N^α-(tert-butoxycarbonyl)-1-methyl-D-tryptophan | 103943-63-1

• 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: N^α-(tert-butoxycarbonyl)-1-methyl-D-tryptophan
• 英文别名: Boc-D-Trp(Me)-OH；N-Boc-1-methyl-(D)-tryptophan；(2R)-3-(1-methylindol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid
• CAS: 103943-63-1
• 化学式: C₁₇H₂₂N₂O₄
• 分子量: 318.373
• InChiKey: OHPBREBKPBFZCY-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 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：

  N^α-(tert-butoxycarbonyl)-1-methyl-D-tryptophan 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 1-甲基-D-色氨酸
  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 N^α-(tert-butoxycarbonyl)-1-methyl-D-tryptophan
  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

• [EN] NOVEL PHTHALAZINONE-PYRROLOPYRIMIDINECARBOXAMIDE DERIVATIVES<br/>[FR] NOUVEAUX DÉRIVÉS DE PHTALAZINONE-PYRROLOPYRIMIDINECARBOXAMIDE
  申请人：NYCOMED GMBH

  公开号：WO2012171900A1

  公开（公告）日：2012-12-20

  The compounds of formula (1), in which R1, R7, R8, R9, R10, R17, R18, R19, R20 and m have the meanings as given in the description, are novel effective inhibitors of type 4 and 5 phosphodiesterase.

  式（1）中的化合物，其中R1、R7、R8、R9、R10、R17、R18、R19、R20和m的含义如描述中所述，是新颖的有效的4型和5型磷酸二酯酶抑制剂。
• NOVEL PHTHALAZINONE-PYRROLOPYRIMIDINECARBOXAMIDE DERIVATIVES
  申请人：Stengel Thomas

  公开号：US20140112945A1

  公开（公告）日：2014-04-24

  The compounds of formula (1) in which R1, R7, R8, R9, R10, R17, R18, R19, R20 and m have the meanings as given in the description, are novel effective inhibitors of type 4 and type 5 phosphodiesterase.

  式（1）中的化合物，其中R1、R7、R8、R9、R10、R17、R18、R19、R20和m的含义如描述中所述，是新颖的有效的磷酸二酯酶4型和5型抑制剂。
• NANO-ENABLED IMMUNOTHERAPY IN CANCER
  申请人：The Regents of the University of California

  公开号：US20200197534A1

  公开（公告）日：2020-06-25

  In certain embodiments a platform technology for the facilitating immune therapy in the treatment of cancer is provided. In certain embodiments nanocarriers are provided that facilitate delivery of an IDO inhibitor in conjunction with an inducer of cell death (ICD-inducer). In certain embodiments the IDO inhibitor is conjugated to a component of a lipid bilayer forming a nanovesicle. In still another embodiment, methods and compositions are provided where an ICD-inducing agent (e.g., doxorubicin, oxaliplatin, mitoxantrone etc.) and an IDO pathway inhibitor (e.g., an IDO inhibitor-prodrug) are integrated into a nanocarrier (e.g. a lipid-bilayer (LB)-coated nanoparticle), that allows systemic delivery to orthotopic pancreatic cancer site.

  在某些实施例中，提供了一种用于促进免疫疗法治疗癌症的平台技术。在某些实施例中，提供了一种纳米载体，可促进与细胞死亡诱导剂（ICD诱导剂）一起传递IDO抑制剂。在某些实施例中，IDO抑制剂与脂质双层的组分结合形成纳米囊泡。在另一实施例中，提供了一种方法和组合物，其中ICD诱导剂（例如多柔比星、奥沙利铂、米托蒽醌等）和IDO途径抑制剂（例如IDO抑制剂前药）被整合到一个纳米载体（例如脂质双层（LB）包被的纳米粒子）中，从而实现对原位胰腺癌部位的全身传递。
• SALTS AND PRODRUGS OF 1-METHYL-D-TRYPTOPHAN
  申请人：NewLink Genetics, Corp.

  公开号：US20170022157A1

  公开（公告）日：2017-01-26

  Presently provided are indoximod prodrug and salt compounds and pharmaceutical compositions comprising salts and prodrugs of indoximod, that produce enhanced plasma concentration and exposure to indoximod compared to direct administration of indoximod, in patients in need of treatment of immunosuppression mediated by the indoleamine-2,3-dioxygenase pathway, such as patients with cancer or chronic infectious diseases.

  目前提供的是吲哚氧化酶抑制剂前药和盐类化合物，以及包含吲哚氧化酶抑制剂前药和盐类的药物组合物，相比直接给予吲哚氧化酶抑制剂，这些组合物在需要治疗由吲哚胺-2,3-二氧化酶途径介导的免疫抑制的患者中，如癌症或慢性传染病患者，能够产生增强的血浆浓度和暴露于吲哚氧化酶抑制剂。
• Tetrapeptide tachykinin antagonists: synthesis and modulation of the physicochemical and pharmacological properties of a new series of partially cyclic analogs
  作者：Nathalie Kucharczyk、Christophe Thurieau、Joseph Paladino、Angela D. Morris、Jacqueline Bonnet、Emmanuel Canet、James E. Krause、Domenico Regoli、Rejean Couture、Jean Luc Fauchere

  DOI：10.1021/jm00063a015

  日期：1993.5

  report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the pseudopeptide pharmacophore cyclo[-Abo-Asp(D-Trp-Phe-N(Me)Bzl)-] which contains the 2-azabicyclo[2.2.2]octane-3(S)-carboxylic acid (Abo) residue. Variation of the substituents on the tryptophan indole nitrogen was shown to modulate water solubility and transport properties of the analogs

  我们报告了基于含有2-氮杂双环[2.2]的假肽药效团环[-Abo-Asp（D-Trp-Phe-N（Me）Bzl）-]的一系列新的速激肽拮抗剂的合成及其药理特性。 .2]辛烷-3（S）-羧酸（Abo）残基。色氨酸吲哚氮上的取代基的变化显示出可调节类似物的水溶性和转运性质以及经典体外反应和结合测定中的效力。一种水溶性化合物，其中的取代基是3-羰基丙酸酯，在静脉内或口服给药后，在小鼠热板试验中均强烈延长了反应时间，并且在大鼠腹膜肥大细胞中没有脱粒活性，该化合物的取代基为3-羰基丙酸酯。