N-(t-butoxycarbonyl)-L-valyl-D-isoglutamine | 77277-43-1

• 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-(t-butoxycarbonyl)-L-valyl-D-isoglutamine
• 英文别名: tert-butoxycarbonyl-L-valyl-D-isoglutamine；t-butyloxycarbonyl-L-valyl-D-isoglutamine；(4R)-5-amino-4-[[(2S)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoyl]amino]-5-oxopentanoic acid
• CAS: 77277-43-1
• 化学式: C₁₅H₂₇N₃O₆
• 分子量: 345.396
• InChiKey: WAAKANNZKYBFBX-KOLCDFICSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  24
• 可旋转键数：
  10
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  148
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(t-butoxycarbonyl)-L-valyl-D-isoglutamine 在 10percent Pd/C N-甲基吗啉 、 TEA 、 氢气 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 32.1h， 生成
  参考文献：
  名称：

  Synthesis and Antitumor Activity of Conjugates of Muramyldipeptide, Normuramyldipeptide, and Desmuramylpeptides with Acridine/Acridone Derivatives

  摘要：

  The synthesis of two groups (Chart 1, types A and B) of conjugates of MDP (muramyldipeptide) and nor-MDP (normurainyldipeptide) with acridine/acridone derivatives and the synthesis of analogues of desmuramylpeptides (Chart 1, types C and D), containing acridine/ acridone derivatives have been described. In type A conjugates, the hydroxyl group at C6 of the sugar moiety was acylated with acridine/acridone N-substituted omega -aminoalkanocarboxylic acids (Scheme 1), whereas the conjugates of type B (Table 2) and three analogues of type C or D (Scheme 2) have an amide bond formed between the carboxylic group of isoglutamine and the amine function of the respective acridine/acridone derivatives. The preliminary screening data indicate that the analogues of groups A, C, and D exhibit small cytotoxic activity, whereas several analogues of type B, 4b, 4c, 4e, 4g, 4h, 4i, and 4l, exhibiting potent in vitro cytotoxic activity against a panel of human cell lines (Table 4), have been selected by the National Cancer Institute (NCI) Evaluation Committee for further testing. Analogues 4b and 4h were active in the in vivo hollow fiber assay (Table 5). Analogue 3a shows an immunostimulating effect on the cytotoxic activity of the NX cells obtained from the spleen of healthy and Ab melanoma bearing animals.

  DOI：

  10.1021/jm001115g
• 作为产物：
  描述：

  t-butoxycarbonyl-L-valyl-D-isoglutamine benzyl ester 在 钯 氢气 作用下， 以 甲醇 为溶剂， 反应 6.0h， 以100%的产率得到N-(t-butoxycarbonyl)-L-valyl-D-isoglutamine
  参考文献：
  名称：

  Synthesis, and the Adjuvant and Tumor-Suppressive Activities of Quinonyl Muramyl Dipeptides

  摘要：

  ω-(1,4-苯醌-2-基)烷酸、2-[10-(5,6-二甲氧基-3-甲基-1,4-苯并苯醌-2-基)癸基]-3-羟基二十四面酸、全反式-5,9,13,17-四甲基-4,8,12,16-十八碳四烯酸和硬脂酸被偶联到脂质双肽 muramyl dipeptide 的糖部分6-O位置上，形成了6-O-酰氨基muramyl dipeptide甲酯。所使用的酰氨基残基为甘氨酸、亮氨酸、己二酸和叔丁基胺。开发了新的合成方法来制备ω-(1,4-苯醌-2-基)烷酸，如22-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)二十二酸，以及α-分支的ω-(1,4-苯醌-2-基)β-羟基酸，即2-[10-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)癸基]-3-羟基二十四酸。测定了这些醌基、多烯丙基乙酰基和硬脂酰基muramyl dipeptide在诱导豚鼠对ABA-酪氨酸迟发型超敏反应和抑制同系BALB/c雌性小鼠肿瘤(meth-A)活性中的作用。结果表明，所有这些muramyl dipeptide衍生物都保留了佐剂活性，而只有醌基muramyl dipeptides显示出较强的肿瘤抑制活性，表明5,6-二甲氧基-3-甲基-1,4-苯醌环对于显现肿瘤抑制活性是必需的。分子的亲脂性-亲水性平衡也很重要。在所测试的化合物中，N-乙酰基-6-O-[10-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)癸酰基]muramyl-l-缬氨酸-d-异谷氨酰胺甲酯显示出最强的肿瘤抑制活性。该化合物在豚鼠中也显示出肿瘤退缩活性，因此是一个有前景的研究候选物。

