(1R,3S,5R,6R,9R,11R,15S,16S,17R,18S,19E,21E,23E,25E,27E,29E,31E,33R,35S,36S,37S)-33-[(2R,3S,4S,5S,6R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-6-methyl-3,5-bis(triethylsilyloxy)oxan-2-yl]oxy-1-methoxy-15,16,18-trimethyl-13-oxo-3,5,6,9,11,17,37-heptakis(triethylsilyloxy)-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid | 136280-49-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯类和类似物
• 英文名称: (1R,3S,5R,6R,9R,11R,15S,16S,17R,18S,19E,21E,23E,25E,27E,29E,31E,33R,35S,36S,37S)-33-[(2R,3S,4S,5S,6R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-6-methyl-3,5-bis(triethylsilyloxy)oxan-2-yl]oxy-1-methoxy-15,16,18-trimethyl-13-oxo-3,5,6,9,11,17,37-heptakis(triethylsilyloxy)-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid
• CAS: 136280-49-4
• 化学式: C₁₁₇H₂₁₁NO₁₉Si₉
• 分子量: 2188.73
• InChiKey: RWWPTVXOZAIFDS-MFMDZWBGSA-N

物化性质

• 沸点：
  1354.6±65.0 °C(Predicted)
• 密度：
  1.03±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  32.21
• 重原子数：
  146.0
• 可旋转键数：
  52.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  221.92
• 氢给体数：
  2.0
• 氢受体数：
  18.0

反应信息

• 作为反应物：
  描述：

  (1R,3S,5R,6R,9R,11R,15S,16S,17R,18S,19E,21E,23E,25E,27E,29E,31E,33R,35S,36S,37S)-33-[(2R,3S,4S,5S,6R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-6-methyl-3,5-bis(triethylsilyloxy)oxan-2-yl]oxy-1-methoxy-15,16,18-trimethyl-13-oxo-3,5,6,9,11,17,37-heptakis(triethylsilyloxy)-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid 在 叠氮磷酸二苯酯 、 三乙胺 作用下， 以 四氢呋喃 、 水 为溶剂， 生成
  参考文献：
  名称：

  [EN] ANTIFUNGAL COMPOUNDS AND METHODS
  [FR] COMPOSÉS ANTIFONGIQUES ET PROCÉDÉS S'Y RAPPORTANT

  摘要：

  本文描述的式(I)和(II)的化合物，或其药学上可接受的盐，以及包含这些化合物、盐或其组合的药物组成物被描述，还描述了制备它们的方法。这些化合物、盐和组成物对抑制真菌生长有用。例如，在一种实施方式中，可以通过向需要治疗的受试者施用这些化合物、盐和/或组成物的有效量来治疗真菌感染。

  公开号：

  WO2017100171A1
• 作为产物：
  描述：

  (1R,3S,5R,6R,9R,11R,15S,16R,17R,18S,19E,21E,23E,25E,27E,29E,31E,33R,35S,36R,37S)-33-[(2R,3S,4S,5S,6R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-3,5,6,9,11,17,37-heptahydroxy-1-methoxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid 、 三乙基硅基三氟甲磺酸酯 在 2,6-二甲基吡啶 作用下， 生成 (1R,3S,5R,6R,9R,11R,15S,16S,17R,18S,19E,21E,23E,25E,27E,29E,31E,33R,35S,36S,37S)-33-[(2R,3S,4S,5S,6R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-6-methyl-3,5-bis(triethylsilyloxy)oxan-2-yl]oxy-1-methoxy-15,16,18-trimethyl-13-oxo-3,5,6,9,11,17,37-heptakis(triethylsilyloxy)-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid
  参考文献：
  名称：

  [EN] ANTIFUNGAL COMPOUNDS AND METHODS
  [FR] COMPOSÉS ANTIFONGIQUES ET PROCÉDÉS S'Y RAPPORTANT

  摘要：

  本文描述的式(I)和(II)的化合物，或其药学上可接受的盐，以及包含这些化合物、盐或其组合的药物组成物被描述，还描述了制备它们的方法。这些化合物、盐和组成物对抑制真菌生长有用。例如，在一种实施方式中，可以通过向需要治疗的受试者施用这些化合物、盐和/或组成物的有效量来治疗真菌感染。

  公开号：

  WO2017100171A1

文献信息

• Derivatives of Amphotericin B
  申请人：Revolution Medicines, Inc.

  公开号：US20160304548A1

  公开（公告）日：2016-10-20

  Disclosed are derivatives of amphotericin B (AmB) characterized by improved therapeutic index compared to AmB. The AmB derivatives include C16 ureas, carbamates, and amides according to Formula (I); C3′-substituted C16 ureas, carbamates, and amides according to Formula (II); C16 acyls according to Formula (III); C2′epi-C16 ureas, carbamates, and amides according to Formula (IV); and C16 oxazolidinone derivatives according to Formula (V). Also disclosed are pharmaceutical compositions comprising the AmB derivatives, and therapeutic methods of using the AmB derivatives.

