Boc-Cys(Bzl)-D-Phg-OEt | 247233-37-0

• 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: Boc-Cys(Bzl)-D-Phg-OEt
• 英文别名: ethyl (2R)-2-[[(2R)-3-benzylsulfanyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-2-phenylacetate
• CAS: 247233-37-0
• 化学式: C₂₅H₃₂N₂O₅S
• 分子量: 472.605
• InChiKey: ZUTXXRSVWRQKBU-LEWJYISDSA-N

物化性质

• 沸点：
  644.8±55.0 °C(Predicted)
• 密度：
  1.177±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  33
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  119
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Boc-Cys(Bzl)-D-Phg-OEt 在 N-甲基吗啉 、 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成 octadecyl (2S)-5-[[(2R)-3-benzylsulfanyl-1-[[(1R)-2-ethoxy-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]amino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoate
  参考文献：
  名称：

  Reversal of Multiple Drug Resistance in Cholangiocarcinoma by the GlutathioneS-Transferase-π-Specific InhibitorO¹-Hexadecyl-γ-glutamyl-S-benzylcysteinyl-D-phenylglycine Ethylester

  摘要：

  胆管癌对化疗有明显的耐药性，预后不良，但其耐药机制尚不清楚。本研究探讨了谷胱甘肽 S-转移酶-π（GSTP1-1）是否参与了胆管癌对抗癌药物的耐药性，以及 GSTP1-1 特异性抑制剂能否克服这种耐药性。首先，免疫组化检查显示，17 例胆管癌标本中的 GSTP1-1 均呈强染色，与组织学类型无关。将GSTP1-1反义表达载体转染到人胆管癌细胞系（HuCCT1）后，细胞内的GSTP1-1浓度明显降低，与模拟转染者相比，转染者对阿霉素（ADR）、顺铂以及美法仑和4-羟基过氧环磷酰胺（4-HC）等烷化剂的敏感性明显增加。接下来，我们通过延长γ-谷氨酰-S-苄基半胱氨酰-苯基甘氨酰二乙基酯 N 端乙酯的碳链，合成了 GSTP1-1 特异性抑制剂，并对其进行了药代动力学研究。在测试的六种 GSTP1-1 抑制剂中，O 1- 十六烷基-γ-谷氨酰-S-苄基半胱氨酰-二苯甘氨酸乙酯（C16C2）的中心区容积和稳态分布容积最小，清除率次之，是体内最有效的抑制剂。用 C16C2 处理 HuCCT1 细胞时，ADR 或 4-HC 的 IC50 值会随着 GSTP1-1 活性的降低而降低，其降低程度与 GSTP1-1 活性的降低程度呈剂量依赖关系。在异种移植模型中，与 C16C2 联合治疗可明显增强 ADR 或环磷酰胺的抗肿瘤活性。总之，我们的研究结果表明，GSTP1-1 是胆管癌抗癌药物的耐药因子，而 C16C2 作为一种 GSTP1-1 特异性抑制剂，是一种有效的抗耐药药物。

  DOI：

  10.1124/jpet.103.052696
• 作为产物：
  描述：

  左旋苯甘氨酸 在 N-甲基吗啉 、 氯化亚砜 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.33h， 生成 Boc-Cys(Bzl)-D-Phg-OEt
  参考文献：
  名称：

  Reversal of Multiple Drug Resistance in Cholangiocarcinoma by the GlutathioneS-Transferase-π-Specific InhibitorO¹-Hexadecyl-γ-glutamyl-S-benzylcysteinyl-D-phenylglycine Ethylester

  摘要：

  胆管癌对化疗有明显的耐药性，预后不良，但其耐药机制尚不清楚。本研究探讨了谷胱甘肽 S-转移酶-π（GSTP1-1）是否参与了胆管癌对抗癌药物的耐药性，以及 GSTP1-1 特异性抑制剂能否克服这种耐药性。首先，免疫组化检查显示，17 例胆管癌标本中的 GSTP1-1 均呈强染色，与组织学类型无关。将GSTP1-1反义表达载体转染到人胆管癌细胞系（HuCCT1）后，细胞内的GSTP1-1浓度明显降低，与模拟转染者相比，转染者对阿霉素（ADR）、顺铂以及美法仑和4-羟基过氧环磷酰胺（4-HC）等烷化剂的敏感性明显增加。接下来，我们通过延长γ-谷氨酰-S-苄基半胱氨酰-苯基甘氨酰二乙基酯 N 端乙酯的碳链，合成了 GSTP1-1 特异性抑制剂，并对其进行了药代动力学研究。在测试的六种 GSTP1-1 抑制剂中，O 1- 十六烷基-γ-谷氨酰-S-苄基半胱氨酰-二苯甘氨酸乙酯（C16C2）的中心区容积和稳态分布容积最小，清除率次之，是体内最有效的抑制剂。用 C16C2 处理 HuCCT1 细胞时，ADR 或 4-HC 的 IC50 值会随着 GSTP1-1 活性的降低而降低，其降低程度与 GSTP1-1 活性的降低程度呈剂量依赖关系。在异种移植模型中，与 C16C2 联合治疗可明显增强 ADR 或环磷酰胺的抗肿瘤活性。总之，我们的研究结果表明，GSTP1-1 是胆管癌抗癌药物的耐药因子，而 C16C2 作为一种 GSTP1-1 特异性抑制剂，是一种有效的抗耐药药物。

