methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(3-chloro-4-methoxyphenyl)propanoate | 162465-44-3

• 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: methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(3-chloro-4-methoxyphenyl)propanoate
• 英文别名: N-(tert-butoxycarbonyl)-3-(3-chloro-4-methoxyphenyl)-D-alanine methyl ester；methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-methoxyphenyl)propanoate；(R)-methyl 3-(3-chloro-4-methoxyphenyl)-2-(tert-butoxycarbonylamino)propanoate；(R)-Methyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-methoxyphenyl)propanoate；methyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate
• CAS: 162465-44-3
• 化学式: C₁₆H₂₂ClNO₅
• 分子量: 343.807
• InChiKey: USCOVXVQFSSNQT-GFCCVEGCSA-N

物化性质

• 沸点：
  463.7±45.0 °C(Predicted)
• 密度：
  1.185±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  73.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(3-chloro-4-methoxyphenyl)propanoate 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 98.5h， 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：

  trimethyl 2-(tert-butoxycarbonylamino)phosphonoacetate 在 (-)-1,2-bis-[(2R,5R)-2,5-diethylphospholano]benzene(cyclooctadiene)rhodium(I) tetrafluoroborate 、 氢气 、 四甲基胍 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 20.0 ℃ 、600.01 kPa 条件下， 反应 37.5h， 生成 methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(3-chloro-4-methoxyphenyl)propanoate
  参考文献：
  名称：

  A two step synthesis of a key unit B precursor of cryptophycins by asymmetric hydrogenation

  摘要：

  开发了一种新的高对映选择性两步法，从商业起始材料中以良好的收率制备出cryptophycins的B单元前体。关键步骤是使用商业化的[(COD)Rh-(R,R)-Et-DuPhos]BF₄催化剂进行不对称氢化反应。该合成路线具有较少的合成步骤、高产率和对映选择性，并避免了危险反应条件。

  DOI：

  10.3762/bjoc.7.32

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
• [EN] NOVEL CRYPTOPHYCIN COMPOUNDS AND CONJUGATES, THEIR PREPARATION AND THEIR THERAPEUTIC USE<br/>[FR] NOUVEAUX COMPOSÉS ET CONJUGUÉS DE CRYPTOPHYCINE, LEUR PRÉPARATION ET LEUR UTILISATION THÉRAPEUTIQUE
  申请人：SANOFI SA

  公开号：WO2017076998A1

  公开（公告）日：2017-05-11

  The present invention relates to cryptophycin compounds of formula (I). The invention also relates to cryptophycin payloads, to cryptophycin conjugates, to compositions containing them and to their therapeutic use, especially as anticancer agents. The invention also relates to the process for preparing these conjugates.

  本发明涉及公式（I）的隐藻素化合物。该发明还涉及隐藻素有效载荷、隐藻素偶联物、含有它们的组合物及其治疗用途，尤其是作为抗癌剂。该发明还涉及制备这些偶联物的过程。
• BIOCATALYTIC SYNTHESIS OF CRYPTOPHYCIN ANTICANCER AGENTS
  申请人：THE REGENTS OF THE UNIVERSITY OF MICHIGAN

  公开号：US20210094942A1

  公开（公告）日：2021-04-01

  The disclosure provides cryptophycin intermediates, cryptophycin analogs, and cryptophycin chimeric molecules useful in treating cancer, as well as methods of producing these compounds and methods of treating cancer.

  该披露提供了在治疗癌症方面有用的隐花链中间体、隐花链类似物和隐花链嵌合分子，以及生产这些化合物的方法和治疗癌症的方法。
• Cryptophycin compounds and conjugates, their preparation and their therapeutic use
  申请人：SANOFI

  公开号：US10941139B2

  公开（公告）日：2021-03-09

  The present invention relates to cryptophycin compounds of formula (I). The invention also relates to cryptophycin payloads, to cryptophycin conjugates, to compositions containing them and to their therapeutic use, especially as anticancer agents. The invention also relates to the process for preparing these conjugates.

  本发明涉及式（I）的隐球霉素化合物。本发明还涉及隐球菌苷有效载荷、隐球菌苷共轭物、含有它们的组合物及其治疗用途，特别是作为抗癌剂。本发明还涉及制备这些共轭物的工艺。
• 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.