N-[(benzyloxy)carbonyl]-L-valyl-N5-carbamoyl-L-ornithine | 159858-06-7

• 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-[(benzyloxy)carbonyl]-L-valyl-N5-carbamoyl-L-ornithine
• 英文别名: Cbz-Val-Cit-OH；(2S)-5-(carbamoylamino)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]pentanoic acid
• CAS: 159858-06-7
• 化学式: C₁₉H₂₈N₄O₆
• 分子量: 408.455
• InChiKey: TVOLTFNETIOQSW-GJZGRUSLSA-N

物化性质

• 沸点：
  698.5±55.0 °C(Predicted)
• 密度：
  1.247±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  29
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  160
• 氢给体数：
  5
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-[(benzyloxy)carbonyl]-L-valyl-N5-carbamoyl-L-ornithine 在 palladium 10% on activated carbon 、 氢气 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 4.5h， 以93%的产率得到L-valyl-N⁵-carbamoyl-L-ornithine
  参考文献：
  名称：

  ANTIBODY DRUG CONJUGATES OF KINESIN SPINDEL PROTEIN (KSP) INHIBITORS WITH ANTIB7H3-ANTIBODIES

  摘要：

  本申请涉及新型结合剂药物偶联物（ADCs），这些ADCs的活性代谢物，制备这些ADCs的过程，将这些ADCs用于治疗和/或预防疾病，以及将这些ADCs用于制备治疗和/或预防疾病的药物，特别是高增殖和/或血管生成异常等疾病，例如癌症等。这种治疗可以作为单独治疗，也可以与其他药物或其他治疗措施结合使用。

  公开号：

  US20200138970A1
• 作为产物：
  描述：

  benzyl N-[(2S)-1-[[(2S)-1-[4-[[(1S,2R)-2-acetamido-1-phenylpropoxy]methyl]anilino]-5-(carbamoylamino)-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate 在 乙二胺四乙酸 、 acetate buffer 、 bovine spleen cathepsin B 作用下， 以 水 为溶剂， 生成 N-[(benzyloxy)carbonyl]-L-valyl-N5-carbamoyl-L-ornithine
  参考文献：
  名称：

  Protease-Mediated Fragmentation of p-Amidobenzyl Ethers:  A New Strategy for the Activation of Anticancer Prodrugs

  摘要：

  A new anticancer prodrug activation strategy based on the 1,6-elimination reaction of p-aminobenzyl ethers is described. Model studies were undertaken with the N-protected peptide benzyloxycarbonyl-valine-citrulline (Z-val-cit), which was attached to the amino groups of p-aminobenzyl ether derivatives of 1-naphthol and N-acetylnorephedrine. The amide bond that formed was designed for hydrolysis by cathepsin B, a protease associated with rapidly growing and metastatic carcinomas. Upon treatment with the enzyme, the Z-val-cit p-amidobenzyl ether of 1-naphthol (2) underwent peptide bond hydrolysis with the rapid release of 1-naphthol. The aliphatic Z-val-cit p-amidobenzyl ether of N-acetylnorephedrine (5) also underwent amide bond hydrolysis, but without the ensuing elimination of N-acetylnorephedrine. On the basis of these results, the phenolic anticancer drugs etoposide (6) and combretastatin A-4 (7) were attached to the Z-val-cit p-amidobenzyl alcohol through ether linkages, forming the peptide-drug derivatives 8 and 9, respectively. Both compounds were stable in aqueous buffers and serum and underwent ether fragmentation upon treatment with cathepsin B, resulting in the release of the parent drugs in chemically unmodified forms. The released drugs were 13-50 times more potent than were the prodrug precursors on a panel of cancer cell lines. In contrast, the corresponding carbonate derivative of combretastatin A-4 (13) was unstable in aqueous environments and was as cytotoxic as combretastatin A-4. This result extends the use of the self-immolative p-aminobenzyl group for the fragmentation of aromatic ethers and provides a new strategy for anticancer prodrug development.

  DOI：

  10.1021/jo016187+

文献信息

• Design, Synthesis, and Biological Evaluation of New Cathepsin B-Sensitive Camptothecin Nanoparticles Equipped with a Novel Multifuctional Linker
  作者：Xuan Zhang、Kaiyong Tang、Hong Wang、Yaqian Liu、Bin Bao、Yanfen Fang、Xiongwen Zhang、Wei Lu

  DOI：10.1021/acs.bioconjchem.6b00099

  日期：2016.5.18

  Traditional antitumor drugs such as camptothecin and paclitaxel derivatives are widely used in cancer chemotherapy. However, the major defects of those agents include severe toxicity and poor water solubility. With these in mind, a novel multifunctional linker was designed and two Cathepsin B (CTB) sensitive CPT conjugates (9a and 9b) were synthesized. Through click chemistry, additional functional group mPEG2000 can be easily introduced into these conjugates. The introduction of mPEG2000 fragment resulted in the formation of nanoparticles 1a and 1b (average particle sizes were 216.9 and 257.9 nm, respectively) with significantly increased water solubility (more than 19 000-fold). The release of therapeutic drug SN-38 in the presence of CTB was confirmed by HPLC and prodrug 1a showed potent in vitro cytotoxicity against all tested cell lines. Impressively, compared with irinotecan, CTB sensitive prodrug 1a displayed similar in vivo efficacy with remarkable decreased in vivo toxicity.