  DOI：

  10.1246/bcsj.57.3182

文献信息

• Glucosamine peptide derivatives, their production and use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US04369178A1

  公开（公告）日：1983-01-18

  Novel glucosamine-peptide derivatives of the formula: ##STR1## wherein m is 0 or 1; n is 0 or an integer of 1 to 9; R is lower alkyl which may be substituted with hydroxyl, or aryl; R.sup.1 is hydrogen or acyl having an acyclic hydrocarbon group, the terminal of which may be substituted with a cyclic hydrocarbon group directly, via a carbonyl group or via an oxygen atom; provided that when R.sup.1 is hydrogen m is 1; R.sup.2 is hydrogen or lower alkyl which may form a ring by connecting its terminal with the .alpha.-nitrogen atom when n is 0, or hydrogen when n is an integer of 1 to 9; R.sup.3 is hydrogen or lower alkyl; R.sup.4 and R.sup.5 are each hydrogen or lower alkyl which may be substituted with hydroxyl or benzyloxyl; R.sup.6 is hydrogen or lower alkyl; R.sup.7 is alkyl which may be substituted with lower alkoxyl or aralkyl; R.sup.8 and R.sup.9 are each hydrogen, lower alkyl or aralkyl; and (D) and (L) each indicate configurations if their respective carbon atoms are asymmetric; or an acid addition salt thereof, have immunostimulatory activity.

  新型葡萄糖胺-肽衍生物的化学式如下：##STR1## 其中m为0或1；n为0或1至9的整数；R为可以用羟基取代的低碳烷基，或芳基；R.sup.1为氢或酰基，具有一个线性碳氢基团，其末端可以直接或通过羰基或氧原子与一个环烃基团相连；当R.sup.1为氢时，m为1；R.sup.2为氢或可以通过将其末端与α-氮原子连接而形成环的低碳烷基，或当n为1至9的整数时为氢；R.sup.3为氢或低碳烷基；R.sup.4和R.sup.5分别为氢或可以用羟基或苄氧基取代的低碳烷基；R.sup.6为氢或低碳烷基；R.sup.7为可以用低碳烷氧基或芳基取代的烷基；R.sup.8和R.sup.9分别为氢、低碳烷基或芳基；(D)和(L)分别表示它们各自的碳原子具有对映异构体；或其酸盐加合物具有免疫刺激活性。
• Glucosamine-peptide derivatives, their production and use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP0014984B1

  公开（公告）日：1982-12-01
• US4369178A
  申请人：——

  公开号：US4369178A

  公开（公告）日：1983-01-18
• Synthesis, and the Adjuvant and Tumor-Suppressive Activities of Quinonyl Muramyl Dipeptides
  作者：Shigeru Kobayashi、Tsunehiko Fukuda、Hidefumi Yukimasa、Masahiko Fujino、Ichiro Azuma、Yuichi Yamamura

  DOI：10.1246/bcsj.57.3182

  日期：1984.11

  ω-(1,4-Benzoquinon-2-yl)alkanoic acids, 2-[10-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)decyl]-3-hydroxytetracosanoic acid, all-trans-5,9,13,17-tetramethyl-4,8,12,16-octadecatetraenoic acid, and stearic acid were coupled to the 6-O-position of the carbohydrate moiety of muramyl dipeptide alkyl esters, and 6-O-aminoacylmuramyl dipeptide methyl esters. The aminoacyl residues used were Gly, Leu, Ahx, and Aud. New synthetic methods were developed for ω-(1,4-benzoquinon-2-yl)alkanoic acids such as 22-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)docosanoic acid, and the α-branched ω-(1,4-benzoquinone-2-yl) β-hydroxy acid, 2-[10-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)decyl]-3-hydroxytetracosanoic acid. The effects of the resulting quinonyl, multiprenylacetyl, and stearoylmuramyl dipetides on the induction of delayed-type hypersensitivity to ABA-Tyr in guinea pigs and the tumor(meth-A)-suppressive activity in syngeneic BALB/c female mice were measured. The results revealed that all these muramyl-dipeptide derivatives retained the adjuvant activity whereas the potent tumor-suppressive activity was observed only in quinonylmuramyl dipeptides, indicating that the 5,6-dimethoxy-3-methyl-1,4-benzoquinone ring is a requisite for the manifestation of the tumor-suppressive activity. The lipophilicity-hydrophilicity balance of the molecule was also important. Among the compounds tested, N-acetyl-6-O-[10-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)decanoyl]muramyl-l-valyl-d-isoglutamine methyl ester showed the most potent tumor-suppressive activity. This compound also showed tumor-regressive activity in guinea pigs, and hence is a good candidate for further studies.

