Roridin A | 14729-29-4

• 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
• 英文名称: Roridin A
• 英文别名: (1R,3R,8R,12S,13R,17R,18E,20Z,24R,25S,26S)-12-hydroxy-17-[(1R)-1-hydroxyethyl]-5,13,25-trimethylspiro[2,10,16,23-tetraoxatetracyclo[22.2.1.03,8.08,25]heptacosa-4,18,20-triene-26,2'-oxirane]-11,22-dione
• CAS: 14729-29-4
• 化学式: C₂₉H₄₀O₉
• 分子量: 532.6
• InChiKey: NSFWWJIQIKBZMJ-PAGWOCKZSA-N

物化性质

• 熔点：
  198-204 °C
• 沸点：
  752.4±60.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)
• 溶解度：
  氯仿：≥10 mg/mL，澄清，无色

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  38
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  124
• 氢给体数：
  2
• 氢受体数：
  9

ADMET

代谢

曲霉菌素是亲脂性的，因此可以通过皮肤、肠道和肺粘膜轻易吸收。它们主要通过肝脏中的细胞色素P-450和曲霉菌素特异性羧酸酯酶活性进行代谢，尽管其他组织，如肾脏、脾脏和肠道也表现出一些代谢活性。曲霉菌素通过水解、羟基化、脱环氧化和葡萄糖苷酸化等反应代谢转化为毒性较低的代谢物。代谢物通过尿液和粪便排出。

Trichothecenes are lipophilic and thus easily absorbed through the skin, gut, and pulmonary mucosa. They are metabolized mainly by cytochrome P-450 and trichothecene-specific carboxylesterase activity in the liver, although other tissues such as the kidney, spleen, and intestine also show some metabolic activity. Trichothecenes are metabolically transformed to less toxic metabolites by such reactions as hydrolysis, hydroxylation, de-epoxidation, and glucuronidation. Metabolites are excreted in the urine and feces. (L1910, L1949)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

与许多其他真菌毒素不同，曲霉毒素不需要代谢激活就能发挥其生物活性，而是直接与细胞组分反应。曲霉毒素对大多数真核细胞具有细胞毒性，这是由于它们强大的抑制蛋白质合成能力。它们通过自由穿过质膜并具有高亲和力地与核糖体结合来实现这一点。具体来说，它们干扰位于大28S核糖核酸3'端的多肽转移酶的活性位点，并抑制蛋白质合成的起始、延伸或终止步骤，以及导致多核糖体解聚。蛋白质合成是所有组织的必备功能，但在积极和快速生长和分裂的细胞组织中，对毒素非常敏感。此外，与核糖体结合被认为会激活与免疫反应和凋亡相关的下游信号事件中的蛋白质，如丝裂原活化蛋白激酶。这被称为核糖体毒性应激反应。曲霉毒素还可能引起一些膜结构的改变，导致脂质过氧化增加和线粒体中电子传递活性的抑制。它们还可以通过产生反应性氧种诱导凋亡。曲霉毒素的进一步次要效果包括抑制RNA和DNA合成，以及抑制有丝分裂。(L1948, L1949, A2962, A2963, A2964, A2980)

Unlike many other mycotoxins, trichothecenes do not require metabolic activation to exert their biological activity, instead directly reacting with cellular components. Trichothecenes are cytotoxic to most eukaryotic cells due to their powerful ability to inhibit protein synthesis. They do this by freely moving across the plasma membrane and binding specifically to ribosomes with high-affinity. Specifically, they interfere with the active site of peptidyl transferase at the 3'-end of large 28S ribosomal RNA and inhibit the initiation, elongation or termination step of protein synthesis, as well as cause polyribosomal disaggregation. Protein synthesis is an essential function in all tissues, but tissues where cells are actively and rapidly growing and dividing are very susceptible to the toxins. Additionally, binding to ribosomes is thought to activate proteins in downstream signalling events related to immune response and apoptosis, such as mitogen-activated protein kinases. This is known as ribotoxic stress response. Trichothecenes may also induce some alterations in membrane structure, leading to increased lipid peroxidation and inhibition of electron transport activity in the mitochondria. They can further induce apoptosis through generation of reactive oxygen species. Further secondary effects of trichothecenes include inhibition of RNA and DNA synthesis, and also inhibition of mitosis. (L1948, L1949, A2962, A2963, A2964, A2980)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

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

Trichothecenes是一种多器官有毒物质，包括厌食和体重下降、生长迟缓、神经系统疾病、心血管改变、免疫抑制、血液凝固失调、皮肤毒性、生殖能力下降、骨髓损伤以及食源性的白细胞减少症。

Trichothecenes have multiorgan effects including anoerxia and weight loss, growth retardation, nervous disorders, cardiovascular alterations, immunodepression, hemostatic derangements, skin toxicity, decreased reproductive capacity, bone marrow damage, and alimentary toxic aleukia. (L1948, L1949, A2964)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

口服、皮肤、吸入和parenteral（被污染的药物）。

Oral, dermal, inhalation, and parenteral (contaminated drugs). (A3101)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