  DOI：

  10.1124/jpet.103.052696

文献信息

• Glutathione derivatives and their dosage forms
  申请人：TEIJIN LIMITED

  公开号：US20040018985A1

  公开（公告）日：2004-01-29

  A glutathione derivative having a dramatically enhanced hematopoiesis promoting effect in the living body, said derivative being represented by the formula (I): 1 wherein, A represents H or a C1-C20 acyl group, R 1 represents a C1-C26 alkyl group or a C3-C26 alkenyl group, and R 2 represents H, a C1-C26 alkyl group, or a C3-C26 alkenyl group, provided that cases in which R 1 represents a C1-C10 alkyl group or a C3-C10 alkenyl group and R 2 represents H, a C1-C10 alkyl group, or a C3-C10 alkenyl group are excluded, a salt of said glutathione derivative, or a colloidal composition that enables the safe and effective development of the effects of said glutathione derivative in the living body.

  一种谷胱甘肽衍生物，在活体中具有显著增强造血促进作用，该衍生物由式(I)表示：其中，A代表H或C1-C20酰基，R1代表C1-C26烷基或C3-C26烯基，R2代表H、C1-C26烷基或C3-C26烯基，但当R1表示C1-C10烷基或C3-C10烯基，R2表示H、C1-C10烷基或C3-C10烯基的情况除外，所述谷胱甘肽衍生物的盐或胶体组合物，能够在活体中安全有效地发挥其作用。
• Peptide-bond modified glutathione conjugate analogs modulate GSTπ function in GSH-conjugation, drug sensitivity and JNK signaling
  作者：Danny Burg、Joey Riepsaame、Chantal Pont、Gerard Mulder、Bob van de Water

  DOI：10.1016/j.bcp.2005.11.003

  日期：2006.1

  Glutathione S-transferase pi (CST, E.C.2.5.1.18) overexpression contributes to resistance of cancer cells towards cytostatic drugs. Furthermore, GST pi is involved in the cellular stress response through inhibition of Jun N-terminal-kinase (JNK), a process that can be modulated by CST inhibitors. GSH conjugates are potent CST inhibitors, but are sensitive towards gamma-glutamyltranspeptidase (gamma GT)-mediated breakdown. In search for new peptidase stable CST inhibitors we employed the following strategy: (1) selection of a suitable (GST inhibiting) peptide-bond isostere from a series of previously synthesized gamma GT stabilized GSH-analogs. (2) The use of this peptidomimetic strategy to prepare a GSTT, selective inhibitor. Two gamma GT stable GSH conjugate analogs inhibited human GSTs, although non-selectively. One of these, a urethane-type peptide-bond is well accepted by GSTs and we selected this modification for the development of a gamma GT stable, GST pi selective inhibitor, UrPhg-Et-2. This compound displayed selectivity for GST pi compared to alpha and mu class enzymes. Furthermore, the inhibitor reversed GST pi-mediated drug resistance (MDR) in breast tumor cells. In addition, short-term exposure of cells to UrPhg-Et-2 led to GST pi oligornerization and JNK activation, suggesting that it activates the JNK-cJun signaling module through GST pi dissociation. Altogether, we show the successful use of peptidomimetic glutathione conjugate analogs as CST inhibitors and MDR-modifiers. As many MDR related enzymes, such as MRP1, glyoxalase 1 and DNA-pk are also inhibited by GSH conjugates, these peptidomimetic compounds can be used as scaffolds for the development of multi-target MDR drugs. (c) 2005 Elsevier Inc. All rights reserved.
• PREPARATION OF CRYSTALLINE EZATIOSTAT HYDROCHLORIDE ANSOLVATE FORM D
  申请人：LECLERC Guyselaine

  公开号：US20110301376A1

  公开（公告）日：2011-12-08

  Provided herein are processes of preparing ezatiostat hydrochloride, and crystalline ezatiostat hydrochloride ansolvate form D.
• US8841476B2
  申请人：——

