(-)-棉子素 | 20300-26-9

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 避孕药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 中文名称: (-)-棉子素
• 中文别名: 棉子醇；棉酚；棉籽酚；棉子酚
• 英文名称: (rac)-gossypol
• 英文别名: Gossypol；AT-101；2,2'-bis(8-formyl-1,6,7-trihydroxy-5-isopropyl-3-methylnaphtalene)；7-(8-formyl-1,6,7-trihydroxy-3-methyl-5-propan-2-ylnaphthalen-2-yl)-2,3,8-trihydroxy-6-methyl-4-propan-2-ylnaphthalene-1-carbaldehyde
• CAS: 20300-26-9；303-45-7；90141-22-3
• 化学式: C₃₀H₃₀O₈
• mdl: MFCD00017352
• 分子量: 518.563
• InChiKey: QBKSWRVVCFFDOT-UHFFFAOYSA-N

物化性质

• 熔点：
  181-183 C
• 沸点：
  522.63°C (rough estimate)
• 密度：
  1.1912 (rough estimate)
• 溶解度：
  DMSO 中≥25.95 mg/mL；不溶于水；乙醇中≥2.1 mg/mL
• LogP：
  5.419 (est)
• 物理描述：
  Solid
• 颜色/状态：
  Yellow, crystalline pigment
• 蒸汽压力：
  7.06X10-21 mm Hg at 25 °C (est)
• 分解：
  When heated to decomposition it emits acrid smoke and irritating fumes.
• 解离常数：
  pKa1 = 6.73; pKa2 = 7.38; pKa3 = 11.82; pKa 4 = 12.68; pKa5 = 13.89 (est)
• 碰撞截面：
  228.1 Ų [M+H-H2O]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  38
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.266
• 拓扑面积：
  156
• 氢给体数：
  6
• 氢受体数：
  8

ADMET

毒理性

• 毒性总结

棉酚可能通过调节Bax和Bcl-2蛋白质来引发细胞凋亡。它也是钙调神经磷酸酶和蛋白激酶C的抑制剂，并且已被证明能与钙调蛋白结合。

Gossypol may cause apoptosis via the regulation of Bax and Bcl-2 proteins. It is also an inhibitor of calcineurin and protein kinases C, and has been shown to bind calmodulin. (L1239)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类无致癌性（未列入国际癌症研究机构IARC清单）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

棉酚可能会导致低钾血症，从而引起暂时性瘫痪。

Gossypol may cause low potassium levels and thus causes temporary paralysis. (L1239)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

口服（摄入）（L1817）；皮肤（L1817）

Oral (ingestion) (L1817) ; dermal (L1817)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

症状包括疲劳、肌肉无力，在极端情况下会导致瘫痪。

Symptoms of gossypol poisoning include fatigue, muscle weakness, and at its most extreme, paralysis. (L1239)

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

脂溶性棉酚从胃肠道容易被吸收。它与氨基酸，特别是赖氨酸和饮食中的铁高度结合。棉酚的共轭、代谢和尿液排泄受限；大部分通过粪便排出。

Lipid-soluble gossypol is readily absorbed from the GI tract. It is highly protein-bound to amino acids, especially lysine, and to dietary iron. Conjugation, metabolism, and urinary excretion of gossypol is limited; most is eliminated in the feces.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

棉酚简介

棉酚（gossypol），又称棉毒素或棉籽醇，是一种从棉属植物中提取的黄色多酚二萘化合物。

生物活性

Gossypol 是一种口服活性多酚，分离自棉籽和根。它能够抑制 5α-reductase 1 和 3α-hydroxysteroid dehydrogenase，IC50 值分别为 3.33 μM 和 0.52 μM。Gossypol 还能与 Bcl 蛋白结合，特别是对 Bcl-XL 和 Bcl-2 的 IC50 值分别为 0.4 μM 和 10 μM。在多种癌细胞中，Gossypol 可诱导凋亡和生长抑制。

