2-{[{2-[(4-硝基苯基)磺酰]肼基<联氨基>}(羰基)乙酰基]氨基}苯甲酸 | 124689-65-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 中文名称: 2-{[{2-[(4-硝基苯基)磺酰]肼基&lt联氨基&gt}(羰基)乙酰基]氨基}苯甲酸
• 英文名称: cryptophycin-1
• 英文别名: Cryptophycin 1；(3S,6R,10R,13E,16S)-10-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-3-(2-methylpropyl)-16-[(1S)-1-[(2R,3R)-3-phenyloxiran-2-yl]ethyl]-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone
• CAS: 124689-65-2
• 化学式: C₃₅H₄₃ClN₂O₈
• 分子量: 655.188
• InChiKey: PSNOPSMXOBPNNV-VVCTWANISA-N

物化性质

• 比旋光度：
  White or light colored glassy solid. D +33.8° (c = 1.83 in methanol)
• 沸点：
  889.4±65.0 °C(Predicted)
• 密度：
  1.171±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  46
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  133
• 氢给体数：
  2
• 氢受体数：
  8

安全信息

• 危险等级：
  6.1(b)
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 危险品运输编号：
  UN 3172

制备方法与用途

生物活性

Cryptophycin 1 是一种从念珠蓝藻（Nostoc sp.）中分离出来的有效的细胞毒性抗微管剂。它能够诱导细胞凋亡，并具有抗肿瘤活性和出色的抗增殖能力。

体外研究

• Cryptophycin 1 (50 pM) 能快速引起 SKOV3 和 MDA-MB-435 细胞的形态变化，这些变化与诱导凋亡一致。
• Cryptophycin 1 (50 pM；12-24 h) 导致 MDA-MB-435 细胞在 G2/M 期积累。
• Cryptophycin 1 (100 nM；1-7 min) 显著减少微管缩短和生长事件的速率与范围，并大大增加了衰减或暂停阶段的持续时间。

凋亡分析

• 细胞系：SKOV3 细胞
• 浓度：50 pM
• 孵育时间：4 小时
• 结果：迅速引起细胞收缩，丧失正常椭圆体状形态，并形成膜突起。

细胞周期分析

• 细胞系：MDA-MB-435 细胞
• 浓度：50 pM
• 孵育时间：12, 18, 和 24 小时
• 结果：
  • 在 12 小时时，G2/M 期细胞数量加倍。
  • 18 小时时，仍有大量（58%）细胞处于 G2/M 期。

体内研究

Cryptophycin 1 (静脉注射) 在小鼠中表现出抗肿瘤活性。

反应信息

• 作为反应物：
  描述：

  2-{[{2-[(4-硝基苯基)磺酰]肼基<联氨基>}(羰基)乙酰基]氨基}苯甲酸 在 盐酸 作用下， 以 乙二醇二甲醚 为溶剂， 反应 18.0h， 以433 mg的产率得到(E)-(3S,6R,10R,16S)-16-((1R,2R,3S)-3-Chloro-2-hydroxy-1-methyl-3-phenyl-propyl)-10-(3-chloro-4-methoxy-benzyl)-3-isobutyl-6-methyl-1,4-dioxa-8,11-diaza-cyclohexadec-13-ene-2,5,9,12-tetraone
  参考文献：
  名称：

  Structure determination, conformational analysis, chemical stability studies, and antitumor evaluation of the cryptophycins. Isolation of 18 new analogs from Nostoc sp. strain GSV 224