直接皮肤应用或口服摄入后，三环脱氧毒素类霉菌毒素可以迅速刺激皮肤或肠粘膜，包括皮肤刺激、灼热和瘙痒、皮疹或水泡，以及出血。眼睛接触可能导致流泪、眼睛疼痛、结膜炎、眼部烧灼感和长达1周的视力模糊。症状还包括恶心、呕吐、疲劳、呼吸困难，以及导致低血压和休克的急性血管效应。(L1948, L1949)

After direct dermal application or oral ingestion, the trichothecene mycotoxins can cause rapid irritation to the skin or intestinal mucosa, including skin irritation, burning and itching, rash or blisters, and bleeding. Eye contact can cause tearing, eye pain, conjunctivitis, burning sensations about the eyes, and blurred vision for up to 1 week. Symptoms also include nausea, vomiting, fatigue, dyspnea, and acute vascular effects leading to hypotension and shock. (L1948, L1949)

来源:Toxin and Toxin Target Database (T3DB)

安全信息

• 危险等级：
  6.1(a)
• 危险品标志：
  T+
• 安全说明：
  S28,S36/37,S45
• 危险类别码：
  R28
• 危险类别：
  6.1(a)
• 危险品运输编号：
  UN 3462 6.1/PG 1

反应信息

• 作为反应物：
  描述：

  、 咪唑 、 Roridin A 、 叔丁基二甲基氯硅烷 、 在 silica gel 、 ethyl acetate n-hexane 、 ethyl 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 以acetate/hexane, to afford 137 mg of the product as a foamy white solid (49%)的产率得到Acetate hexane
  参考文献：
  名称：

  Two-step pretargeting methods using improved biotin-active agent

  摘要：

  本文披露了与预先靶向递送诊断和治疗剂有关的方法、化合物、组合物和工具包。具体地，描述了生物素的放射金属标记方法和改进的生物素放射卤素化方法，以及相关化合物。此外，还讨论了清除剂、抗配体靶向基团共轭物、靶细胞保留增强基团和其他方法。

  公开号：

  US05630996A1

文献信息

• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。
• CYCLIC ETHER PYRAZOL-4-YL-HETEROCYCLYL-CARBOXAMIDE COMPOUNDS AND METHODS OF USE
  申请人：Genentech, Inc.

  公开号：US20140088117A1

  公开（公告）日：2014-03-27

  Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R 2 is a cyclic ether and X is thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  公式I的环醚吡唑-4-基-杂环基-羧酰胺化合物，包括立体异构体、几何异构体、互变异构体和其药学上可接受的盐，其中R2为环醚，X为噻唑基、吡啶基、吡啶基或嘧啶基，可用于抑制Pim激酶，并用于治疗由Pim激酶介导的癌症等疾病。公开了使用公式I化合物进行体外、体内和体内诊断、预防或治疗哺乳动物细胞中的这类疾病或相关病理条件的方法。
• [EN] COMPOUNDS COMPRISING CLEAVABLE LINKER AND USES THEREOF<br/>[FR] COMPOSÉS COMPRENANT UN LIEUR CLIVABLE ET LEURS UTILISATIONS
  申请人：INTOCELL INC

  公开号：WO2019008441A1

  公开（公告）日：2019-01-10

  Provided are a compound including a cleavable linker, a use thereof, and an intermediate compound for preparing the same, and more particularly, the compound including a cleavable linker of the present invention may include an active agent (for example, a drug, a toxin, a ligand, a probe for detection, etc.) having a specific function or activity, a SO2 functional group which is capable of selectively releasing the active agent, and a functional group which triggers a chemical reaction, a physicochemical reaction and/or a biological reaction by external stimulation, and may further include a ligand (for example, oligopeptide, polypeptide, antibody, etc.) having binding specificity for a desired target receptor.

  提供了一种包括可切割连接物的化合物，其用途，以及用于制备该化合物的中间体化合物，更具体地，本发明的包括可切割连接物的化合物可能包括具有特定功能或活性的活性剂（例如，药物，毒素，配体，用于检测的探针等），能够选择性释放活性剂的SO2官能团，以及通过外部刺激触发化学反应，物理化学反应和/或生物反应的官能团，并且还可以包括具有与所需靶受体结合特异性的配体（例如，寡肽，多肽，抗体等）。
• [EN] HETEROCYCLIC LSF INHIBITORS AND THEIR USES<br/>[FR] INHIBITEURS DE LSF HÉTÉROCYCLES ET LEURS UTILISATIONS
  申请人：UNIV BOSTON

  公开号：WO2021150835A1

  公开（公告）日：2021-07-29

  The present invention is directed to heterocyclic SV40 Factor (LSF) inhibitors and their uses. In some implementations, the present invention discloses small-molecule compounds of Formula (I). In some implementations, the compounds of Formula (I) are used in methods for inhibiting LSF in a subject. In some implementations, the compounds of Formula (I) are used in methods for treating cancer in a subject.

  本发明涉及杂环SV40因子（LSF）抑制剂及其用途。在某些实施例中，本发明揭示了化合物的分子式（I）。在某些实施例中，分子式（I）的化合物用于抑制受试者中的LSF。在某些实施例中，分子式（I）的化合物用于治疗受试者中的癌症。