| 1313220-66-4

• 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
• CAS: 1313220-66-4
• 化学式: C₆₁H₇₇N₁₉O₁₆
• 分子量: 1332.4
• InChiKey: CIAWJDFDNJNSPK-UILVTTEASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.73
• 重原子数：
  96.0
• 可旋转键数：
  36.0
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  536.12
• 氢给体数：
  18.0
• 氢受体数：
  18.0

反应信息

• 作为反应物：
  描述：

  道诺霉素 、 反应 24.0h， 生成
  参考文献：
  名称：

  GnRH-III based multifunctional drug delivery systems containing daunorubicin and methotrexate

  摘要：

  Here we report on the design, synthesis and biochemical characterization of multifunctional bio-conjugates containing two chemotherapeutic agents, daunorubicin and methotrexate, coupled to the GnRH-III decapeptide, which served as a targeting moiety. This represents a possible approach to increase the receptor mediated tumor targeting and consequently the cytostatic effect of anticancer drug-peptide bioconjugates. The multifunctional bioconjugates were prepared according to two drug design approaches recently developed by our group. Both bifunctional GnRH-III derivatives, [(4)Lys]-GnRH-III (Glp-His-Trp-Lys-His-Asp-Trp-Lys-Pro-Gly-NH2) and [(8)Lys(Lys)]-GnRH-III (Glp-His-Trp-Ser-His-Asp-Trp-Lys(Lys)-Pro-Gly-NH2), contain two free amino groups suitable for the attachment of two anticancer drugs, such as methotrexate and daunorubicin. The drugs were chosen with respect to their different mechanisms of action, with the goal of increasing the antitumor effect of the bioconjugates. The in vitro cytostatic effect of the bioconjugates was determined on MCF-7 human breast, HT-29 human colon and LNCaP human prostate cancer cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Their in vitro stability/degradation in human serum and in the presence of rat liver lysosomal homogenate was investigated by liquid chromatography in combination with mass spectrometry. The influence of the multifunctional bioconjugates on the cell adhesion and cell proliferation was studied on Mono Mac 6 human leukemic monocytes. It was found that (1) all synthesized bioconjugates had in vitro cytostatic effect; (2) they were stable in human serum for at least 24 h; (3) they were hydrolyzed in the presence of lysosomal homogenate and (4) they exerted a moderate cell cell adhesion inducing effect. These results demonstrate that multifunctional bioconjugates containing two different anticancer drugs attached to the same GnRH-Ill targeting moiety could be successfully prepared and resulted in higher in vitro cytostatic effect than the monofunctional bioconjugates containing either methotrexate or daunorubicin, in particular on HT-29 human colon cancer cells. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.03.016
• 作为产物：
  描述：

  Fmoc-甘氨酸 、 Fmoc-L-脯氨酸 、 FMOC-O-叔丁基-L-丝氨酸 、 Fmoc-L-天冬氨酸 beta-叔丁酯 、 N-Fmoc-N'-三苯甲基-L-组氨酸 、 Fmoc-L-色氨酸(Boc)-OH 、 L-焦谷氨酸 、 Fmoc-N'-甲基三苯甲基-L-赖氨酸 、 双叔丁氧羰基氨基氧乙酸 在 哌啶 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  GnRH-III based multifunctional drug delivery systems containing daunorubicin and methotrexate

