4-[4-(4-pentoxyphenyl)phenyl]-N-[(3S,6S,9S,11R,15S,18S,20R,24S,25S,26S)-11,20,25-trihydroxy-3,15-bis[(1R)-1-hydroxyethyl]-6-[(1R)-1-hydroxy-2-(4-hydroxyphenyl)ethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-18-yl]benzamide | 179118-65-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 4-[4-(4-pentoxyphenyl)phenyl]-N-[(3S,6S,9S,11R,15S,18S,20R,24S,25S,26S)-11,20,25-trihydroxy-3,15-bis[(1R)-1-hydroxyethyl]-6-[(1R)-1-hydroxy-2-(4-hydroxyphenyl)ethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-18-yl]benzamide
• CAS: 179118-65-1
• 化学式: C₅₈H₇₃N₇O₁₅
• 分子量: 1108.26
• InChiKey: PASUSXDXQLBYHO-LBNAWZSASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  80
• 可旋转键数：
  14
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  337
• 氢给体数：
  12
• 氢受体数：
  15

反应信息

• 作为反应物：
  描述：

  甲基膦酞二氯 、 4-[4-(4-pentoxyphenyl)phenyl]-N-[(3S,6S,9S,11R,15S,18S,20R,24S,25S,26S)-11,20,25-trihydroxy-3,15-bis[(1R)-1-hydroxyethyl]-6-[(1R)-1-hydroxy-2-(4-hydroxyphenyl)ethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-18-yl]benzamide 在 lithium hexamethyldisilazane 作用下， 生成
  参考文献：
  名称：

  棘皮菌素B的水溶性前药类似物的合成。

  摘要：

  据报道，在两个棘皮菌素半合成衍生物的酚羟基上可以轻松合成膦酸酯和磷酸酯前药。ECB化合物的水溶性和稳定性特征随所用烷基的选择而变化。在某些情况下，脂族侧链较小的酯前药保留了抗真菌活性，同时增强了水溶性。

  DOI：

  10.1016/s0960-894x(99)00290-5
• 作为产物：
  描述：

  阿尼芬净 在 三乙基硅烷 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 以70%的产率得到4-[4-(4-pentoxyphenyl)phenyl]-N-[(3S,6S,9S,11R,15S,18S,20R,24S,25S,26S)-11,20,25-trihydroxy-3,15-bis[(1R)-1-hydroxyethyl]-6-[(1R)-1-hydroxy-2-(4-hydroxyphenyl)ethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-18-yl]benzamide
  参考文献：
  名称：

  棘皮菌素B的水溶性前药类似物的合成。

  摘要：

  据报道，在两个棘皮菌素半合成衍生物的酚羟基上可以轻松合成膦酸酯和磷酸酯前药。ECB化合物的水溶性和稳定性特征随所用烷基的选择而变化。在某些情况下，脂族侧链较小的酯前药保留了抗真菌活性，同时增强了水溶性。

  DOI：

  10.1016/s0960-894x(99)00290-5

文献信息

• Reshaping Echinocandin Antifungal Drugs To Circumvent Glucan Synthase Point‐Mutation‐Mediated Resistance
  作者：Moriah Jospe‐Kaufman、Efrat Ben‐Zeev、Austin Mottola、Anna Dukhovny、Judith Berman、Shmuel Carmeli、Micha Fridman

  DOI：10.1002/anie.202314728

  日期：2024.2.26

  Echinocandins are a class of antifungal drugs that inhibit the activity of the β‐(1,3)‐glucan synthase complex, which synthesizes fungal cell wall β‐(1,3)‐glucan. Echinocandin resistance is linked to mutations in the FKS gene, which encodes the catalytic subunit of the glucan synthase complex. We present a molecular‐docking‐based model that provides insight into how echinocandins interact with the target Fks protein: echinocandins form a ternary complex with both Fks and membrane lipids. We used reductive dehydration of alcohols to generate dehydroxylated echinocandin derivatives and evaluated their potency against a panel of Candida pathogens constructed by introducing resistance‐conferring mutations in the FKS gene. We found that removing the hemiaminal alcohol, which drives significant conformational alterations in the modified echinocandins, reduced their efficacy. Conversely, eliminating the benzylic alcohol of echinocandins enhanced potency by up to two orders of magnitude, in a manner dependent upon the resistance‐conferring mutation. Strains that have developed resistance to either rezafungin, the most recently clinically approved echinocandin, or its dehydroxylated derivative RZF‐1, exhibit high resistance to rezafungin while demonstrating moderate resistance to RZF‐1. These findings provide valuable insight for combating echinocandin resistance through chemical modifications.