10-acetoxymethyl-2'O-acetyl-10,11-anhydro-10-desmethyl-6-O-methyl-descladinosyl-erythromycin A | 717889-08-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 10-acetoxymethyl-2'O-acetyl-10,11-anhydro-10-desmethyl-6-O-methyl-descladinosyl-erythromycin A
• CAS: 717889-08-2
• 化学式: C₃₄H₅₇NO₁₂
• 分子量: 671.826
• InChiKey: DQEUBTHJRTWSFO-CHURYVBZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.58
• 重原子数：
  47.0
• 可旋转键数：
  8.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  167.36
• 氢给体数：
  2.0
• 氢受体数：
  13.0

反应信息

• 作为反应物：
  描述：

  10-acetoxymethyl-2'O-acetyl-10,11-anhydro-10-desmethyl-6-O-methyl-descladinosyl-erythromycin A 在 sodium hydride 、 戴斯-马丁氧化剂 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 2'O-acetyl-11N,12O-cyclocarbamate-11-deshydroxy-10-desmethyl-O⁶-methyl-10-methylene-3-oxodescladinosylerythromycin A
  参考文献：
  名称：

  Introduction of a nitrogen-containing side chain appended on C-10 of cethromycin leads to reduced CYP3A4 inhibition (WO2014049356A1)

  摘要：

  Introduction: Infections caused by antibiotic-resistant bacteria pose an increasing risk for clinical treatment. Macrolide-lincosamide-streptogramin B is becoming increasingly ineffective due to the methylation at the binding site of bacteria. Despite great efforts on the natural product, erythromycin, only one derivative, that is, telithromycin, capable of fighting against resistant bacteria has so far been marketed. However, the 3'-dimethylamino group is readily metabolized to a nitroso group, which would inhibit CYP3A4, a very important metabolic enzyme responsible for nearly half of all marketed drugs.Areas covered: Modifications at C-10 of erythromycin were seldom reported. This invention disclosed novel ketolides that had a side chain comprising additional nitrogen atoms in place of the original 10-methyl group. Surprisingly, introduction of the side chain at C-10 led to reduced cytochrome inhibition and increased metabolic stability. As a result, the limited ability to inhibit CYP3A4 would relieve the drug-drug interaction and improve the safety of drug co-administration.Expert opinion: This invention opens a new avenue for future modifications to the erythromycin family. It remains unclear how the side chain effected on reduction of CYP inhibition. To fully identify structure-activity relationships, the MIC data of the derivatives on gram-negative bacteria is desirable.

  DOI：

  10.1517/13543776.2014.971754
• 作为产物：
  描述：

  3-hydroxy-6-O-methyl-10,11-anhydroerythromycin A 在 N-氯代丁二酰亚胺 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 10-acetoxymethyl-2'O-acetyl-10,11-anhydro-10-desmethyl-6-O-methyl-descladinosyl-erythromycin A
  参考文献：
  名称：

  Introduction of a nitrogen-containing side chain appended on C-10 of cethromycin leads to reduced CYP3A4 inhibition (WO2014049356A1)

  摘要：

  Introduction: Infections caused by antibiotic-resistant bacteria pose an increasing risk for clinical treatment. Macrolide-lincosamide-streptogramin B is becoming increasingly ineffective due to the methylation at the binding site of bacteria. Despite great efforts on the natural product, erythromycin, only one derivative, that is, telithromycin, capable of fighting against resistant bacteria has so far been marketed. However, the 3'-dimethylamino group is readily metabolized to a nitroso group, which would inhibit CYP3A4, a very important metabolic enzyme responsible for nearly half of all marketed drugs.Areas covered: Modifications at C-10 of erythromycin were seldom reported. This invention disclosed novel ketolides that had a side chain comprising additional nitrogen atoms in place of the original 10-methyl group. Surprisingly, introduction of the side chain at C-10 led to reduced cytochrome inhibition and increased metabolic stability. As a result, the limited ability to inhibit CYP3A4 would relieve the drug-drug interaction and improve the safety of drug co-administration.Expert opinion: This invention opens a new avenue for future modifications to the erythromycin family. It remains unclear how the side chain effected on reduction of CYP inhibition. To fully identify structure-activity relationships, the MIC data of the derivatives on gram-negative bacteria is desirable.

  DOI：

  10.1517/13543776.2014.971754

文献信息

• Clarithromycin macrolides modified by unsaturation at the C10-position
  作者：Mioara Andrei、Kjell Undheim

  DOI：10.1016/j.phytol.2022.06.001

  日期：2022.8

  C10-C-unsaturated clarithromycin congeners have been developed from corresponding C10-methyl erythromycin A ketolides. Activation of the unreactive C10-methyl group and subsequent Pd-catalyzed cross-coupling reactions afford novel C-10-unsaturated clarithromycins for antibacterial screening programs. By related methodology azides can be prepared and used for the preparation of corresponding 1,2,3-triazoles

  已经从相应的 C10-甲基红霉素 A 酮内酯开发了用于合成C10- C-不饱和克拉霉素同系物的方法。非反应性 C10-甲基的活化和随后的 Pd 催化的交叉偶联反应为抗菌筛选程序提供了新的 C-10-不饱和克拉霉素。通过相关的方法可以制备叠氮化物并用于通过点击化学制备相应的1,2,3-三唑。这项工作证明了过渡金属催化在天然产物半合成和潜在 SAR 研究中的重要性。筛选产品对肺炎链球菌和金黄色葡萄球菌的呼吸道病原体菌株的体外MIC值表明新的抗菌剂与克拉霉素参考化合物接近等效。
• [EN] 10-SUBSTITUTED MACROLIDE ANTIBIOTICS<br/>[FR] MACROLIDES
  申请人：ALPHARMA APS

  公开号：WO2004056843A3

  公开（公告）日：2004-10-21