  ω-(1,4-苯醌-2-基)烷酸、2-[10-(5,6-二甲氧基-3-甲基-1,4-苯并苯醌-2-基)癸基]-3-羟基二十四面酸、全反式-5,9,13,17-四甲基-4,8,12,16-十八碳四烯酸和硬脂酸被偶联到脂质双肽 muramyl dipeptide 的糖部分6-O位置上，形成了6-O-酰氨基muramyl dipeptide甲酯。所使用的酰氨基残基为甘氨酸、亮氨酸、己二酸和叔丁基胺。开发了新的合成方法来制备ω-(1,4-苯醌-2-基)烷酸，如22-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)二十二酸，以及α-分支的ω-(1,4-苯醌-2-基)β-羟基酸，即2-[10-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)癸基]-3-羟基二十四酸。测定了这些醌基、多烯丙基乙酰基和硬脂酰基muramyl dipeptide在诱导豚鼠对ABA-酪氨酸迟发型超敏反应和抑制同系BALB/c雌性小鼠肿瘤(meth-A)活性中的作用。结果表明，所有这些muramyl dipeptide衍生物都保留了佐剂活性，而只有醌基muramyl dipeptides显示出较强的肿瘤抑制活性，表明5,6-二甲氧基-3-甲基-1,4-苯醌环对于显现肿瘤抑制活性是必需的。分子的亲脂性-亲水性平衡也很重要。在所测试的化合物中，N-乙酰基-6-O-[10-(5,6-二甲氧基-3-甲基-1,4-苯醌-2-基)癸酰基]muramyl-l-缬氨酸-d-异谷氨酰胺甲酯显示出最强的肿瘤抑制活性。该化合物在豚鼠中也显示出肿瘤退缩活性，因此是一个有前景的研究候选物。
• Synthesis and Antitumor Activity of Conjugates of Muramyldipeptide, Normuramyldipeptide, and Desmuramylpeptides with Acridine/Acridone Derivatives
  作者：Krystyna Dzierzbicka、Aleksander M. Kołodziejczyk、Barbara Wysocka-Skrzela、Andrzej Myśliwski、Danuta Sosnowska

  DOI：10.1021/jm001115g

  日期：2001.10.1

  The synthesis of two groups (Chart 1, types A and B) of conjugates of MDP (muramyldipeptide) and nor-MDP (normurainyldipeptide) with acridine/acridone derivatives and the synthesis of analogues of desmuramylpeptides (Chart 1, types C and D), containing acridine/ acridone derivatives have been described. In type A conjugates, the hydroxyl group at C6 of the sugar moiety was acylated with acridine/acridone N-substituted omega -aminoalkanocarboxylic acids (Scheme 1), whereas the conjugates of type B (Table 2) and three analogues of type C or D (Scheme 2) have an amide bond formed between the carboxylic group of isoglutamine and the amine function of the respective acridine/acridone derivatives. The preliminary screening data indicate that the analogues of groups A, C, and D exhibit small cytotoxic activity, whereas several analogues of type B, 4b, 4c, 4e, 4g, 4h, 4i, and 4l, exhibiting potent in vitro cytotoxic activity against a panel of human cell lines (Table 4), have been selected by the National Cancer Institute (NCI) Evaluation Committee for further testing. Analogues 4b and 4h were active in the in vivo hollow fiber assay (Table 5). Analogue 3a shows an immunostimulating effect on the cytotoxic activity of the NX cells obtained from the spleen of healthy and Ab melanoma bearing animals.