  摘要：

  Here we report on the design, synthesis and biochemical characterization of multifunctional bio-conjugates containing two chemotherapeutic agents, daunorubicin and methotrexate, coupled to the GnRH-III decapeptide, which served as a targeting moiety. This represents a possible approach to increase the receptor mediated tumor targeting and consequently the cytostatic effect of anticancer drug-peptide bioconjugates. The multifunctional bioconjugates were prepared according to two drug design approaches recently developed by our group. Both bifunctional GnRH-III derivatives, [(4)Lys]-GnRH-III (Glp-His-Trp-Lys-His-Asp-Trp-Lys-Pro-Gly-NH2) and [(8)Lys(Lys)]-GnRH-III (Glp-His-Trp-Ser-His-Asp-Trp-Lys(Lys)-Pro-Gly-NH2), contain two free amino groups suitable for the attachment of two anticancer drugs, such as methotrexate and daunorubicin. The drugs were chosen with respect to their different mechanisms of action, with the goal of increasing the antitumor effect of the bioconjugates. The in vitro cytostatic effect of the bioconjugates was determined on MCF-7 human breast, HT-29 human colon and LNCaP human prostate cancer cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Their in vitro stability/degradation in human serum and in the presence of rat liver lysosomal homogenate was investigated by liquid chromatography in combination with mass spectrometry. The influence of the multifunctional bioconjugates on the cell adhesion and cell proliferation was studied on Mono Mac 6 human leukemic monocytes. It was found that (1) all synthesized bioconjugates had in vitro cytostatic effect; (2) they were stable in human serum for at least 24 h; (3) they were hydrolyzed in the presence of lysosomal homogenate and (4) they exerted a moderate cell cell adhesion inducing effect. These results demonstrate that multifunctional bioconjugates containing two different anticancer drugs attached to the same GnRH-Ill targeting moiety could be successfully prepared and resulted in higher in vitro cytostatic effect than the monofunctional bioconjugates containing either methotrexate or daunorubicin, in particular on HT-29 human colon cancer cells. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.03.016

文献信息

• Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin–GnRH-III conjugates developed for targeted drug delivery
  作者：Sabine Schuster、Beáta Biri-Kovács、Bálint Szeder、Viktor Farkas、László Buday、Zsuzsanna Szabó、Gábor Halmos、Gábor Mező

  DOI：10.3762/bjoc.14.64

  日期：——

  Gonadotropin releasing hormone-III (GnRH-III), a native isoform of the human GnRH isolated from sea lamprey, specifically binds to GnRH receptors on cancer cells enabling its application as targeting moieties for anticancer drugs. Recently, we reported on the identification of a novel daunorubicin–GnRH-III conjugate (GnRH-III–[⁴Lys(Bu), ⁸Lys(Dau=Aoa)] with efficient in vitro and in vivo antitumor activity. To get a deeper insight into the mechanism of action of our lead compound, the cellular uptake was followed by confocal laser scanning microscopy. Hereby, the drug daunorubicin could be visualized in different subcellular compartments by following the localization of the drug in a time-dependent manner. Colocalization studies were carried out to prove the presence of the drug in lysosomes (early stage) and on its site of action (nuclei after 10 min). Additional flow cytometry studies demonstrated that the cellular uptake of the bioconjugate was inhibited in the presence of the competitive ligand triptorelin indicating a receptor-mediated pathway. For comparative purpose, six novel daunorubicin–GnRH-III bioconjugates have been synthesized and biochemically characterized in which ⁶Asp was replaced by D-Asp, D-Glu and D-Trp. In addition to the analysis of the in vitro cytostatic effect and cellular uptake, receptor binding studies with ¹²⁵I-triptorelin as radiotracer and degradation of the GnRH-III conjugates in the presence of rat liver lysosomal homogenate have been performed. All derivatives showed high binding affinities to GnRH receptors and displayed in vitro cytostatic effects on HT-29 and MCF-7 cancer cells with IC₅₀ values in a low micromolar range. Moreover, we found that the release of the active drug metabolite and the cellular uptake of the bioconjugates were strongly affected by the amino acid exchange which in turn had an impact on the antitumor activity of the bioconjugates.