  公开号：US8841476B2

  公开（公告）日：2014-09-23
• Reversal of Multiple Drug Resistance in Cholangiocarcinoma by the Glutathione<i>S</i>-Transferase-π-Specific Inhibitor<i>O</i>¹-Hexadecyl-γ-glutamyl-<i>S</i>-benzylcysteinyl-D-phenylglycine Ethylester
  作者：Takaharu Nakajima、Tetsuji Takayama、Koji Miyanishi、Atsushi Nobuoka、Tsuyoshi Hayashi、Tomoyuki Abe、Junji Kato、Kiyoyuki Sakon、Yoshimitsu Naniwa、Hirohumi Tanabe、Yoshiro Niitsu

  DOI：10.1124/jpet.103.052696

  日期：2003.9

  Cholangiocarcinoma is markedly resistant to chemotherapy and has a dismal prognosis, but its mechanism of drug resistance is unknown. This study examines whether glutathione S -transferase-π (GSTP1-1) is involved in resistance to anticancer drugs in cholangiocarcinoma and whether GSTP1-1-specific inhibitors can overcome this resistance. First, immunohistochemical examination disclosed strong staining of all our 17 cholangiocarcinoma specimens for GSTP1-1, irrespective of histological type. Transfection of the GSTP1-1 antisense expression vector into a human cholangiocarcinoma cell line (HuCCT1) apparently decreased its intracellular GSTP1-1 concentration, and the sensitivity of transfectants to adriamycin (ADR), cisplatin, and alkylating agents such as melphalan and 4-hydroxyperoxycyclophosphamide (4-HC) was increased significantly, compared with that of mock transfectants. We next synthesized GSTP1-1-specific inhibitors by elongating the carbon chain of the ethylester at the N -terminal of γ-glutamyl- S -benzylcysteinyl-phenylglycyl diethylester and performed a pharmacokinetic study on them. Of six GSTP1-1 inhibitors tested, O 1-hexadecyl-γ-glutamyl- S -benzylcysteinyl-d-phenylglycine ethylester (C16C2) showed the smallest volume of central compartment and smallest volume of distribution at steady state and the second smallest clearance, being the most effective inhibitor in vivo. The IC50 value of ADR or 4-HC for HuCCT1 cells decreased greater by treatment with C16C2 in a dose-dependent manner, paralleling the decrease in GSTP1-1 activity, than that of ADR or 4-HC alone. The antitumor activity of ADR or cyclophosphamide was clearly enhanced by combination therapy with C16C2 in a xenograft model. In conclusion, our results demonstrated that GSTP1-1 is a resistance factor for anticancer drugs in cholangiocarcinoma and that C16C2, a GSTP1-1-specific inhibitor, is a potent agent against the resistance.

  胆管癌对化疗有明显的耐药性，预后不良，但其耐药机制尚不清楚。本研究探讨了谷胱甘肽 S-转移酶-π（GSTP1-1）是否参与了胆管癌对抗癌药物的耐药性，以及 GSTP1-1 特异性抑制剂能否克服这种耐药性。首先，免疫组化检查显示，17 例胆管癌标本中的 GSTP1-1 均呈强染色，与组织学类型无关。将GSTP1-1反义表达载体转染到人胆管癌细胞系（HuCCT1）后，细胞内的GSTP1-1浓度明显降低，与模拟转染者相比，转染者对阿霉素（ADR）、顺铂以及美法仑和4-羟基过氧环磷酰胺（4-HC）等烷化剂的敏感性明显增加。接下来，我们通过延长γ-谷氨酰-S-苄基半胱氨酰-苯基甘氨酰二乙基酯 N 端乙酯的碳链，合成了 GSTP1-1 特异性抑制剂，并对其进行了药代动力学研究。在测试的六种 GSTP1-1 抑制剂中，O 1- 十六烷基-γ-谷氨酰-S-苄基半胱氨酰-二苯甘氨酸乙酯（C16C2）的中心区容积和稳态分布容积最小，清除率次之，是体内最有效的抑制剂。用 C16C2 处理 HuCCT1 细胞时，ADR 或 4-HC 的 IC50 值会随着 GSTP1-1 活性的降低而降低，其降低程度与 GSTP1-1 活性的降低程度呈剂量依赖关系。在异种移植模型中，与 C16C2 联合治疗可明显增强 ADR 或环磷酰胺的抗肿瘤活性。总之，我们的研究结果表明，GSTP1-1 是胆管癌抗癌药物的耐药因子，而 C16C2 作为一种 GSTP1-1 特异性抑制剂，是一种有效的抗耐药药物。