N-(S-γ-benzyloxycarbonylamino-α-hydroxybutyryloxy)succinimide | 40371-52-6

• 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: N-(S-γ-benzyloxycarbonylamino-α-hydroxybutyryloxy)succinimide
• 英文别名: N-[(S)-4-benzyloxycarbonylamino-2-hydroxy-butyryloxy]succinimide；N-[(S)-4-(Benzyloxycarbonylamino)-2-hydroxybutanoyloxy]succinimide；(2,5-dioxopyrrolidin-1-yl) (2S)-2-hydroxy-4-(phenylmethoxycarbonylamino)butanoate
• CAS: 40371-52-6
• 化学式: C₁₆H₁₈N₂O₇
• 分子量: 350.328
• InChiKey: GXUXZODCJQNXBE-LBPRGKRZSA-N

物化性质

• 熔点：
  110-114oC
• 密度：
  1.41±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（轻微）、甲醇（轻微、加热）

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  122
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  安普霉素 、 N-(S-γ-benzyloxycarbonylamino-α-hydroxybutyryloxy)succinimide 在 zinc diacetate 作用下， 生成 N¹-<(S)-γ-<(benzyloxycarbonyl)amino>-α-hydroxybutyryl>apramycin
  参考文献：
  名称：

  Comparison of aminoglycoside antibiotics with respect to uptake and lethal activity in Escherichia coli

  摘要：

  Forty-five aminoglycoside antibiotics and related compounds were compared for their ability to induce the accumulation of dihydrostreptomycin in Escherichia coli K12. The common aminoglycosides and a streptothricin antibiotic all induced enhanced uptake within a relatively narrow concentration range. These concentrations were lethal to the bacteria. Comparison of aminoacyl derivatives of tobramycin and apramycin, the latter synthesized utilizing transition-metal cations to selectively control the site of substitution, revealed that 1-N-aminoacyl modifications resulted in an increased ability to induce enhanced uptake. 2'-N-Aminoacyl modifications were also effective at inducing enhanced uptake, albeit without noticeable improvement over parent. The findings from this structure-activity comparison support the proposition that aminoglycosides share a common critical target (most likely the ribosome), which, when acted upon, results in both drug accumulation and killing.

  DOI：

  10.1021/jm00385a015
• 作为产物：
  描述：

  氯甲酸苄酯 在 sodium carbonate 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 2.0h， 生成 N-(S-γ-benzyloxycarbonylamino-α-hydroxybutyryloxy)succinimide
  参考文献：
  名称：

  Design of Novel Antibiotics that Bind to the Ribosomal Acyltransfer Site

  摘要：

  The structure of neamine bound to the A site of the bacterial ribosomal RNA was used in the design of novel aminoglycosides. The design took into account stereo and electronic contributions to interactions between RNA and aminoglycosides, as well as a random search of 273 000 compounds from the Cambridge structural database and the National Cancer Institute 3-D database that would fit in the ribosomal aminoglycoside-binding pocket. A total of seven compounds were designed and subsequently synthesized, with the expectation that they would bind to the A-site RNA. Indeed, all synthetic compounds were found to bind to the target RNA comparably to the parent antibiotic neamine, with dissociation constants in the lower micromolar range. The synthetic compounds were evaluated for antibacterial activity against a set of important pathogenic bacteria. These designer antibiotics showed considerably enhanced antibacterial activities against these pathogens, including organisms that hyperexpressed resistance enzymes to aminoglycosides. Furthermore, analyses of four of the synthetic compounds with two important purified resistance enzymes for aminoglycosides indicated that the compounds were very poor substrates; hence the activity of these synthetic antibiotics does not appear to be compromised by the existing resistance mechanisms, as supported by both in vivo and in vitro experiments. The design principles disclosed herein hold the promise of the generation of a large series of designer antibiotics uncompromised by the existing mechanisms of resistance.

  DOI：

  10.1021/ja011695m

文献信息

• Syntheses of 2′,3′-Dideoxykanamycin A, 2′,3′-Dideoxyamikacin and Related Substances
  作者：Yoshihiko Kobayashi、Tsutomu Tsuchiya、Sumio Umezawa、Toshio Yoneta、Shunzo Fukatsu、Hamao Umezawa