  摘要：

  Using a modified isolation procedure devoid of methanol, 18 new cyclic cryptophycins have been isolated from Nostoc sp. GSV 224 as minor constituents in addition to cryptophycins-1 (A), -2 (B), -3 (C), and -4 (D). Acyclic cryptophycins are not found, indicating that the previously reported cryptophycins-5 (E methyl ester), -6 (F methyl ester), and -7 (G) are artifacts produced as a consequence of using methanol in the isolation scheme. Seventeen of the new cyclic analogs differ in structure in either one of the two hydroxy acid units, viz. unit A [(5S,6S,7R,8R)-7,8-epoxy-5-hydroxy-6-methyl-8-phenyl-2(E)-octenoic acid for cryptophycin-1 or (5S,6S)-5-hydroxy-6-methyl-8-phenyl-2(E),7(E)-octadienoic acid for cryptophycin-3] and unit D [(2S)-2-hydroxy-4-methylvaleric acid], or one of the two amino acid units, viz. unit B [(2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid] and unit C [(2R)3-amino-2-methylpropionic acid], found in the cyclic ABCD peptolide. In unit A of cryptophycins-26, -28, -30, and -40, the methyl group on C-6 is missing or the Delta(2)-double bond is hydrated. In unit B of cryptophycins-16, -17, -23, 31, -43, and -45, the aromatic ring is phenolic and/or possesses two or zero chlorines. In unit C of cryptophycins-21 and -29, the methyl group on C-2 is missing. In unit D of cryptophycins-18, -19, -49, -50, and -54, a different alkyl group (propyl, isopropyl, or sec-butyl) is attached to C-2. Only one of the new analogs, cryptophycin-24, differs in structure for two units by lacking chlorine in unit B and the methyl group in unit C. Revised structures are presented for cryptophycins-5, -6, and -7 and are correlated with cryptophycin-3, the relative stereochemistry of which has been further rigorously established by X-ray crystallography. NOE studies show that the preferred conformations of most cryptophycins in solution differ from the conformation of cryptophycin-3 in the crystal state. Although cryptophycin-1 is relatively stable at pH 7, both in ionic and nonionic media, the ester bond linking units C and D is fairly labile to solvolysis and mild base hydrolysis. Structure-activity relationship studies indicate that the intact macrolide ring, the epoxide group, the chloro and 0-methyl groups in unit B, and the methyl group in unit C are needed for the in vivo activity of cryptophycin-1.

  DOI：

  10.1021/ja00154a002
• 作为产物：
  描述：

  (E)-methyl 4-phenylbut-3-enoate 在 4-二甲氨基吡啶 、 lead 、 sodium azide 、 phosphate buffer 、 五氟苯基二苯基磷酸酯 、 碘 、 二异丁基氢化铝 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 N,N'-二环己基碳二亚胺 、 锌 、 lithium diisopropyl amide 作用下， 以 乙醚 、 正己烷 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 158.92h， 生成 2-{[{2-[(4-硝基苯基)磺酰]肼基<联氨基>}(羰基)乙酰基]氨基}苯甲酸
  参考文献：
  名称：

  Total Synthesis of Cryptophycins via a Chemoenzymatic Approach

  摘要：

  A highly convergent synthesis of cryptophycins in their enantiomerically-pure forms was achieved. Our strategy consists of the synthesis of the two units 3 and 4 and linking them together to form the macrocyclic ring. The upper unit 3 was prepared from 10 in four steps, and the lower unit 4 was prepared from 20 in three steps. Enantioselective biocatalytic methodology was used to prepare the requisite chiral building blocks, (R)-11 and (R)-19. The stereochemical versatility of this synthetic approach is demonstrated by the synthesis of cryptophycin A and the four diastereomers of cryptophycin C.

  DOI：

  10.1021/jo960972i

文献信息

• Di-substituted maleic amide linker for antibody drug conjugating and preparation method and use thereof
  申请人：Mabwell (shanghai) Bioscience Co., Ltd.

  公开号：US10987430B2

  公开（公告）日：2021-04-27

  Provided in the present invention are a di-substituted maleic amide linker conjugated to an antibody and a preparation method and use thereof. In particular, the present invention conjugates a strongly cytotoxic active substance to a biomacromolecule through a class of new linkers. The class of linkers can selectively act simultaneously with disulphide chains, so as to greatly improve the substance homogeneity of a conjugate. The conjugate prepared by the linker of the present invention has a high inhibitory activity on a cell strain expressing the corresponding antigen. Also provided is a method for preparing the above-mentioned conjugate and the use.

