour activity and biocompatibility. A series of D-tryptophan (D-Trp) derivatives were synthesised, with a range of aliphatic N-alkyl chains (methyl to pentyl) on the indole nitrogen (N-ind). These were incorporated into the pentapeptide sequence by substitution of the N-ind-tert-prenylated D-Trp 4th residue with the N-ind-alkylated D-Trp derivatives. These pentapeptides were significantly more potent than tert-Prenyl4th-NH2, with the N-ind-butyl modification generating the most cytotoxic peptides. Compared to tert-Prenyl4th-NH2, a single butyl modification on the 4th D-Trp residue (Butyl4th-NH2) showed a similar to 3 fold enhancement in cytotoxicity in either the chemo-naive H69 or the DMS79 (originating from a patient treated with chemotherapeutics and radiation therapy) SCLC cell lines. In addition, the di-butylated sequence on the 2nd and 4th D-Trp residues (Butyl2nd.4th-NH2) gave similar to 4.5 times higher cytotoxicity against the H69 cell line and a similar to 2 fold increase against the DMS79 cell line, compared to tert-Prenyl4th-NH2. The favoured position for butyl modification was the 4th D-Trp residue, as the Butyl2nd-NH2 peptide gave lower cytotoxicity on both cell lines. Butylated peptide sequences, when exposed to neat mouse plasma for 24 h at 37 degrees C, were found to resist degradation with >80% remaining intact compared to similar to 58% for tert-Prenyl4th-NH2. The degradation pathway in plasma occurs via de-amidation of the C-terminus, confirmed by mass spectrometry and RP-HPLC analysis. The butyl modification also conferred resistance to metabolism when tested using S9 liver fraction from mouse. The optimum analogue responsive against the DMS79 cell line was the Butyl4th-NH2 pentapeptide, which revealed a concentration dependent increase in apoptosis: the level of late apoptotic cells rose from similar to 36% at 2 mu M to similar to 96% at 6 mu M, as determined by flow cytometry, compared to the unmodified peptide that showed no such effect. Concluding, the butyl substitutions offered the best perspective for high cytotoxicity, induction of apoptosis and metabolic compatibility thereby comprising an improved broad spectrum SP antagonist candidate for treatment of SCLC. (C) 2017 The Authors. Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2017.05.053
• 作为产物：
  描述：

  BOC-D-色氨酸 在 potassium tert-butylate 、 水 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.33h， 生成 Boc-D-Trp(N-propyl)-OH
  参考文献：
  名称：

  Pentapeptides for the treatment of small cell lung cancer: Optimisation by N ind -alkyl modification of the tryptophan side chain

