di-tert-butyl dodecane-1,12-diylbis((3-aminopropyl)carbamate) | 336881-11-9

• 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: di-tert-butyl dodecane-1,12-diylbis((3-aminopropyl)carbamate)
• 英文别名: tert-butyl N-(3-aminopropyl)-N-[12-[3-aminopropyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]dodecyl]carbamate
• CAS: 336881-11-9
• 化学式: C₂₈H₅₈N₄O₄
• 分子量: 514.793
• InChiKey: KMVMYFDANWYNKV-UHFFFAOYSA-N

物化性质

• 沸点：
  593.0±43.0 °C(Predicted)
• 密度：
  0.990±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  36
• 可旋转键数：
  23
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.93
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  di-tert-butyl dodecane-1,12-diylbis((3-aminopropyl)carbamate) 在 碳酸氢钠 、 苯甲醚 、 三氟乙酸 作用下， 以 乙醇 为溶剂， 反应 3.0h， 生成 N²-[3-(12-[(3-[4-amino-6-(dimethylamino)-1,3,5-triazin-2-yl]aminopropyl)amino]dodecylamino)propyl]-N⁴,N⁴-dimethyl-1,3,5-triazine-2,4,6-triamine
  参考文献：
  名称：

  Synthesis and Biological Evaluation of s-Triazine Substituted Polyamines as Potential New Anti-Trypanosomal Drugs

  摘要：

  The P2 transporter is a nucleoside transporter which is unique to the protozoan parasite Trypanosoma brucei, the causative organism of Human African Trypanosomasis. The transporter has been shown to bind some structural motifs not recognized by other transporters. In this paper we describe the use of the melamine motif, a substrate of the P2 transporter, as a potential tool to selectively deliver polyamine analogues to the parasites. The synthesis of a number of polyamine analogues attached to a variety of melamine analogues is described. Many of the compounds were shown to competitively inhibit uptake of adenosine, indicating that they are recognized by the transporter. Some of the compounds showed good in vitro activity against the parasites.

  DOI：

  10.1021/jm010854+
• 作为产物：
  描述：

  1,12-二氨基十二烷 在 Ra-Ni lithium hydroxide 、 氢气 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 为溶剂， 反应 64.0h， 生成 di-tert-butyl dodecane-1,12-diylbis((3-aminopropyl)carbamate)
  参考文献：
  名称：

  Synthesis and Biological Evaluation of s-Triazine Substituted Polyamines as Potential New Anti-Trypanosomal Drugs

  摘要：

  The P2 transporter is a nucleoside transporter which is unique to the protozoan parasite Trypanosoma brucei, the causative organism of Human African Trypanosomasis. The transporter has been shown to bind some structural motifs not recognized by other transporters. In this paper we describe the use of the melamine motif, a substrate of the P2 transporter, as a potential tool to selectively deliver polyamine analogues to the parasites. The synthesis of a number of polyamine analogues attached to a variety of melamine analogues is described. Many of the compounds were shown to competitively inhibit uptake of adenosine, indicating that they are recognized by the transporter. Some of the compounds showed good in vitro activity against the parasites.

  DOI：

  10.1021/jm010854+

文献信息

• Investigation of Indolglyoxamide and Indolacetamide Analogues of Polyamines as Antimalarial and Antitrypanosomal Agents
  作者：Jiayi Wang、Marcel Kaiser、Brent Copp

  DOI：10.3390/md12063138

  日期：——

  Pure compound screening has previously identified the indolglyoxy lamidospermidine ascidian metabolites didemnidine A and B (2 and 3) to be weak growth inhibitors of Trypanosoma brucei rhodesiense (IC50 59 and 44 μM, respectively) and Plasmodium falciparum (K1 dual drug resistant strain) (IC50 41 and 15 μM, respectively), but lacking in selectivity (L6 rat myoblast, IC50 24 μM and 25 μM, respectively). To expand the structure–activity relationship of this compound class towards both parasites, we have prepared and biologically tested a library of analogues that includes indoleglyoxyl and indoleacetic “capping acids”, and polyamines including spermine (PA3-4-3) and extended analogues PA3-8-3 and PA3-12-3. 7-Methoxy substituted indoleglyoxylamides were typically found to exhibit the most potent antimalarial activity (IC50 10–92 nM) but with varying degrees of selectivity versus the L6 rat myoblast cell line. A 6-methoxyindolglyoxylamide analogue was the most potent growth inhibitor of T. brucei (IC50 0.18 μM) identified in the study: it, however, also exhibited poor selectivity (L6 IC50 6.0 μM). There was no apparent correlation between antimalarial and anti-T. brucei activity in the series. In vivo evaluation of one analogue against Plasmodium berghei was undertaken, demonstrating a modest 20.9% reduction in parasitaemia.