  本发明提供了一种二取代马来酰胺连接物与抗体结合的制备方法及其用途。具体而言，本发明通过一类新连接物将一种强烈细胞毒活性物质与生物大分子结合。这类连接物可以与二硫键同时选择性地作用，从而极大地提高结合物质的均一性。本发明连接物制备的结合物对表达相应抗原的细胞株具有高抑制活性。还提供了制备上述结合物的方法和用途。
• Interleukin-2:remodeling and glycoconjugation of interleukin-2
  申请人：DeFrees Shawn

  公开号：US20050031584A1

  公开（公告）日：2005-02-10

  The invention includes methods and compositions for remodeling a peptide molecule, including the addition or deletion of one or more glycosyl groups to a peptide, and/or the addition of a modifying group to a peptide.

  该发明包括重塑肽分子的方法和组合物，包括向肽分子中添加或删除一个或多个糖基团，和/或向肽分子中添加修饰基团。
• A Versatile Chemoenzymatic Synthesis for the Discovery of Potent Cryptophycin Analogs
  作者：Jennifer J. Schmidt、Yogan Khatri、Scott I. Brody、Catherine Zhu、Halina Pietraszkiewicz、Frederick A. Valeriote、David H. Sherman

  DOI：10.1021/acschembio.9b00998

  日期：2020.2.21

  demonstrated the exceptional flexibility of this enzyme. Semipreparative scale reactions were conducted for isolation and structural characterization of new cryptophycins. Each was then evaluated as a substrate for CrpE P450 and its ability to generate the epoxidized products from these substrates that possess altered electronics at the unit A styrenyl double bond position. Finally, biological evaluation of

  隐藻霉素是大环二肽天然产物的家族，对抗药性癌症显示出异常有效的抗增殖活性。复杂分子的合成和衍生化所面临的独特挑战促使我们研究化学酶法合成方法，该方法旨在获得用于生物学评估的新类似物。隐藻霉素硫酯酶（CrpTE）和隐霉素环氧化酶（CrpE）是一组通用的酶，可催化20多种天然隐藻毒素代谢产物的大环化和环氧化。因此，我们设想了一种药物开发策略，其中涉及将它们用作生产非天然衍生物的独立生物催化剂。在这里 我们开发了12种新的ABCD线性链伸长中间体的可扩展合成方法，该中间体包含杂环芳族基团作为天然A苄基的替代品。使用野生型CrpTE评估了每种中间体的N-乙酰半胱胺活化形式向大环产物的转化，这证明了该酶的出色灵活性。进行了半制备规模的反应，用于新隐藻霉素的分离和结构表征。然后评估每种化合物作为CrpE P450的底物，以及它们从这些底物生成环氧化产物的能力，这些底物在单元A苯乙烯基双键位置具有改变的
• NOVEL CONJUGATES, PREPARATION THEREOF, AND THERAPEUTIC USE THEREOF
  申请人：BOUCHARD Hervé

  公开号：US20120225089A1

  公开（公告）日：2012-09-06

  Provided herein are cryptophycin conjugates and compositions containing them. Methods of making and using such compounds also are provided.

  本发明提供了隐藻素偶联物及其包含它们的组合物。还提供了制备和使用此类化合物的方法。
• Stereospecific Synthesis of Cryptophycin 1
  作者：Lian-Hai Li、Marcus A. Tius

  DOI：10.1021/ol020001r

  日期：2002.5.1

  [reaction: see text] A brief stereospecific synthesis of cryptophycin 1 is described in which (R)-mandelic acid serves as the sole source of asymmetry for unit A. The key step is a hetero-Diels-Alder cycloaddition.

  [反应：见正文]描述了隐藻霉素1的简短立体定向合成，其中（R）-扁桃酸是单元A不对称的唯一来源。关键步骤是异Diels-Alder环加成反应。