制霉菌素 | 34786-70-4

• 物质功能分类: 原料药 - 抗生素类药物 - 多烯类药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 制霉菌素
• 中文别名: 制霉菌素A1；制菌霉素
• 英文名称: nystatin
• 英文别名: nystatin A1；nystatine；mycostatin；(1S,3R,4R,7R,9R,11R,15S,16R,17R,18S,19E,21E,25E,27E,29E,31E,33R,35S,36R,37S)-33-[(2R,3S,4S,5S,6R)-4-azaniumyl-3,5-dihydroxy-6-methyloxan-2-yl]oxy-1,3,4,7,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,25,27,29,31-hexaene-36-carboxylate
• CAS: 34786-70-4
• 化学式: C₄₇H₇₅NO₁₇
• 分子量: 926.109
• InChiKey: VQOXZBDYSJBXMA-NQTDYLQESA-N

物化性质

• 熔点：
  >300°C
• 沸点：
  1132.2±65.0 °C(Predicted)
• 密度：
  1.33±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（轻微）、甲醇（轻微、超声处理）、吡啶（轻微）
• 颜色/状态：
  Light yellow powder
• 气味：
  Odor suggestive of cereals
• 蒸汽压力：
  8.7X10-7 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Solutions and aqueous suspensions begin to lose activity soon after preparation. Aqueous suspensions are stable for 10 minutes on heating to 100 °C at pH 7; also stable in moderately alkaline media, but labile at pH 9 and pH 2. Heat, light, and oxygen accelerate decomposition.

• 旋光度：
  Optical rotation at 25 °C/D: -10 deg (glacial acetic acid); +21 deg (pyridine); +12 deg (dimethylformamide); max absorption (ethanol): 290, 307 and 322 nm; optical rotation at 25 °C/D: -7 deg (0.1 N HCl in methanol)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  65
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  320
• 氢给体数：
  12
• 氢受体数：
  18

ADMET

毒理性

• 肝毒性

制霉菌素治疗与血清酶异常的低发生率有关，尽管很难将这些升高归因于制霉菌素。尽管使用了数十年，但没有确凿的急性肝损伤与制霉菌素治疗有关的病例。虽然制霉菌素通常不被吸收，但在胃肠道炎症和损伤的患者中，低浓度的制霉菌素可能会进入血液循环。尽管如此，制霉菌素被认为非常安全，不太可能引起肝损伤。

Nystatin therapy has been associated with a low rate of serum enzyme abnormalities, although it has been difficult to attribute these elevations to nystatin. Despite its use for several decades, there have been no convincing cases of acute hepatic injury linked to nystatin therapy. While nystatin is usually is not normally absorbed, low concentrations may enter the circulation in patients with inflammation and damage to the gastrointestinal tract. Nevertheless, nystatin is considered very safe and is unlikely to cause hepatic injury.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：制霉菌素

Compound:nystatin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

制霉菌素很难渗透眼部。

Nystatin penetrates eye poorly.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

制霉菌素从胃肠道吸收不良，常规剂量后无法获得可检测的血药浓度。口服给药后，制霉菌素几乎全部以未改变的形式随粪便排出。

Nystatin is poorly absorbed from the GI tract, and detectable blood concentrations are not obtained after usual doses. Following oral administration, nystatin is excreted almost entirely in feces as unchanged drug.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在健康的个体中，服用两片溶菌酶含片（400,000单位）后，唾液中制霉菌素的平均浓度超过体外抑制临床重要念珠菌生长所需的浓度，持续时间大约为2小时。

In healthy individuals, mean salivary nystatin concentrations in excess of those required in vitro for growth inhibition of clinically important Candida persist for approximately 2 hours after the beginning of oral dissolution of two nystatin lozenges (400,000 units) administered simultaneously.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

未通过完整皮肤或粘膜的局部应用被吸收。

Not absorbed following topical application to intact skin or mucous membranes.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2942000000

制备方法与用途

化学性质
淡黄色粉末。含有A₁、A₂和A₃三种生物活性成分，还原性较强。悬浮液在pH值7.0时，在100℃下能稳定保持10分钟；光、热、氧会加速其分解；无熔点，加热至160℃以上开始分解。其比旋光度分别为：[α]²⁵D+21°（吡啶）、+12°（二甲基甲酰胺）、-7°（0.1mol/L盐酸的甲醇溶液）和-10°（冰乙酸）。该物质在乙醇中的最大吸收波长为290nm、307nm和322nm。常温下的溶解度如下：水4mg/ml、甲醇11.2mg/ml、乙醇1.2mg/ml、乙二醇8.75 mg/ml、四氯化碳1.23mg/ml、氯仿0.48mg/ml、苯0.28mg/ml。其半数致死量（小鼠，腹腔注射）约为200mg/kg。

用途
用于生化研究，作为高纯细胞培养的防腐剂，并具有抗霉菌作用。

生产方法
通过Streptomyces noursei菌株培养液过滤取菌丝，在50-60℃真空干燥后，用甲醇提取，除去溶剂后干燥获得。

反应信息

• 作为反应物：
  描述：

  N-苄基马来酰亚胺 、 制霉菌素 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以80 mg的产率得到N-(N'-benzylsuccinimidyl)nystatin A1
  参考文献：
  名称：