靶点

Target	Value
Bcl-xL (Cell-free assay)	0.4 μM
3α-hydroxysteroid dehydrogenase (Cell-free assay)	0.52 μM
5α-reductase 1 (Cell-free assay)	3.33 μM
Bcl-2 (Cell-free assay)	10 μM

体外研究

Gossypol 是一种从棉籽和根中分离出来的天然产物，已作为抗肿瘤剂进行研究。其对 Bcl-xL 的 Ki 值为 0.5 至 0.6 μM；对 Bcl-2 的 Ki 值为 0.2-0.3 mM。Gossypol 包含两种手性异构体，即 (-)-Gossypol 和 (+)-Gossypol。在 6 天 MTT 检测中，(-)-Gossypol 对 UM-SCC-6 和 UM-SCC-14A 细胞系的生长抑制作用显著高于 (±)-Gossypol（P<0.001）。(±)-Gossypol 在较高剂量（10 μM）时显示出中等程度的生长抑制效应（P<0.0001）。

化学性质

棉酚为棕黄色粉末，易溶于甲醇、乙醇和 DMSO 等有机溶剂。它来源于锦葵植物棉花的根、茎、叶和种子，其中棉籽仁含量最高。

用途

棉酚具有抗肿瘤作用，并可用作男性避孕药。

类别

有毒物质

毒性分级

高毒

急性毒性

• 大鼠 LD50: 325 毫克/公斤
• 小鼠 LD50: 765 毫克/立方米（4 小时）

火灾危险特性

可燃，火场排出辛辣刺激烟雾

储运特性

库房应低温、通风和干燥；与食品原料分开存放

灭火剂

水、二氧化碳、干粉、砂土

反应信息

• 作为反应物：
  描述：

  (-)-棉子素 在 硫酸 、 溶剂黄146 作用下， 以 乙醚 、 二氯甲烷 、 水 、 异丙醇 为溶剂， 反应 7.0h， 生成
  参考文献：
  名称：

  Synthesis of gossypol atropisomers and derivatives and evaluation of their anti-proliferative and anti-oxidant activity

  摘要：

  Gossypol 1, gossypolone 2, and a series of bis 3 and half Schiffs bases 4 of gossypol were synthesised and tested for anti-proliferative and anti-oxidant activity. (-)-Gossypol (-)-1 was the most potent inhibitor of the proliferation of the HPV-16 keratinocyte cell line (using an MTT viability assay) with a GI(50) of 4.8 mu M. The bis Schiffs base of (-)-gossypol with L-tyrosine ethyl ester (-)-3b was the most potent inhibitor of iron/ascorbate dependent lipid peroxidation (using the thiobarbituric acid test), with an IC50 of 11.7 mu M, with (-)-gossypol being the next most potent of the series, with an IC50 of 13.1 mu M. The results from these initial assays suggest that gossypol, as either a racemic mixture rac-1, or the individual atropisomers (-)-1 or (+)-1, has potential for the treatment of psoriasis. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.04.026
• 作为产物：
  描述：

  gossypol acetic acid 以 乙醚 、 水 为溶剂， 反应 0.17h， 以105 mg的产率得到(-)-棉子素
  参考文献：
  名称：

  一种以醋酸棉酚为原料制备游离棉酚的方法

  摘要：

  本发明涉及一种以醋酸棉酚为原料制备游离棉酚的方法，该方法通过超声破坏醋酸棉酚中醋酸和棉酚之间的分子间氢键，然后让醋酸进入水溶液或饱和食盐水溶液中，实现游离棉酚和醋酸的分离，将粗制游离棉酚进行重结晶得到高纯度的游离棉酚，整个制备过程在室温下进行，并且制备时间短，有效避免棉酚结构氧化和各种异构体之间的转换，该方法原料成本低，工艺流程短，重复性好，纯度高、安全性高，时间短，效率高，本发明具有一定的经济价值和实用价值。

  公开号：

  CN108276263B

文献信息

• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。
• BRM TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
  申请人：Arvinas Operations, Inc.