  摘要：

  The pentapeptide, tert-Prenyl4th-NH2 (DMePhe-DTrp-Phe-DTrp(N-tert-prenyl)-Leu-NH2), has recently been reported by our group to exhibit properties of substance P (SP) antagonist G against small cell lung cancer (SCLC). In this study, we undertook a systematic structure activity investigation to optimise this lead compound to improve its in vitro anti-tumour activity and biocompatibility. A series of D-tryptophan (D-Trp) derivatives were synthesised, with a range of aliphatic N-alkyl chains (methyl to pentyl) on the indole nitrogen (N-ind). These were incorporated into the pentapeptide sequence by substitution of the N-ind-tert-prenylated D-Trp 4th residue with the N-ind-alkylated D-Trp derivatives. These pentapeptides were significantly more potent than tert-Prenyl4th-NH2, with the N-ind-butyl modification generating the most cytotoxic peptides. Compared to tert-Prenyl4th-NH2, a single butyl modification on the 4th D-Trp residue (Butyl4th-NH2) showed a similar to 3 fold enhancement in cytotoxicity in either the chemo-naive H69 or the DMS79 (originating from a patient treated with chemotherapeutics and radiation therapy) SCLC cell lines. In addition, the di-butylated sequence on the 2nd and 4th D-Trp residues (Butyl2nd.4th-NH2) gave similar to 4.5 times higher cytotoxicity against the H69 cell line and a similar to 2 fold increase against the DMS79 cell line, compared to tert-Prenyl4th-NH2. The favoured position for butyl modification was the 4th D-Trp residue, as the Butyl2nd-NH2 peptide gave lower cytotoxicity on both cell lines. Butylated peptide sequences, when exposed to neat mouse plasma for 24 h at 37 degrees C, were found to resist degradation with >80% remaining intact compared to similar to 58% for tert-Prenyl4th-NH2. The degradation pathway in plasma occurs via de-amidation of the C-terminus, confirmed by mass spectrometry and RP-HPLC analysis. The butyl modification also conferred resistance to metabolism when tested using S9 liver fraction from mouse. The optimum analogue responsive against the DMS79 cell line was the Butyl4th-NH2 pentapeptide, which revealed a concentration dependent increase in apoptosis: the level of late apoptotic cells rose from similar to 36% at 2 mu M to similar to 96% at 6 mu M, as determined by flow cytometry, compared to the unmodified peptide that showed no such effect. Concluding, the butyl substitutions offered the best perspective for high cytotoxicity, induction of apoptosis and metabolic compatibility thereby comprising an improved broad spectrum SP antagonist candidate for treatment of SCLC. (C) 2017 The Authors. Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2017.05.053

文献信息

• 3,8-diaminotetrahydroquinoline derivative
  申请人：Zeria Pharmaceutical Co., Ltd.

  公开号：US08299255B2

  公开（公告）日：2012-10-30

  To provide a compound which has a potent agonistic activity on GHS-R and which is useful as a therapeutic agent for systemic wasting diseases such as cachexia. A 3,8-diaminotetrahydroquinoline derivative represented by formula (1a) (wherein X represents CH2, C═O, CH—OR, CH—SR, or CH—NRR′; m is a number of 1 or 2; Ar represents a phenyl group, a naphthyl group, a 5-membered or 6-membered aromatic heterocyclic group having one or two elements selected from S, N, and O, or a similar group; R1 and R2, which may be identical to or different from each other, each represent a hydrogen atom or a methyl group; R3 represents a C1 to C6 alkyl group or a similar group; n is a number of 0 or 1; R4 and R5, which may be identical to or different from each other, each represent a hydrogen atom, or a C1 to C6 alkyl group, etc.; and R6, R7, R, and R′, which may be identical to or different from one another, each represent a hydrogen atom or a C1 to C6 alkyl group), or a salt thereof.

  提供一种在GHS-R上具有强烈激动作用的化合物，可用作治疗全身性消耗性疾病（如恶病质）的治疗剂。该化合物为3,8-二氨基四氢喹啉衍生物，其化学式为（1a），其中X代表CH2、C═O、CH—OR、CH—SR或CH—NRR′；m为1或2；Ar代表苯基、萘基、含有S、N和O中的一种或两种元素的5-或6-成员芳香杂环基或类似基团；R1和R2可以相同或不同，分别代表氢原子或甲基基团；R3代表C1到C6烷基或类似基团；n为0或1；R4和R5可以相同或不同，分别代表氢原子或C1到C6烷基等；而R6、R7、R和R′可以相同或不同，分别代表氢原子或C1到C6烷基。该化合物或其盐可用于治疗全身性消耗性疾病。
• EP1707560
  申请人：——

  公开号：——

  公开（公告）日：——
• 3,8-DIAMINOTETRAHYDROQUINOLINE DERIVATIVE
  申请人：Zeria Pharmaceutical Co., Ltd.

  公开号：EP2241564B1

  公开（公告）日：2014-04-30
• US8299255B2
  申请人：——

  公开号：US8299255B2

  公开（公告）日：2012-10-30
• US8501772B2
  申请人：——

  公开号：US8501772B2

  公开（公告）日：2013-08-06