  纯化合物筛选之前已确定，indolglyoxy lamidospermidine海鞘代谢物didemnidine A和B（2和3）对锥虫（Trypanosoma brucei rhodesiense）的生长抑制作用较弱（IC50分别为59和44 μM），以及对抗疟原虫（Plasmodium falciparum K1双重耐药株）（IC50分别为41和15 μM），但缺乏选择性（L6大鼠肌母细胞，IC50分别为24 μM和25 μM）。为了扩展这种化合物类别的结构-活性关系，针对这两种寄生虫，我们准备并进行了包括indoleglyoxyl和indoleacetic“封端酸”的类似物库，以及多胺如精胺（PA3-4-3）及其扩展的类似物PA3-8-3和PA3-12-3的生物测试。7-甲氧基取代的indoleglyoxylamides通常表现出最强的抗疟活动（IC50 10–92 nM），但与L6大鼠肌母细胞系相比，选择性程度各异。6-甲氧基indolglyoxylamide类似物是本研究中发现的对T. brucei的最强生长抑制剂（IC50 0.18 μM）；然而，它的选择性也较差（L6 IC50 6.0 μM）。在系列化合物中，抗疟活动与抗T. brucei活动之间没有明显相关性。对一种类似物进行抗Plasmodium berghei的体内评估，显示出寄生血症减少20.9%的适度效果。
• Synthesis and in vitro and in vivo evaluation of antimalarial polyamines
  作者：Lydia P.P. Liew、A. Norrie Pearce、Marcel Kaiser、Brent R. Copp

  DOI：10.1016/j.ejmech.2013.07.055

  日期：2013.11

  found to exhibit the most potent activity towards the dual drug resistant strain K1 of P. falciparum with IC50's in the range of 1.3–9.5 nM, and selectivity indices (SI) of 42,300 to 4880. In vivo evaluation of three analogues against Plasmodium berghei was undertaken, with one demonstrating a modest 27.9% reduction in parasitaemia.

  我们最近报道，精胺的1,14-二苯乙酰胺衍生物表现出有效的nM恶性疟原虫体外生长抑制特性。为了扩大该化合物类别与疟疾的结构-活性关系，我们准备并进行了生物学测试，该库包括苯甲酰胺和3-苯基丙酰胺“封端酸”基团，以及包括精胺（PA3-4-3）的多胺和扩链类似物PA3-8-3和PA3-12-3。通常发现2-羟基和2,5-二甲氧基类似物对恶性疟原虫的双重耐药菌株K1表现出最有效的活性，IC 50在1.3–9.5 nM范围内，并且选择性指数（SI）在42,300至4880之间。体内评估三种类似物对进行了伯氏疟原虫，其中一个表明寄生虫血症的适度降低了27.9％。
• 6-Bromoindolglyoxylamido derivatives as antimicrobial agents and antibiotic enhancers
  作者：Steven A. Li、Melissa M. Cadelis、Kenneth Sue、Marine Blanchet、Nicolas Vidal、Jean Michel Brunel、Marie-Lise Bourguet-Kondracki、Brent R. Copp

  DOI：10.1016/j.bmc.2019.04.004

  日期：2019.5

  increased incidence of drug-resistant strains of bacteria and a lack of novel drugs in development creates an urgency for the search for new antimicrobials. Initial screening of compounds from an in-house library identified two 6-bromoindolglyoxylamide polyamine derivatives (3 and 4) that exhibited intrinsic antimicrobial activity towards Gram-positive bacteria, Staphylococcus aureus and S. intermedius with

  细菌耐药菌株的发生率增加与开发中缺乏新药的结合为寻找新的抗菌剂提供了紧迫性。从内部库中对化合物进行的初步筛选鉴定出了两种6-溴吲哚基乙酰胺酰胺多胺衍生物（3和4），它们对革兰氏阳性细菌，金黄色葡萄球菌和中间链球菌与多胺3均表现出固有的抗菌活性，并且还显示出针对其的体外抗生素增强特性抗革兰氏阴性菌铜绿假单胞菌。制备了一系列的6-溴衍生物（5-15）并进行了生物学评估，鉴定出对大肠杆菌具有增强的抗菌活性并且具有中等至优异的抗真菌特性的类似物。包含精胺链的多胺3，
• Indole-3-Acetamido-Polyamines as Antimicrobial Agents and Antibiotic Adjuvants
  作者：Kenneth Sue、Melissa M. Cadelis、Evangelene S. Gill、Florent Rouvier、Marie-Lise Bourguet-Kondracki、Jean Michel Brunel、Brent R. Copp