  传统的抗肿瘤药物，如喜树碱和紫杉醇衍生物，在癌症化疗中被广泛应用。然而，这些药物的主要缺陷包括严重的毒性和较差的亲水性。考虑到这些问题，设计了一种新型多功能连接体，并合成了两种组织蛋白酶B（CTB）敏感的CPT偶联物（9a和9b）。通过点击化学，可以轻松地将额外的功能团mPEG2000引入这些偶联物中。引入mPEG2000片段后，形成了纳米粒子1a和1b（平均粒径分别为216.9和257.9 nm），其水溶性显著增加（超过19,000倍）。通过HPLC确认了在存在CTB的情况下治疗药物SN-38的释放，且前药1a对所有测试的细胞系显示出了强有力的体外细胞毒性。值得注意的是，与伊立替康相比，CTB敏感的前药1a在体内显示出相似的疗效，但体内毒性显著降低。
• [EN] CONJUGATE COMPOUNDS<br/>[FR] COMPOSÉS CONJUGUÉS
  申请人：CALLAGHAN INNOVATION RES LTD

  公开号：WO2014088432A1

  公开（公告）日：2014-06-12

  The invention relates to sphingoglycolipid analogues and peptide derivatives thereof, which are useful in treating or preventing diseases or such as those relating to infection, atopic disorders, autoimmune diseases or cancer.

  这项发明涉及鞘氨醇糖脂类似物及其肽衍生物，可用于治疗或预防与感染、特应性疾病、自身免疫疾病或癌症相关的疾病。
• ANTIBODY DRUG CONJUGATES (ADCS) AND ANTIBODY PRODRUG CONJUGATES (APDCS) WITH ENZYMATICALLY CLEAVABLE GROUPS
  申请人：Bayer Pharma Aktiengesellschaft

  公开号：US20180169256A1

  公开（公告）日：2018-06-21

  The present invention relates to novel binder-prodrug conjugates (APDCs) where binders are conjugated with inactive precursor compounds of kinesin spindle protein inhibitors, and to antibody-drug conjugates ADCs and to processes for producing these APDCs and ADCs.

  这项发明涉及新型结合物-前药偶联物（APDCs），其中结合物与动力蛋白纺锤体抑制剂的非活性前体化合物偶联，以及抗体药物偶联物ADCs以及制备这些APDCs和ADCs的方法。
• 一种应用于靶向给药系统的新的支链连接体
  申请人：华东师范大学

  公开号：CN104587487B

  公开（公告）日：2018-01-16

  本发明公开了一种应用于靶向给药系统的新的支链连接体、合成及在靶向给药系统中的应用，其中肽链通过对氨基连接到支链连接体，药物通过苄基醇的部分连接到支链连接体，修饰片段及靶头部分通过炔基连接到支链连接体；本发明使给药后在体内到达病变组织过程中有一定的稳定性，并且靶向到特定组织或细胞后，在特定的条件下，释放出药物，达到治疗效果并减少毒副作用。
• [EN] ELONGATED AND MULTIPLE SPACERS IN ACTIVATIBLE PRODRUGS<br/>[FR] ESPACEURS ALLONGES ET MULTIPLES DE PRODROGUES ACTIVABLES
  申请人：DE GROOT FRANCISCUS MARINUS HE

  公开号：WO2002083180A1

  公开（公告）日：2002-10-24

  This invention is directed to prodrugs that can be activated at the preferred site of action in order to selectively deliver the corresponding therapeutic parent drugs to target cells or to the target site. This invention will therefore primarily but not exclusively relate to tumor cells as target cells. More specifically the prodrugs are compounds of the formula V-(W)k-(X)1-A-Z, wherein: V is a specifier; (W)k-(X)1-A is an elongated self-elimination spacer system; W and X are each a 1,(4+2n) electronic cascade spacer, being the same or different; A is either a spacer group of formula (Y)m wherein: Y is a 1,(4+2n) electronic cascade spacer, or a group of formula U being a cyclisation elimination spacer; Z is a therapeutic drug; k, 1 and m are integers from 0 (included) to 5 (included); n is an integer of 0 (included) to 10 (included), with the provisos that: - when A is (Y)m: k+1+m ≥ 1, and if k+1+m = 1; - when A is U: k+1 ≥ 1.

  本发明涉及一种前药，可以在首选作用部位激活，以有选择地将相应的治疗母药物传递到目标细胞或目标部位。因此，本发明主要但不仅限于将肿瘤细胞作为目标细胞。更具体地，前药是化合物V-(W)k-(X)1-A-Z，其中：V是说明符；(W)k-(X)1-A是一个延长的自我消除间隔系统；W和X分别是1，（4+2n）电子级联间隔器，相同或不同；A是公式（Y）m的间隔基团，其中：Y是1，（4+2n）电子级联间隔器，或者是公式U的基团，是环化消除间隔器；Z是治疗药物；k，1和m是从0（包括）到5（包括）的整数；n是0（包括）到10（包括）的整数，但前提是：当A为（Y）m时：k+1+m≥1，如果k+1+m=1；当A为U时：k+1≥1。