  DOI：10.1246/bcsj.60.713

  日期：1987.2

  2′,3′-Dideoxykanamycin A has been prepared via two ways. 2″-O-Acetyl-4″,6″-O-benzylidene-6′-N,4′-O-carbonyl-1,3,3″-tri-N-tosylkanamycin A was converted to a 2′,3′-unsaturated compound by a modified Tipson and Cohen method. Hydrogenation followed by deblocking gave 2′,3′-dideoxykanamycin A (12). Another route for 12 was through 2′,3′-anhydro-4′,2″,4″,6″-tetra-O-benzoyl-2′-epi-1,3,6′,3″-tetrakis(N-ethoxycarbonyl)kanamycin A (16). Epoxide-ring opening of 16 with hydrogen iodide gave the 3′,2′-iodohydrin, which, after 2′-O-mesylation, led to the 2′,3′-unsaturated compound (19). Deblocking and hydrogenation of 19 gave 12. 2′,3′-Dideoxykanamycin A thus synthesized was led to 2′,3′-dideoxyamikacin and other related compounds by amino protection of 12 other than the 1-amino group by zinc acetate–ethyl trifluoroacetate method followed by 1-N-acyl or 1-urethane formation with appropriate reagents. Their antibacterial activities were described.

  2′,3′-双脱氧卡那霉素A已通过两种方法制备。2″-O-乙酰基-4″,6″-O-苄叉-6′-N,4′-O-羰基-1,3,3″-三-N-甲苯磺酰卡那霉素A通过改良的Tipson和Cohen方法转化为2′,3′-不饱和化合物。随后进行氢化和脱保护，得到2′,3′-双脱氧卡那霉素A（12）。另一条途径是通过2′,3′-环氧-4′,2″,4″,6″-四-O-苯甲酰基-2′-表-1,3,6′,3″-四(N-乙氧羰基)卡那霉素A（16）进行。16与氢碘酸反应开环生成3′,2′-碘醇，经2′-O-甲磺酰化后，得到2′,3′-不饱和化合物（19）。19的脱保护和氢化得到12。合成的2′,3′-双脱氧卡那霉素A通过乙酸锌-乙基三氟乙酸酯法保护除1-氨基外的其他氨基，随后用适当试剂形成1-N-酰基或1-氨基甲酸酯，进一步转化为2′,3′-双脱氧阿米卡星和其他相关化合物。描述了它们的抗菌活性。
• TREATMENT OF BACTERIAL INFECTIOUS DISEASES
  申请人：Boettger Erik

  公开号：US20130165397A1

  公开（公告）日：2013-06-27

  The present invention relates to a novel pharmacological treatment of bacterial infectious diseases in humans. Specifically the invention relates to the use of apramycin of formula (I) or apramycin derivatives to treat bacterial infectious diseases in humans. It is demonstrated that apramycin surprisingly does not have the expected high level of toxicity observed with related aminoglycoside antibiotics but actually is even significantly less toxic than compounds already used in human medicine such as gentamicin.

  本发明涉及一种新型的药理治疗人类细菌感染疾病的方法。具体而言，该发明涉及使用式（I）的阿帕霉素或阿帕霉素衍生物来治疗人类细菌感染疾病。实验证明，阿帕霉素出人意料地并没有观察到与相关氨基糖苷类抗生素相似的高毒性水平，而实际上甚至比已在人类医学中使用的庆大霉素等化合物毒性显著更低。
• 超多剤耐性グラム陰性菌に有効な新規アミノ配糖体抗菌剤
  申请人：公益財団法人微生物化学研究会

  公开号：JP2021178793A

  公开（公告）日：2021-11-18

  【課題】優れた抗菌作用、特に、１６Ｓ ｒＲＮＡメチラーゼやＮＤＭを産生するグラム陰性菌に対して優れた抗菌作用を有する新規化合物、又はそれらの薬学的に許容可能な塩、又はそれらの溶媒和物、並びに前記新規化合物を含有する、組成物、抗菌剤、及び医薬組成物を提供する。【解決手段】一般式（Ａ）で表される化合物、又はそれらの薬学的に許容可能な塩、又はそれらの溶媒和物、並びに前記化合物、又はそれらの薬学的に許容可能な塩、又はそれらの溶媒和物を含有する、組成物、抗菌剤、及び医薬組成物である。【選択図】なし

  这段文本描述了一种新型化合物，具有优良的抗菌作用，特别是对产生16S rRNA甲基转移酶或NDM的革兰氏阴性菌具有优秀的抗菌作用。该新型化合物或其药学上可接受的盐，或其溶剂物，以及含有该新型化合物的组合物、抗菌剂和药物组合物。解决方案是一种由通式（A）表示的化合物，或其药学上可接受的盐，或其溶剂物，以及含有该化合物或其药学上可接受的盐、或其溶剂物的组合物、抗菌剂和药物组合物。
• Assessment of 6′- and 6′′′-N-acylation of aminoglycosides as a strategy to overcome bacterial resistance
  作者：Pazit Shaul、Keith D. Green、Roi Rutenberg、Maria Kramer、Yifat Berkov-Zrihen、Elinor Breiner-Goldstein、Sylvie Garneau-Tsodikova、Micha Fridman

