Boc-d-3-氯酪氨酸 | 478183-57-2

• 物质功能分类: 生物化工 - 氨基酸及其衍生物 - 酪氨酸类衍生物
• 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: Boc-d-3-氯酪氨酸
• 中文别名: BOC-D-3-氯酪氨酸
• 英文名称: (2R)-2-[(tert-butoxycarbonyl)amino]-3-(3-chloro-4-hydroxyphenyl)propanoic acid
• 英文别名: Boc-D-Tyr(3-Cl)-OH；N-Boc-3-chloro-D-tyrosine；(2R)-3-(3-chloro-4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid
• CAS: 478183-57-2
• 化学式: C₁₄H₁₈ClNO₅
• 分子量: 315.754
• InChiKey: ZEMKCIHCRJIZOO-SNVBAGLBSA-N

物化性质

• 沸点：
  490.6±45.0 °C(Predicted)
• 密度：
  1.321±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  21
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  95.9
• 氢给体数：
  3
• 氢受体数：
  5

安全信息

• 海关编码：
  2924299090
• 储存条件：
  存储温度应为 0-5°C。

反应信息

• 作为反应物：
  描述：

  Boc-d-3-氯酪氨酸 在 吗啉 、 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 三甲基氯硅烷 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 、 水 、 乙腈 为溶剂， 反应 100.5h， 生成 cryptophycin 52
  参考文献：
  名称：

  Cryptophycin-55/52 based antibody-drug conjugates: Synthesis, efficacy, and mode of action studies

  摘要：

  Cryptophycin-52 (CR52), a tubulin inhibitor, exhibits promising antitumor activity in vitro (picomolar level) and in mouse xenograft models. However, the narrow therapeutic window in clinical trials limits its further development. Antibody-drug conjugate (ADC), formed by coupling cytotoxic compound (payload) to an antibody via a linker, can deliver drug to tumor locations in a targeted manner by antibody, enhancing the therapeutic effects and reducing toxic and side effects. In this study, we aim to explore the possibility of CR52-based ADC for tumor targeted therapy. Due to the lack of a coupling site in CR52, its prodrug cryptophycin-55 (CR55) containing a free hydroxyl was synthesized and conjugated to the model antibody trastuzumab (anti-HER2 antibody drug approved by FDA for breast cancer therapy) via the linkers based on Mc-NHS and Mc-Val-Cit-PAB-PNP. The average drug-to-antibody ratios (DARs) of trastuzumab-CR55 conjugates (named T-L1-CR55, T-L2-CR55, and T-L3-CR55) were 3.50, 3.29, and 3.35, respectively. These conjugates exhibited potent cytotoxicity in HER2-positive tumor cell lines with IC50 values at low nanomolar levels (0.58-1.19 nM). Further, they displayed significant antitumor activities at the doses of 10 mg/kg in established ovarian cancer (SKOV3) and gastric cancer (NCI-N87) xenograft models without overt toxicities. Finally, the drug releases were analyzed and the results indicated that T-L3-CR55 was able to effectively release CR55 and further epoxidized to CR52, which may be responsible for its best performance in antitumor activities. In conclusion, our results demonstrated that these conjugates have the potential for tumor targeted therapy, which provides insights to further research the CR55/CR52-based ADC for tumor therapy. (C) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112364
• 作为产物：
  描述：

  D-酪氨酸 在 氯化亚砜 、 溶剂黄146 、 三乙胺 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 8.25h， 生成 Boc-d-3-氯酪氨酸
  参考文献：
  名称：

  Cryptophycin-55/52 based antibody-drug conjugates: Synthesis, efficacy, and mode of action studies

  摘要：

  Cryptophycin-52 (CR52), a tubulin inhibitor, exhibits promising antitumor activity in vitro (picomolar level) and in mouse xenograft models. However, the narrow therapeutic window in clinical trials limits its further development. Antibody-drug conjugate (ADC), formed by coupling cytotoxic compound (payload) to an antibody via a linker, can deliver drug to tumor locations in a targeted manner by antibody, enhancing the therapeutic effects and reducing toxic and side effects. In this study, we aim to explore the possibility of CR52-based ADC for tumor targeted therapy. Due to the lack of a coupling site in CR52, its prodrug cryptophycin-55 (CR55) containing a free hydroxyl was synthesized and conjugated to the model antibody trastuzumab (anti-HER2 antibody drug approved by FDA for breast cancer therapy) via the linkers based on Mc-NHS and Mc-Val-Cit-PAB-PNP. The average drug-to-antibody ratios (DARs) of trastuzumab-CR55 conjugates (named T-L1-CR55, T-L2-CR55, and T-L3-CR55) were 3.50, 3.29, and 3.35, respectively. These conjugates exhibited potent cytotoxicity in HER2-positive tumor cell lines with IC50 values at low nanomolar levels (0.58-1.19 nM). Further, they displayed significant antitumor activities at the doses of 10 mg/kg in established ovarian cancer (SKOV3) and gastric cancer (NCI-N87) xenograft models without overt toxicities. Finally, the drug releases were analyzed and the results indicated that T-L3-CR55 was able to effectively release CR55 and further epoxidized to CR52, which may be responsible for its best performance in antitumor activities. In conclusion, our results demonstrated that these conjugates have the potential for tumor targeted therapy, which provides insights to further research the CR55/CR52-based ADC for tumor therapy. (C) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112364

