incednine aglycon | 1009805-53-1

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: incednine aglycon
• 英文别名: incednam；(3Z,5E,7E,9E,11R,12S,13Z,15E,17E,19E,21E,24S)-11,12-dihydroxy-3-methoxy-5,11,17,21,24-pentamethyl-1-azacyclotetracosa-3,5,7,9,13,15,17,19,21-nonaen-2-one
• CAS: 1009805-53-1
• 化学式: C₂₉H₃₉NO₄
• 分子量: 465.633
• InChiKey: VTLZZYINHDUOQU-DCKIOERHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  34
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  78.8
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  incednine aglycon 、 甲氧基-三氟甲基苯 在 吡啶 作用下， 反应 4.0h， 以92.4%的产率得到(3Z,5E,7E,9E,11R,12S,13Z,15E,17E,19E,21E,24S)-11-hydroxy-3-methoxy-5,11,17,21,24-pentamethyl-2-oxoazacyclotetracosa-3,5,7,9,13,15,17,19,21-nonaen-12-yl (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
  参考文献：
  名称：

  Discovery of Incednine as a Potent Modulator of the Anti-apoptotic Function of Bcl-xL from Microbial Origin

  摘要：

  Anti-apoptotic oncoproteins Bcl-2 and BcI-xL are overexpressed in many cancers and play a crucial role in cancer initiation, progression, and resistance to chemotherapy. Therefore, the discovery of a functional inhibitor for these proteins and improved understanding of the molecular mechanisms of these proteins will be an aid to novel anti-tumor therapies. Here, using chemical-genetic cell-based screening, we have discovered a chemically and biologically unique substance, incednine, as a novel functional modulator of Bcl-2/Bcl-xL from the fermentation broth of Streptomyces sp. ML-693-90F3. This compound was isolated as a HCI salt by solvent extraction and using centrifugal liquid-liquid partition chromatography. Its structure was elucidated by spectroscopic analysis, X-ray crystallographic analysis, and computational studies. Incednine has a molecular formula, C42H63N3O8, and consists of a novel skeletal structure, enol-ether amide in a 24-membered macrolactam core, with two aminosugars. Bcl-xL-overexpressing Ms-1 cells displayed resistance to several anti-tumor agents; however, anti-tumor agent-induced cell death was observed only when cells were treated with incednine. Overexpression of BcI-xL inhibited cell death in Bax-overexpressing HEK293T cells by forming a complex with Bax, whereas Bcl-xL failed to inhibit cell death in the presence of incednine without affecting the heterodimerization of Bcl-xL and Bax. These findings suggest that incednine serves as a potent modulator of the anti-apoptotic Bcl-2/Bcl-xL distinct from the other known Bcl-2 inhibitors and could provide a chemical probe to study the underlying mechanisms of Bcl-2/Bcl-xL.

  DOI：

  10.1021/ja710124p
• 作为产物：
  描述：

  incednam 10,11-bis-trimethylsilyl ether 在 四丁基氟化铵 、 溶剂黄146 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 以87%的产率得到incednine aglycon
  参考文献：
  名称：

  Incednine的糖苷配基-Incednam的全合成

  摘要：

  描述了incednam（1）的第一个全合成，即抗生素incednine（2）的糖苷配基。据报道，Incednine对抗凋亡的癌蛋白Bcl-2和Bcl-xL表现出显着的抑制活性。1的合成从C1-C13亚基3和C14-C23亚基4的制备开始。通过在3和4之间应用Stille偶联，然后进行内酰胺化，可实现新型24元大环化合物的构建。

  DOI：

  10.1021/ol102400c

文献信息

• Total Synthesis of Incednam, the Aglycon of Incednine
  作者：Takashi Ohtani、Shinya Tsukamoto、Hiroshi Kanda、Kensuke Misawa、Yoshifumi Urakawa、Takahiro Fujimaki、Masaya Imoto、Yoshikazu Takahashi、Daisuke Takahashi、Kazunobu Toshima

  DOI：10.1021/ol102400c

  日期：2010.11.5

  The first total synthesis of incednam (1), the aglycon of antibiotic incednine (2), is described. Incednine has been reported to exhibit significant inhibitory activity against the antiapoptotic oncoproteins Bcl-2 and Bcl-xL. The synthesis of 1 commenced with the preparation of the C1−C13 subunit 3 and the C14−C23 subunit 4. The construction of the novel 24-membered macrocycle was achieved by the application

  描述了incednam（1）的第一个全合成，即抗生素incednine（2）的糖苷配基。据报道，Incednine对抗凋亡的癌蛋白Bcl-2和Bcl-xL表现出显着的抑制活性。1的合成从C1-C13亚基3和C14-C23亚基4的制备开始。通过在3和4之间应用Stille偶联，然后进行内酰胺化，可实现新型24元大环化合物的构建。
• Discovery of Incednine as a Potent Modulator of the Anti-apoptotic Function of Bcl-xL from Microbial Origin
  作者：Yushi Futamura、Ryuichi Sawa、Yoji Umezawa、Masayuki Igarashi、Hikaru Nakamura、Kimiko Hasegawa、Mikio Yamasaki、Etsu Tashiro、Yoshikazu Takahashi、Yuzuru Akamatsu、Masaya Imoto

  DOI：10.1021/ja710124p

  日期：2008.2.1

  Anti-apoptotic oncoproteins Bcl-2 and BcI-xL are overexpressed in many cancers and play a crucial role in cancer initiation, progression, and resistance to chemotherapy. Therefore, the discovery of a functional inhibitor for these proteins and improved understanding of the molecular mechanisms of these proteins will be an aid to novel anti-tumor therapies. Here, using chemical-genetic cell-based screening, we have discovered a chemically and biologically unique substance, incednine, as a novel functional modulator of Bcl-2/Bcl-xL from the fermentation broth of Streptomyces sp. ML-693-90F3. This compound was isolated as a HCI salt by solvent extraction and using centrifugal liquid-liquid partition chromatography. Its structure was elucidated by spectroscopic analysis, X-ray crystallographic analysis, and computational studies. Incednine has a molecular formula, C42H63N3O8, and consists of a novel skeletal structure, enol-ether amide in a 24-membered macrolactam core, with two aminosugars. Bcl-xL-overexpressing Ms-1 cells displayed resistance to several anti-tumor agents; however, anti-tumor agent-induced cell death was observed only when cells were treated with incednine. Overexpression of BcI-xL inhibited cell death in Bax-overexpressing HEK293T cells by forming a complex with Bax, whereas Bcl-xL failed to inhibit cell death in the presence of incednine without affecting the heterodimerization of Bcl-xL and Bax. These findings suggest that incednine serves as a potent modulator of the anti-apoptotic Bcl-2/Bcl-xL distinct from the other known Bcl-2 inhibitors and could provide a chemical probe to study the underlying mechanisms of Bcl-2/Bcl-xL.