  DOI：10.3390/biom13081226

  日期：——

  The widespread incidence of antimicrobial resistance necessitates the discovery of new classes of antimicrobials as well as adjuvant molecules that can restore the action of ineffective antibiotics. Herein, we report the synthesis of a new class of indole-3-acetamido-polyamine conjugates that were evaluated for antimicrobial activities against a panel of bacteria and two fungi, and for the ability to enhance the action of doxycycline against Pseudomonas aeruginosa and erythromycin against Escherichia coli. Compounds 14b, 15b, 17c, 18a, 18b, 18d, 19b, 19e, 20c and 20d exhibited strong growth inhibition of methicillin-resistant Staphylococcus aureus (MRSA) and Cryptococcus neoformans, with minimum inhibitory concentrations (MIC) typically less than 0.2 µM. Four analogues, including a 5-bromo 15c and three 5-methoxyls 16d–f, also exhibited intrinsic activity towards E. coli. Antibiotic kill curve analysis of 15c identified it to be a bactericide. While only one derivative was found to (weakly) enhance the action of erythromycin against E. coli, three examples, including 15c, were found to be strong enhancers of the antibiotic action of doxycycline against P. aeruginosa. Collectively, these results highlight the promising potential of α,ω-disubstituted indole-3-acetamido polyamine conjugates as antimicrobials and antibiotic adjuvants.

  由于抗菌药耐药性的广泛存在，因此有必要发现新的抗菌药类别以及能够恢复无效抗生素作用的辅助分子。在此，我们报告了一类新的吲哚-3-乙酰胺基多胺共轭物的合成，并评估了它们对一系列细菌和两种真菌的抗菌活性，以及增强强力霉素对绿脓杆菌和红霉素对大肠杆菌作用的能力。化合物 14b、15b、17c、18a、18b、18d、19b、19e、20c 和 20d 对耐甲氧西林金黄色葡萄球菌（MRSA）和新型隐球菌具有很强的生长抑制作用，最低抑制浓度（MIC）通常低于 0.2 µM。四种类似物，包括一种 5-溴 15c 和三种 5-甲氧基 16d-f，对大肠杆菌也具有内在活性。15c 的抗生素杀灭曲线分析表明它是一种杀菌剂。虽然只有一种衍生物被发现能（弱）增强红霉素对大肠杆菌的作用，但包括 15c 在内的三种衍生物被发现能强烈增强强力霉素对绿脓杆菌的抗生素作用。总之，这些结果凸显了α,ω-二取代吲哚-3-乙酰胺基多胺共轭物作为抗菌剂和抗生素佐剂的巨大潜力。
• Structure–Activity Relationship Studies of Indolglyoxyl-Polyamine Conjugates as Antimicrobials and Antibiotic Potentiators
  作者：Melissa M. Cadelis、Tim Liu、Kenneth Sue、Florent Rouvier、Marie-Lise Bourguet-Kondracki、Jean Michel Brunel、Brent R. Copp

  DOI：10.3390/ph16060823

  日期：——

  Antibiotic resistance is a growing global health threat, requiring urgent attention. One approach to overcome antibiotic resistance is to discover and develop new antibiotic enhancers, molecules that work with legacy antibiotics to enhance their efficacy against resistant bacteria. Our previous screening of a library of purified marine natural products and their synthetic analogues led to the discovery

  抗生素耐药性是一个日益严重的全球健康威胁，需要紧急关注。克服抗生素耐药性的一种方法是发现和开发新的抗生素增强剂，即与传统抗生素配合使用以增强其对抗耐药细菌的功效的分子。我们之前对纯化海洋天然产物及其合成类似物库的筛选发现了一种吲哚乙酰精胺衍生物，该衍生物表现出内在的抗菌特性，并且还能够增强多西环素对难以治疗的革兰氏阴性细菌的作用铜绿假单胞菌。现在已经制备了一组类似物，探索多胺链的5-和7-位以及长度上的吲哚取代对生物活性的影响。虽然观察到许多类似物具有有限的细胞毒性和/或溶血活性，但发现两种 7-甲基取代的类似物（23b 和 23c）对革兰氏阳性菌表现出强活性，而没有可检测到的细胞毒性或溶血特性。抗生素增强特性需要不同的分子属性，其中一个例子是 5-甲氧基取代的类似物 (19a)，它是两种四环素抗生素（多西环素和米诺环素）作用的无毒、非溶血性增强剂，铜绿假单胞菌。这些结果为在海洋天然产物和