  公开号：US20190300521A1

  公开（公告）日：2019-10-03

  The present disclosure relates to bifunctional compounds, which find utility as modulators of SMARCA2 or BRM (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand that binds to the Von Hippel-Lindau E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为SMARCA2或BRM（靶蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合Von Hippel-Lindau E3泛素连接酶的配体，另一端结合靶蛋白的双功能化合物，使得靶蛋白与泛素连接酶靠近以实现靶蛋白的降解（和抑制）。本公开展示了与靶蛋白降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由靶蛋白聚集或积累导致的疾病或紊乱。
• [EN] ALANINE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE<br/>[FR] MODULATEURS DE PROTÉOLYSE À BASE D'ALANINE ET PROCÉDÉS D'UTILISATION ASSOCIÉS
  申请人：ARVINAS INC

  公开号：WO2017011590A1

  公开（公告）日：2017-01-19

  The description relates to inhibitors of Apoptosis Proteins (TAPs) binding compounds, including Afunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the IAP E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

  描述涉及抑制凋亡蛋白（TAPs）结合化合物，包括包含相同的A功能化合物，这些化合物作为靶向泛素化的调节剂发挥作用，特别是根据本发明的双功能化合物抑制各种多肽和其他蛋白质的化合物。具体而言，描述提供了一端含有结合到IAP E3泛素连接酶的配体，另一端含有结合到靶蛋白的基团的化合物，使得靶蛋白靠近泛素连接酶以促使该蛋白的降解（和抑制）。可以合成化合物，表现出与几乎任何类型的靶向多肽的降解/抑制一致的广泛药理活性。
• [EN] COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF BROMODOMAIN-CONTAINING PROTEINS<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR LA DÉGRADATION CIBLÉE DE PROTÉINES CONTENANT UN BROMODOMAINE
  申请人：ARVINAS INC

  公开号：WO2017030814A1

  公开（公告）日：2017-02-23

  The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

  本发明涉及双功能化合物，其作为靶向泛素化的调节剂具有实用性，特别是根据本发明抑制各种多肽和其他蛋白质的化合物。具体而言，本发明涉及一端含有结合泛素连接酶的VHL配体，另一端含有结合靶蛋白的基团的化合物，使得靶蛋白靠近泛素连接酶以促使该蛋白的降解（和抑制）。根据本发明的化合物表现出与靶向多肽的降解/抑制一致的广泛的药理活性。
• NAPHTHALENE-BASED INHIBITORS OF ANTI-APOPTOTIC PROTEINS
  申请人：Pellecchia Maurizio

  公开号：US20090105319A1

  公开（公告）日：2009-04-23

  Methods of using apogossypol and its derivatives for treating inflammation is disclosed. Also, there is described a group of compounds having structure A, or a pharmaceutically acceptable salt, hydrate, N-oxide, or solvate thereof are provided: wherein each R is independently selected from the group consisting of H, C(O)X, C(O)NHX, NH(CO)X, SO 2 NHX, and NHSO 2 X, wherein X is selected from the group consisting of an alkyl, a substituted alkyl, an aryl, a substituted aryl, an alkylaryl, and a heterocycle. Compounds of group A may be used for treating various diseases or disorders, such as cancer.

  使用阿波戈司宝及其衍生物治疗炎症的方法被披露。此外，还描述了一组具有结构A的化合物，或其药学上可接受的盐、水合物、N-氧化物或溶剂化合物： 其中每个R独立地选自H、C(O)X、C(O)NHX、NH(CO)X、SO2NHX和NHSO2X组成的组，其中X选自烷基、取代烷基、芳基、取代芳基、烷基芳基和杂环的组。A组化合物可用于治疗各种疾病或疾病，如癌症。