  披露了与AmB相比具有改善的治疗指数的Amphotericin B（AmB）衍生物。这些AmB衍生物包括根据公式（I）的C16脲、碳酸酯和酰胺；根据公式（II）的C3′-取代的C16脲、碳酸酯和酰胺；根据公式（III）的C16酰基；根据公式（IV）的C2′epi-C16脲、碳酸酯和酰胺；以及根据公式（V）的C16噁唑烷酮衍生物。还披露了包括这些AmB衍生物的药物组合物，以及使用这些AmB衍生物的治疗方法。
• [EN] AMPHOTERICIN B DERIVATIVE WITH REDUCED TOXICITY<br/>[FR] DÉRIVÉ D'AMPHOTÉRICINE B À TOXICITÉ RÉDUITE
  申请人：UNIV ILLINOIS

  公开号：WO2014165676A1

  公开（公告）日：2014-10-09

  Provided are an amphotericin B (AmB) derivative with an improved therapeutic index over amphotericin B, pharmaceutical compositions comprising the AmB derivative, methods of making the AmB derivative and the pharmaceutical composition, and their use in methods of inhibiting growth of a yeast or fungus and treating a yeast or fungal infection. The amphotericin B derivative, denoted C2'deOAmB, differs from the parent compound in that it lacks the hydroxyl group at the 2' position on mycosamine. This difference in structure results in (i) retained capacity to bind ergosterol and inhibit growth of yeast, (ii) greatly reduced capacity to bind cholesterol, and (iii) essentially no toxicity to human cells.

  提供了一种改进了治疗指数的两性霉素B（AmB）衍生物，其中包括该AmB衍生物的制药组合物，制备该AmB衍生物和制药组合物的方法，以及它们在抑制酵母或真菌生长和治疗酵母或真菌感染的方法中的使用。该两性霉素B衍生物被标记为C2'deOAmB，与母体化合物不同的是，它在蘑菇糖胺上的2'位置缺乏羟基团。这种结构上的差异导致（i）保留了结合麦角固醇和抑制酵母生长的能力，（ii）大大降低了结合胆固醇的能力，（iii）对人类细胞基本没有毒性。
• A Post-PKS Oxidation of the Amphotericin B Skeleton Predicted to be Critical for Channel Formation Is Not Required for Potent Antifungal Activity
  作者：Daniel S. Palacios、Thomas M. Anderson、Martin D. Burke

  DOI：10.1021/ja075739o

  日期：2007.11.1

  The clinically vital antimycotic agent amphotericin B represents the archetypal example of a channel-forming small molecule. The leading model for self-assembly of the amphotericin B channel predicts that the C(41) carboxylate and the C(3') ammonium ions form intermolecular salt bridges/hydrogen bonds that are critical for stability. We herein report a flexible degradative synthesis pathway that enables the removal of either or both of these groups from amphotericin B. We further demonstrate with extensive NMR experiments that deleting these groups does not alter the conformation of the polyene macrolide skeleton. As predicted by the leading model, amphotericin B derivatives lacking the mycosamine sugar that contains the C(3') ammonium ion are completely inactive against Saccharomyces cerevisiae. However, strikingly-and in strong contradiction with the current model-the amphotericin B derivative lacking the C(41) carboxylate is at least equipotent to the natural product. Collectively, these findings demonstrate that the leading model for the mechanism of action of amphotericin B must be significantly revised-either the C(41) carboxylate is not required for channel formation or channel formation is not required for antifungal activity.
• C2′-OH of Amphotericin B Plays an Important Role in Binding the Primary Sterol of Human Cells but Not Yeast Cells
  作者：Brandon C. Wilcock、Matthew M. Endo、Brice E. Uno、Martin D. Burke

  DOI：10.1021/ja403255s

  日期：2013.6.12

  Amphotericin B (AmB) is a clinically vital antimycotic but is limited by its severe toxicity. Binding ergosterol, independent of channel formation, is the primary mechanism by which AmB kills yeast, and binding cholesterol may primarily account for toxicity to human cells. The leading structural model predicts that the C2' hydroxyl group on the mycosamine appendage is critical for binding both sterols. To test this, the C2'-OH was synthetically deleted, and the sterol binding capacity of the resulting derivative, C2'deOAmB, was directly characterized via isothermal titration calorimetry. Surprisingly, C2'deOAmB binds ergosterol and, within the limits of detection of this experiment, does not bind cholesterol. Moreover, C2'deOAmB is nearly equipotent to AmB against yeast but, within the limits of detection of our assays, is nontoxic to human cells in vitro. Thus, the leading structural model for AmB/sterol binding interactions is incorrect, and C2'deOAmB is an exceptionally promising new antifungal agent