trichodermin | 4682-50-2

• 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: trichodermin
• 英文别名: [(1S,2R,7R,9R,11R,12S)-1,2,5-trimethylspiro[8-oxatricyclo[7.2.1.02,7]dodec-5-ene-12,2'-oxirane]-11-yl] acetate
• CAS: 4682-50-2
• 化学式: C₁₇H₂₄O₄
• 分子量: 292.375
• InChiKey: HNEGCRMUYSKRRR-IKIFYQGPSA-N

物化性质

• 熔点：
  46°, 58-60° (Colvin)
• 比旋光度：
  D20 -11° (c = 1 in chloroform)
• 沸点：
  bp0.05 110-112°
• 密度：
  1.19±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  48.1
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

代谢

曲霉菌素是亲脂性的，因此能够轻易通过皮肤、肠道和肺粘膜被吸收。它们主要在肝脏通过细胞色素P-450和特定于曲霉菌素的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定的代谢活性。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体外。

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

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）。 (A3101)

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

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

接触皮肤或口服摄入后，三环唑霉毒素会导致皮肤或肠粘膜迅速出现刺激反应，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。

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)

反应信息

• 作为反应物：
  描述：

  trichodermin 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 5.0h， 以89%的产率得到(4β)-12,13-epoxytrichothec-9-en-4-ol
  参考文献：
  名称：

  曲霉毒素衍生物作为杀真菌剂在水稻上的合成及抗真菌活性。

  摘要：

  合成并表征了二十种新的Trichoderminmin衍生物2a-5，它们在4、8、9、10、16位上含有烷氧基，酰氧基和Br基。评价了新化合物对水稻假黑穗病（Ustilaginoidea virens），水稻鞘枯病（Rhizoctonia solani）和稻瘟病（Magnaporthe grisea）的抗真菌活性。生物测定的结果表明，抗真菌活性特别容易受到4、8和16位变化的影响，而对9和10位变化却不敏感。这些目标化合物中的大多数在浓度为50 mg l（-1）时均表现出良好的抗真菌活性。在9位带有CHO基团的化合物4（9-甲酰三氯薄荷醇; EC50为0.80 mg l（-1））与商用杀真菌剂原杀虫威（prochloraz）（EC50 0）表现出几乎相同的抗Ustilaginoidea virens真菌活性水平。82 mg l（-1）），而化合物3f（（8R）-8-{[（（E）-3-phenylprop-2-enoyl]

  DOI：

  10.1002/cbdv.201200135

文献信息

• Synthesis and antifungal activity of trichodermin derivatives
  作者：Jing Li Cheng、Yong Zhou、Jin Hao Zhao、Chulong Zhang、Fu Cheng Lin

  DOI：10.1016/j.cclet.2010.04.033

  日期：2010.9

  Abstract A series of derivatives were synthesized from trichodermin ( 1 ) which was an antifungal metabolite produced by Trichoderma taxi sp. nov. Their structures were confirmed by 1 H NMR, MS spectrum. Their antifungal activities were evaluated in vitro . The preliminary structure activity relationships (SAR) results indicated that the double bond, epoxide moiety and ester group were main pharmacophore

  摘要从木霉出租车蛋白产生的抗真菌代谢产物trichodermin（1）合成了一系列衍生物。十一月 它们的结构通过1 H NMR，MS光谱确认。他们的抗真菌活性进行了体外评价。初步的结构活性关系（SAR）结果表明，双键，环氧化物部分和酯基是主要的药效团元素，C4位的立体化学也起关键作用，化合物1e-1g对稻瘟病菌具有较强的抗真菌活性。比1。
• Synthesis and biological evaluation of novel trichodermin derivatives as antifungal agents
  作者：Min Zheng、Ting-Ting Yao、Xiao-Jun Xu、Jing-Li Cheng、Jin-Hao Zhao、Guo-Nian Zhu

  DOI：10.1016/j.bmcl.2014.05.047

  日期：2014.8

  discover more potential antifungal agents, 17 novel trichodermin derivatives were designed and synthesized by modification of 3 and 4a. The structures of all the synthesized compounds were confirmed by 1H NMR, ESI-MS and HRMS. Their antifungal activities against Ustilaginoidea oryzae and Pyricularia oryzae were evaluated. Most of the target compounds showed potent inhibitory activity, in which 4g showed

  为了发现更多潜在的抗真菌剂，通过修饰3和4a设计并合成了17种新颖的trichoderminmin衍生物。通过1 H NMR，ESI-MS和HRMS确认所有合成化合物的结构。评价了它们对米曲霉和稻瘟病菌的抗真菌活性。大多数目标化合物均显示出有效的抑制活性，其中4g的抑制作用优于4a和市售的杀菌剂丙草胺。此外，4h表现出与4a相当的抑制活性。此外，4i和4l对稻瘟病菌表现出优异的抑制作用。另外，发现化合物9对所有测试的真菌菌株比3更具活性，EC 50值分别为0.47和3.71 mg L -1。
• Synthesis, antifungal activity, and QSAR study of novel trichodermin derivatives
  作者：Jing-Li Cheng、Min Zheng、Ting-Ting Yao、Xiao-Liang Li、Jin-Hao Zhao、Min Xia、Guo-Nian Zhu