文献信息

• Total Synthesis of Cryptophycins. Revision of the Structures of Cryptophycins A and C
  作者：Russell A. Barrow、Thomas Hemscheidt、Jian Liang、Seunguk Paik、Richard E. Moore、Marcus A. Tius

  DOI：10.1021/ja00114a011

  日期：1995.3

  The convergent total synthesis of cryptophycins C and D is described. It has been shown that in both natural products the absolute configuration of the a-amino acid corresponds to the D-series. The structural assignment for cryptophycin C has been corrected to reflect this fact. Since the structure of cryptophycin A has been correlated to cryptophycin C, the chloro-0-methyltyrosine unit in cryptophycin

  描述了隐霉素 C 和 D 的收敛全合成。已经表明，在两种天然产物中，α-氨基酸的绝对构型对应于 D 系列。已更正了隐藻素 C 的结构分配以反映这一事实。由于隐藻素A的结构与隐藻素C相关，隐藻素A中的氯-0-甲基酪氨酸单元具有D-构型。隐藻素是与陆生蓝绿藻 Nostoc sp. 相关的强效肿瘤选择性细胞毒素。GSV 224' 和 Nostoc sp。ATCC 53789.2 每种藻类中的主要细胞毒素，cryptophycin A，对植入小鼠的实体瘤（包括耐药性肿瘤）显示出极好的活性。超过 20 种相关的细胞毒素作为次要成分存在于 GSV 224 菌株中，以及这些化合物中的一些，例如，隐藻素 B 和 C，已被分离出足够的量用于体内评估。~为了获得足够数量的选定天然存在的隐藻素和合成类似物，用于构效关系 (SAR) 研究、临床前评估和人类临床试验，我们设计了一个通用的合成。正如原始论文中所述，Cryptophycins
• Novel unit B cryptophycin analogues as payloads for targeted therapy
  作者：Eduard Figueras、Adina Borbély、Mohamed Ismail、Marcel Frese、Norbert Sewald

  DOI：10.3762/bjoc.14.109

  日期：——

  Cryptophycins are naturally occurring cytotoxins with great potential for chemotherapy. Since targeted therapy provides new perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to homing devices are required. We describe the design, synthesis and biological evaluation of three new unit B cryptophycin analogues. The O-methyl group of the unit

  隐藻素是天然存在的细胞毒素，具有巨大的化疗潜力。由于靶向疗法为癌症治疗提供了新的视角，因此需要新的有效的含细胞毒性剂的类似物，其包含与缀合装置结合的官能团。我们描述了三种新的单位B隐藻霉素类似物的设计，合成和生物学评估。B D-酪氨酸类似物的O-甲基被O-（烯丙氧基乙基）部分，O-（羟乙基）基团或O-（（（叠氮基乙氧基）乙氧基）乙氧乙基）取代基取代。尽管前两个保持亚纳摩尔范围内的细胞毒性，但三甘醇间隔基与末端叠氮化物的连接导致活性完全丧失。
• Total Synthesis of Cryptophycin Analogues via a Scaffold Approach
  作者：J. Adam McCubbin、Matthew L. Maddess、Mark Lautens

  DOI：10.1021/ol0609356

  日期：2006.7.1

  Allylation of in situ generated beta,gamma-unsaturated aldehydes affords rapid access to vinyl halide analogues of fragment A of the cryptophycins. Three scaffolds are prepared in gram quantities by a ring-closing metathesis approach. Derivatization via a variety of cross-coupling protocols is possible, which affords novel analogues of these potent antimitotic agents.
• US06013626
  申请人：——

  公开号：——

  公开（公告）日：——
• EP0830136A4
  申请人：——

  公开号：EP0830136A4

  公开（公告）日：2001-01-24