  DOI：10.1039/c0ob01133a

  日期：——

  Amongst the many synthetic aminoglycoside analogues that were developed to regain the efficacy of this class of antibiotics against resistant bacterial strains, the 1-N-acylated analogues are the most clinically used. In this study we demonstrate that 6′-N-acylation of the clinically used compound tobramycin and 6′′′-N-acylation of paromomycin result in derivatives resistant to deactivation by 6′-aminoglycoside acetyltransferase (AAC(6′)) which is widely found in aminoglycoside resistant bacteria. When tested against AAC(6′)- or AAC(3)-expressing bacteria as well as pathogenic bacterial strains, some of the analogues demonstrated improved antibacterial activity compared to their parent antibiotics. Improvement of the biological performance of the N-acylated analogues was found to be highly dependent on the specific aminoglycoside and acyl group. Our study indicates that as for 1-N-acylation, 6′- and 6′′′-N-acylation of aminoglycosides offer an additional promising direction in the search for aminoglycosides capable of overcoming infections by resistant bacteria.

  为了恢复这类抗生素对耐药菌株的疗效，人们开发了许多合成氨基糖苷类似物，其中 1-N-acylated 类似物在临床上使用最多。在这项研究中，我们证明了临床常用化合物妥布霉素的 6â²-N-酰化和副黏菌素的 6â²â²-N-酰化可产生抗 6â²-氨基糖苷乙酰转移酶（AAC(6â²)）失活的衍生物。在对表达 AAC（6â²）或 AAC（3）的细菌以及致病细菌菌株进行测试时，与母体抗生素相比，一些类似物显示出更强的抗菌活性。研究发现，N-酰化类似物生物性能的提高与特定的氨基糖苷和酰基有很大关系。我们的研究表明，与 1-N-acylation 一样，氨基糖苷的 6â²- 和 6â²â²â²-N-acylation 也为寻找能够克服耐药菌感染的氨基糖苷类药物提供了另一个有前途的方向。
• Syntheses of 1-Epikanamycin A and Its 1-<i>N</i>-[(<i>S</i>)-4-Amino-2-hydroxybutyryl] Derivative
  作者：Yoshiaki Takahashi、Tsutomu Tsuchiya、Yukiko Suzuki、Sumio Umezawa、Hamao Umezawa、Shunzo Fukatsu

  DOI：10.1246/bcsj.56.1807

  日期：1983.6

  The titled compounds were prepared from 3,6′-bis(N-benzyloxycarbonyl)-3″-N-(trifluoroacetyl)kanamycin A (1). Oxidation of 1 with hydrogen peroxide in the presence of sodium tungstate gave the 1-hydroxyimino derivative, which, after deblocking, gave 1-deamino-1-dehydro-1-hydroxyiminokanamycin A (6). Reduction of 6 with Raney nickel–hydrogen in aqueous ammonia gave a mixture of kanamycin A and 1-epikanamycin A (9), which were separated through derivation to the corresponding tetrakis-N-(t-butoxycarbonyl) derivatives, which showed different solubility in chloroform. 1-N-[(S)-4-Amino-2-hydroxybutyryl]-1-epikanamycin A was prepared from 9 by the zinc acetate–ethyl trifluoroacetate method [to give 3,6′-bis(N-benzyloxycarbonyl)-1-epi-3″-trifluoroacetamidokanamycin A] followed by a regiospecific 1-N-acylation with (S)-4-benzyloxycarbonylamino-2-hydroxybutyryl group and successive deblocking.

  标题化合物由 3,6′-双（N-苄氧羰基）-3″-N-（三氟乙酰基）卡那霉素 A（1）制备而成。在钨酸钠存在下，用过氧化氢氧化 1，得到 1-羟基亚氨基衍生物，脱锁后得到 1-脱氨基-1-脱氢-1-羟基亚氨基卡那霉素 A（6）。在氨水中用 Raney 镍氢还原 6，得到卡那霉素 A 和 1-epikanamycin A 的混合物（9），通过衍生分离出相应的四-N-（t-丁氧羰基）衍生物，它们在氯仿中的溶解度不同。1-N-[(S)-4-氨基-2-羟基丁酰基]-1-表卡那霉素 A 由 9 通过醋酸锌-三氟乙酸乙酯法制备[得到 3、6′-双(N-苄氧羰基)-1-表-3″-三氟乙酰氨基卡那霉素 A]，然后与(S)-4-苄氧羰基氨基-2-羟基丁酰基进行区域特异性 1-N-酰化，并连续脱锁。