  DOI：10.1080/10286020.2014.962522

  日期：2015.1.2

  to discover more potential antifungal agents, in this study, 21 novel trichodermin derivatives containing conjugated oxime ester (5a–5u) were designed and synthesized and were screened for in vitro antifungal activity. The bioassay tests showed that some of them exhibited good inhibitory activity against the tested pathogenic fungi. Compound 5a exhibited better activity against Pyricularia oryzae and

  为了发现更多潜在的抗真菌剂，在这项研究中，设计并合成了21种含有共轭肟酯（5a - 5u）的新型trichoderminmin衍生物，并对其体外抗真菌活性进行了筛选。生物测定测试表明，其中一些对被测病原真菌表现出良好的抑制活性。化合物5a中显示出更好的活性抗Pyriculari一个米曲霉和Sclerotonia菌核病比木霉，和化合物5J显示特定的活动对P.米曲霉和灰葡萄孢。定量构效关系（QSAR）表明，log  P和硬度是生物活性的两个关键参数。结果表明，这些可能是开发具有进一步结构修饰作用的杀菌剂的潜在先导化合物。
• Synthesis and Antifungal Activities of Trichodermin Derivatives as Fungicides on Rice
  作者：Xiaojun Xu、Jingli Cheng、Yong Zhou、Chulong Zhang、Xiaoming Ou、Weike Su、Jinhao Zhao、Guonian Zhu

  DOI：10.1002/cbdv.201200135

  日期：2013.4

  group at C(8) exhibited much higher antifungal activities against Rhizoctonia solani and Magnaporthe grisea than the commercial fungicides prochloraz (EC50 0.96 mg l(-1) ) and propiconazole (EC50 5.92 mg l(-1) ), respectively. These data reveal that compounds 3f and 4 possess high antifungal activities and may serve as lead compounds for the development of fungicides in the future.

  合成并表征了二十种新的Trichoderminmin衍生物2a-5，它们在4、8、9、10、16位上含有烷氧基，酰氧基和Br基。评价了新化合物对水稻假黑穗病（Ustilaginoidea virens），水稻鞘枯病（Rhizoctonia solani）和稻瘟病（Magnaporthe grisea）的抗真菌活性。生物测定的结果表明，抗真菌活性特别容易受到4、8和16位变化的影响，而对9和10位变化却不敏感。这些目标化合物中的大多数在浓度为50 mg l（-1）时均表现出良好的抗真菌活性。在9位带有CHO基团的化合物4（9-甲酰三氯薄荷醇; EC50为0.80 mg l（-1））与商用杀真菌剂原杀虫威（prochloraz）（EC50 0）表现出几乎相同的抗Ustilaginoidea virens真菌活性水平。82 mg l（-1）），而化合物3f（（8R）-8-[（（E）-3-phenylprop-2-enoyl]
• Synthesis of Trichodermin Derivatives and Their Antimicrobial and Cytotoxic Activities
  作者：Javier E. Barúa、Mercedes de la Cruz、Nuria de Pedro、Bastien Cautain、Rosa Hermosa、Rosa E. Cardoza、Santiago Gutiérrez、Enrique Monte、Francisca Vicente、Isidro G. Collado

  DOI：10.3390/molecules24203811

  日期：——

  valuable tool in preparing new molecules with a trichothecene skeleton. In this work, we developed the hemisynthesis of trichodermin and trichodermol derivatives in order to evaluate their antimicrobial and cytotoxic activities and to study the chemo-modulation of their bioactivity. Some derivatives with a short chain at the C-4 position displayed selective antimicrobial activity against Candida albicans

  单端孢霉烯真菌毒素被认为是具有高度生物活性的化合物，可用于设计新的有用的生物活性分子。在 Trichoderma brevicompactum 中，单端孢霉烯生物合成的第一个特定步骤是由萜烯环化酶、单端孢霉烯合酶进行的，该酶催化二磷酸法呢基转化为单端孢霉烯并由 tri5 基因编码。tri5 的过度表达导致木霉菌素（一种单端孢霉烯型毒素）水平增加，这是制备具有单端孢霉烯骨架的新分子的宝贵工具。在这项工作中，我们开发了木霉素和木霉酚衍生物的半合成，以评估它们的抗菌和细胞毒性活性并研究其生物活性的化学调节。一些在 C-4 位置具有短链的衍生物显示出对白色念珠菌的选择性抗菌活性，并且它们的 MIC 值与木霉所显示的值相似。重要的是要强调对化合物 9、13 和 15 观察到的细胞毒性选择性，它们的平均 IC50 值为 2 μg/mL，并且对致瘤细胞系 MCF-7（乳腺癌）和对 Fa2N4（非肿瘤细胞）具有细胞毒性。永生化的人肝细胞）。