3,2',6'-tris-N-(tert-butoxycarbonyl)-3''-N-(trifluoroacetyl)kanamycin B | 132260-10-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3,2',6'-tris-N-(tert-butoxycarbonyl)-3''-N-(trifluoroacetyl)kanamycin B
• 英文别名: tert-butyl N-[(1S,2R,3R,4S,5R)-5-amino-4-[(2S,3R,4S,5S,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2,2,2-trifluoroacetyl)amino]oxan-2-yl]oxy-2-[(2R,3R,4R,5S,6R)-4,5-dihydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-6-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]oxan-2-yl]oxy-3-hydroxycyclohexyl]carbamate
• CAS: 132260-10-7
• 化学式: C₃₅H₆₀F₃N₅O₁₇
• 分子量: 879.88
• InChiKey: HKZZHRATHMGTHQ-VQKYFWTQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.91
• 重原子数：
  60.0
• 可旋转键数：
  10.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  328.41
• 氢给体数：
  11.0
• 氢受体数：
  18.0

反应信息

• 作为反应物：
  描述：

  3,2',6'-tris-N-(tert-butoxycarbonyl)-3''-N-(trifluoroacetyl)kanamycin B 在 ammonium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 54.0h， 生成 1-N-<(benzyloxy)carbonyl>-3,2',6'-tris-N-(tert-butoxycarbonyl)kanamycin B
  参考文献：
  名称：

  New derivatives of kanamycin B obtained by combined modifications in positions 1 and 6". Synthesis, microbiological properties, and in vitro and computer-aided toxicological evaluation

  摘要：

  Substitution of the C-1 atom in the 2-deoxystreptamine moiety of gentamicin C2, a broad-spectrum aminoglycoside antibiotic, by an axial hydroxymethyl group has been reported to confer protection against most clinically important bacterial enzymes inactivating aminoglycosides, while simultaneously reducing the nephrotoxic potential of this drug. We report here on a similar modification of kanamycin B. Microbiological evaluation, however, revealed no useful protection, as established by the almost complete lack of activity of 1-C-(hydroxymethyl)kanamycin B against an array of organisms producing defined types of aminoglycoside-inactivating enzymes and against which 1-C-(hydroxymethyl)gentamicin C2 and amikacin (1-N-[(S)-2-hydroxy-4-aminobutyryl]kanamycin A) are active. Moreover, toxicological evaluation, based on the in vitro measurement of the drug inhibitory potential toward lysosomal phospholipases, a predictive test of the intrinsic nephrotoxic potential of aminoglycosides, showed not decreased but rather increased toxicity. Comparative conformational analysis of the interactions of the drug with a phosphatidylinositol monolayer explained the lack of protective effect, since no significant change of the mode of insertion of the derivative in this monolayer was detected compared to that of kanamycin B. Combination of a 1-C-(hydroxymethyl) substituent with a 6"-chloro, 6"-azido, or 6"-acetamido substituent resulted in a partial improvement of the toxicological behavior with no loss of activity for the 6"-chloro and the 6"-azido derivatives, but not to the extent of obtaining better derivatives than kanamycin B itself. We, therefore, suggest that the advantages of an axial hydroxymethyl substituent at C-1 are probably restricted to the gentamicin family and do not extend to kanamycins. It might be concluded that the structural differences between gentamicins and kanamycins play an important, still undescribed role both in their effective recognition by aminoglycoside-inactivating enzymes, which are responsible for most of the clinically important cases of resistance to aminoglycosides, and also in the interactions with phospholipids, which in turn cause nephrotoxicity.

  DOI：

  10.1021/jm00108a037
• 作为产物：
  描述：

  二碳酸二叔丁酯 在 zinc(II) acetate dihydrate 作用下， 以 二甲基亚砜 为溶剂， 反应 10.0h， 生成 3,2',6'-tris-N-(tert-butoxycarbonyl)-3''-N-(trifluoroacetyl)kanamycin B
  参考文献：
  名称：

  [EN] NOVEL ANTIBACTERIAL 3"-DERIVATIVES OF 4,6-DISUBSTITUTED 2,5-DIDEOXYSTREPTAMINE AMINOGLYCOSIDE ANTIBIOTICS
  [FR] NOUVEAUX DÉRIVÉS 3" ANTIBACTÉRIENS D'ANTIBIOTIQUES À BASE D'AMINOGLYCOSIDE 2,5-DIDÉSOXYSTREPTAMINE 4,6-DISUBSTITUÉS

  摘要：

  本发明涉及具有抗微生物特性的新型氨基糖苷化合物，适用于作为治疗剂，例如用于治疗哺乳动物疾病的治疗剂，特别是适用于治疗哺乳动物微生物感染的新型治疗剂。本发明还涉及包含所述治疗剂的药物组合物在治疗哺乳动物的医疗状况中的使用，特别是在治疗微生物感染中的使用。本发明的治疗剂和药物组合物在治疗与抗生素耐药微生物相关的疾病方面具有特殊意义。本发明还涉及用于治疗因抗生素类相关细菌耐药而导致治疗变得困难的疾病的化合物，并提供适用于治疗多药耐药（MDR）感染的新型治疗剂。

  公开号：

  WO2020115190A1

文献信息

• SCHEPDAEL, A. VAN;BUSSON, R.;VANDERHAEGHE, H. J.;CLAES, P. J.;VERBIST, L.+, J. MED. CHEM., 34,(1991) N, C. 1483-1492
  作者：SCHEPDAEL, A. VAN、BUSSON, R.、VANDERHAEGHE, H. J.、CLAES, P. J.、VERBIST, L.+

  DOI：——

  日期：——