benzyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[5-[[6-[[bis(pyridin-2-ylmethyl)amino]methyl]pyridin-2-yl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoate | 1435485-75-8

• 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: benzyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[5-[[6-[[bis(pyridin-2-ylmethyl)amino]methyl]pyridin-2-yl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoate
• CAS: 1435485-75-8
• 化学式: C₆₄H₇₅N₁₇O₇
• 分子量: 1194.41
• InChiKey: VCUIZCGQFOKITD-RWNJCICYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  88
• 可旋转键数：
  34
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  374
• 氢给体数：
  11
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  六氟磷酸钾 、 benzyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[5-[[6-[[bis(pyridin-2-ylmethyl)amino]methyl]pyridin-2-yl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoate 、 、 水 、 cobalt(II) chloride 在 N,N-二异丙基乙胺 、 氧气 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.25h， 以49%的产率得到
  参考文献：
  名称：

  New Peptides with Metal Binding Abilities and Their Use as Drug Carriers

  摘要：

  Many new designed molecules that target efficiently in vitro bacterial metalloproteases were completely inactive in cellulo against Gram negative bacteria. Their activities were limited by the severe restriction of the penetration/diffusion rate through the outer membrane barrier. To bypass this limitation, we have assayed the strategy of metallodrugs, to improve the delivery of hydroxamic acid inhibitors to peptide deformylase. In this metal-chaperone, to facilitate bacterial uptake, the ancillary ligand tris(2-pyridylmethyl)amine (TPA) or di(picolyl)amine (DPA) was functionalized by a tetrapeptide analogue of antimicrobial peptide, RWRW(OBn) (AA08 with TPA) and/or an efflux pump modulator PA beta N (AA09 with TPA and AA27 with DPA). We prepared Co(III), Zn(II), and Cu(II) metallodrugs. Using a fluorescent hydroxamic acid, we showed that, in contrast to Cu(II) metallodrugs, Co(III) metallodrugs were stable in the Mueller Hinton (MH) broth during the time required for bacterial assays. The antibacterial activities were determined against E. coli strain wild-type (AG100) and E. coli strain deleted from acrAB efflux pump (AG100A). While none of the PDFinhs used in this study (SMP289 with an indole scaffold, AT015 and AT019 built on a 1,2,4-oxadiazole scaffold) displayed activity higher than 128 mu M, all the metallodrugs were active with MICs around 8 mu M both against AG100 and AG100A. However, compared to the activities of equimolar combinations of PDFinhs and the free chelating peptides (AA08, AA09, or AA27), they showed similar activities. A synergistic association between AT019 and AA08 or AA09 was determined using the fractional inhibitory concentration with AG100 and AG100A. Combinations of peptides lacking the chelating group with PDFinhs were inefficient. LC-MS analyses showed that the chelating peptides bind Zn(II) cation when incubated in MH broth. These results support the in situ formation of a zinc metallodrug, but we failed to detect it by LC-MS in MH. Nevertheless, this chelating peptides metalated with zinc act as permeabilizers which are more efficient than PA beta N to facilitate the uptake of PDFinhs by Gram(-) bacteria.

  DOI：

  10.1021/bc500317u
• 作为产物：
  描述：

  (5-((6-((bis(pyridin-2-ylmethyl)amino)methyl)pyridin-2-yl)amino)-5-oxopentanoyl)-L-arginyl-L-tryptophyl-L-arginine 、 L-色氨酸苯甲酯 在 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以89 mg的产率得到benzyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[5-[[6-[[bis(pyridin-2-ylmethyl)amino]methyl]pyridin-2-yl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoate
  参考文献：
  名称：

  New Peptide-Based Antimicrobials for Tackling Drug Resistance in Bacteria: Single-Cell Fluorescence Imaging

  摘要：

  New peptide molecules with metal binding :abilities proved to he active against multidrug resistant clinical isolates. One of them, labeled with a dansylated lysine has been imaged inside single-multidrug resistant bacteria cells by deep ultraviolet fluorescence, showing a heterogeneous Subcellular localization. The fluorescence intensity is clearly related to the accumulation of the drug inside the bacteria, being dependent both on its concentration and on the incubation time with cells.

  DOI：

  10.1021/ml400073g

文献信息

• New Peptides with Metal Binding Abilities and Their Use as Drug Carriers
  作者：Anas Allam、Laure Maigre、Mickael Alimi、Rodolphe Alves de Sousa、Assia Hessani、Erwan Galardon、Jean-Marie Pagès、Isabelle Artaud

  DOI：10.1021/bc500317u

  日期：2014.10.15

  Many new designed molecules that target efficiently in vitro bacterial metalloproteases were completely inactive in cellulo against Gram negative bacteria. Their activities were limited by the severe restriction of the penetration/diffusion rate through the outer membrane barrier. To bypass this limitation, we have assayed the strategy of metallodrugs, to improve the delivery of hydroxamic acid inhibitors to peptide deformylase. In this metal-chaperone, to facilitate bacterial uptake, the ancillary ligand tris(2-pyridylmethyl)amine (TPA) or di(picolyl)amine (DPA) was functionalized by a tetrapeptide analogue of antimicrobial peptide, RWRW(OBn) (AA08 with TPA) and/or an efflux pump modulator PA beta N (AA09 with TPA and AA27 with DPA). We prepared Co(III), Zn(II), and Cu(II) metallodrugs. Using a fluorescent hydroxamic acid, we showed that, in contrast to Cu(II) metallodrugs, Co(III) metallodrugs were stable in the Mueller Hinton (MH) broth during the time required for bacterial assays. The antibacterial activities were determined against E. coli strain wild-type (AG100) and E. coli strain deleted from acrAB efflux pump (AG100A). While none of the PDFinhs used in this study (SMP289 with an indole scaffold, AT015 and AT019 built on a 1,2,4-oxadiazole scaffold) displayed activity higher than 128 mu M, all the metallodrugs were active with MICs around 8 mu M both against AG100 and AG100A. However, compared to the activities of equimolar combinations of PDFinhs and the free chelating peptides (AA08, AA09, or AA27), they showed similar activities. A synergistic association between AT019 and AA08 or AA09 was determined using the fractional inhibitory concentration with AG100 and AG100A. Combinations of peptides lacking the chelating group with PDFinhs were inefficient. LC-MS analyses showed that the chelating peptides bind Zn(II) cation when incubated in MH broth. These results support the in situ formation of a zinc metallodrug, but we failed to detect it by LC-MS in MH. Nevertheless, this chelating peptides metalated with zinc act as permeabilizers which are more efficient than PA beta N to facilitate the uptake of PDFinhs by Gram(-) bacteria.
• New Peptide-Based Antimicrobials for Tackling Drug Resistance in Bacteria: Single-Cell Fluorescence Imaging
  作者：Jean-Marie Pagès、Slavka Kascàkovà、Laure Maigre、Anas Allam、Mickael Alimi、Jacqueline Chevalier、Erwan Galardon、Matthieu Réfrégiers、Isabelle Artaud

  DOI：10.1021/ml400073g

  日期：2013.6.13

  New peptide molecules with metal binding :abilities proved to he active against multidrug resistant clinical isolates. One of them, labeled with a dansylated lysine has been imaged inside single-multidrug resistant bacteria cells by deep ultraviolet fluorescence, showing a heterogeneous Subcellular localization. The fluorescence intensity is clearly related to the accumulation of the drug inside the bacteria, being dependent both on its concentration and on the incubation time with cells.