1-C-(hydroxymethyl)-1-deamino-1-nitro-3,2',6',3''-tetrakis-N-(tert-butoxycarbonyl)kanamycin B | 132260-16-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-C-(hydroxymethyl)-1-deamino-1-nitro-3,2',6',3''-tetrakis-N-(tert-butoxycarbonyl)kanamycin B
• 英文别名: tert-butyl N-[(1S,2R,3S,4S,5S)-4-[(2S,3R,4S,5S,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2-methylpropan-2-yl)oxycarbonylamino]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-hydroxy-5-(hydroxymethyl)-5-nitrocyclohexyl]carbamate
• CAS: 132260-16-3
• 化学式: C₃₉H₆₉N₅O₂₁
• 分子量: 943.998
• InChiKey: QBFBALDZCDAEMM-AKDBYQOLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.38
• 重原子数：
  65.0
• 可旋转键数：
  12.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  374.99
• 氢给体数：
  11.0
• 氢受体数：
  21.0

反应信息

• 作为反应物：
  描述：

  1-C-(hydroxymethyl)-1-deamino-1-nitro-3,2',6',3''-tetrakis-N-(tert-butoxycarbonyl)kanamycin B 在 Raney nickel W₂ catalyst 氢气 、 三氟乙酸 作用下， 以 甲醇 为溶剂， 25.0 ℃ 、405.3 kPa 条件下， 反应 3.0h， 生成 1-C-(hydroxymethyl)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：

  卡那霉素 B 在 palladium on activated charcoal ammonium hydroxide 、 4,4'-硫联二(6-叔丁基-2-甲基苯酚) 、 zinc diacetate 、 氢气 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 氯仿 、 水 、 二甲基亚砜 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 25.0~90.0 ℃ 、303.98 kPa 条件下， 反应 67.25h， 生成 1-C-(hydroxymethyl)-1-deamino-1-nitro-3,2',6',3''-tetrakis-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

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：——