  [EN] SEMISYNTHETIC DERIVATIVES OF NYSTATIN A1
  [FR] DÉRIVÉS SEMI-SYNTHÉTIQUES DE NYSTATINE A1

  摘要：

  该发明提供了Nystatin A1的半合成衍生物，水溶性盐和络合物，包括这些衍生物的药物组合物和植物保护产品，以及它们作为抗真菌抗生素的用途（公式1a）。

  公开号：

  WO2013132014A1

文献信息

• Fluorescence Imaging of Human Cells with a Novel Conjugate of the Antifungal Nystatin
  作者：Sumbla Sheikh、Alexander Sturzu、Hubert Kalbacher、Thomas Nagele、Christopher Weidenmaier、Marius Horger、Ulrike Ernemann、Stefan Heckl

  DOI：10.2174/15734064113099990028

  日期：2014.4

  The antitumor activity of antibacterial and antifungal compounds has been of interest in the past. In several investigations glycopeptide antibiotics like bleomycin and antifungal agents like itraconazole have shown direct positive results whereas antifungal polyenes such as amphotericin B have been shown to potentiate the effects of antitumor agents. After having investigated the fluorescence-marked antibacterial glycopeptides vancomycin and ramoplanin on various malignant and healthy human cells in previous studies, the present work is focused on the antifungal polyene nystatin. We coupled nystatin to the fluorescent dye fluorescein isothiocyanate (FITC). After confirming the correct mass by mass spectrometry the effect of the conjugate on nine different human cell lines (two benign and seven tumor cell lines) was examined. The character of the uptake was determined by confocal laser scanning microscopy (CLSM) and the uptake was quantified by fluorescence activated cell sorting (FACS). The addition of propidium iodide (PI) allowed for detection and quantification of cell membrane disruption caused by the fluorescein-nystatin conjugate. Uptake of the conjugate was found to vary among the nine cell lines investigated. Conjugate uptake was strongest after 6 hours in most cell lines. Only the two prostate carcinoma cell lines PC3 and LNCaP showed further increase in uptake after long-time (24h) incubation. PI staining in general correlated well with the conjugate FITC staining values. The Colo205 colon carcinoma cell line and the U373 and LN18 glioblastoma cell lines exhibited very low conjugate uptake and PI staining. The results indicate that this conjugate shows potential for future imaging studies on certain human cancer cells.

  过去，抗菌和抗真菌化合物的抗肿瘤活性一直备受关注。在多次调查中 博来霉素等糖肽抗生素和伊曲康唑等抗真菌药物已显示出直接的积极结果 而抗真菌多烯（例如两性霉素 B）已被证明可以增强抗肿瘤药物的作用。 在研究了荧光标记的抗菌糖肽万古霉素和雷莫拉宁对各种 以前的研究主要针对恶性和健康的人体细胞，目前的工作重点是抗真菌多烯制霉菌素。 我们将制霉菌素与荧光染料异硫氰酸荧光素 (FITC) 偶联。按质量确认正确的质量后 光谱分析法测定了缀合物对九种不同人类细胞系（两种良性细胞系和七种肿瘤细胞系）的影响 检查了。通过共焦激光扫描显微镜（CLSM）确定摄取的特征，并通过 通过荧光激活细胞分选术（FACS）进行定量。添加碘化丙啶 (PI) 可进行检测 以及荧光素-制霉菌素缀合物引起的细胞膜破坏的定量。 发现所研究的九种细胞系对缀合物的吸收有所不同。 6 后结合物吸收最强 大多数细胞系中的小时。只有两种前列腺癌细胞系 PC3 和 LNCaP 在治疗后显示摄取进一步增加。 长时间（24小时）孵化。一般来说，PI 染色与缀合物 FITC 染色值相关性良好。这 Colo205 结肠癌细胞系以及 U373 和 LN18 胶质母细胞瘤细胞系表现出非常低的缀合物摄取 和PI染色。 结果表明，这种结合物显示出未来对某些人类癌细胞进行成像研究的潜力。
• EP2174944
  申请人：——

  公开号：——

  公开（公告）日：——
• WO2007/96137
  申请人：——

  公开号：——

  公开（公告）日：——
• Chemical modification of tetraene macrolide antibiotic nystatin A1 with organophosphorus alcohols
  作者：V. V. Belakhov、Yu. D. Shenin、A. V. Dogadina、D. V. Aleshunina、B. I. Ionin

  DOI：10.1134/s1070363214020248

  日期：2014.2

  Esterification of tetraene macrolide antibiotic nystatin A(1) with organophosphorus alcohols has been studied; formation of the corresponding organophosphorus esters of the antibiotic has been confirmed. Physicochemical, spectral, and biological properties of the prepared esters have been studied. The esterification products have revealed high antifungal activity towards the Candida yeast fungi.
• METHODS OF QUALITATIVELY AND/OR QUANTITATIVELY ANALYZING PROPERTIES OF ACTIVATABLE ANTIBODIES AND USES THEREOF
  申请人：CytomX Therapeutics, Inc.

  公开号：EP3655779A1

  公开（公告）日：2020-05-27