  促性腺激素释放激素-III（GnRH-III）是从海丽鱼中分离出的人类GnRH的本源同种形式，特异性地结合到癌细胞上的GnRH受体，使其能够作为抗癌药物的靶向部分。最近，我们报道了一种新型多柔比星-GnRH-III结合物（GnRH-III-[⁴Lys(Bu), ⁸Lys(Dau=Aoa)]），在体外和体内表现出高效的抗肿瘤活性。为了更深入地了解我们首创化合物的作用机制，通过共聚焦激光扫描显微镜跟踪了细胞摄取过程。通过随着时间的推移追踪药物在不同亚细胞区域的定位，可以在不同亚细胞区域可视化多柔比星药物。共定位研究证明了药物存在于溶酶体（早期阶段）和作用位点（10分钟后的细胞核）中。额外的流式细胞术研究表明，在存在竞争性配体三氨丙胺的情况下，生物结合物的细胞摄取受到抑制，表明存在受体介导的途径。为了比较研究目的，合成了六种新型多柔比星-GnRH-III生物结合物，并进行了生物化学特性分析，其中⁶Asp被D-Asp、D-Glu和D-Trp替代。除了分析体外细胞静止效应和细胞摄取外，还进行了与¹²⁵I-三氨丙胺作为放射示踪剂的受体结合研究，并在大鼠肝溶酶体匀浆存在下对GnRH-III结合物的降解进行了实验。所有衍生物均显示出高亲和力与GnRH受体结合，并在HT-29和MCF-7癌细胞上表现出体外细胞静止效应，IC₅₀值在低微摩尔范围内。此外，我们发现活性药物代谢物的释放和生物结合物的细胞摄取受氨基酸交换的影响，从而影响了生物结合物的抗肿瘤活性。
• Drug targeting to decrease cardiotoxicity – determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells
  作者：Livia Polgár、Eszter Lajkó、Pál Soós、Orsolya Láng、Marilena Manea、Béla Merkely、Gábor Mező、László Kőhidai

  DOI：10.3762/bjoc.14.136

  日期：——

  difference to the control was analysed. Results: Doxorubicin and daunorubicin exhibited a cytotoxic effect on both cell types, at the highest concentrations tested. Doxorubicin-based conjugates (AN-152, GnRH-III(Dox-O-glut), GnRH-III(Dox-glut-GFLG) and GnRH-III(Dox=Aoa-GFLG) showed the same cytotoxic effect on cardiomyocytes. Among the daunorubicin-based conjugates, [4Lys(Ac)]-GnRH-III(Dau=Aoa), GnRH-III(Dau=Aoa-YRRL)

  背景：由化学治疗药物阿霉素和柔红霉素诱导的心肌病是其在癌症治疗中应用的主要限制因素。趋化药物靶向可能会增加药物的肿瘤选择性并降低其心脏毒性。据报道，促性腺激素释放激素（GnRH）受体在肿瘤细胞表面的表达增加。因此，前述化学治疗药物与基于GnRH的肽的附接可导致具有增加的治疗功效的化合物。本研究的目的是研究抗癌药物-GnRH-缀合物对两种必需的心血管细胞类型，例如心肌细胞和内皮细胞的细胞毒性作用。十六种先前开发的含有阿霉素的GnRH偶联物，本研究对柔红霉素和氨甲蝶呤进行了研究。使用xCELLigence SP系统测定了原代人心肌细胞（HCM）和人脐静脉内皮细胞（HUVEC）的细胞毒性，该系统可测量细胞粘附在孔底部金色电极阵列上引起的阻抗变化。计算阻抗-时间曲线的斜率，并且为了定量确定细胞毒性，分析与对照的差异。结果：在最高测试浓度下，阿霉素和柔红霉素对两种细胞均表现出细胞毒性作用。基于阿霉素
• Design, synthesis, in vitro stability and cytostatic effect of multifunctional anticancer drug-bioconjugates containing GnRH-III as a targeting moiety
  作者：Ulrike Leurs、Gábor Mező、Erika Orbán、Peter Öhlschläger、Andreas Marquardt、Marilena Manea

  DOI：10.1002/bip.21640

  日期：——

  attachment of more than one chemotherapeutic agent to one GnRH‐III molecule. Here we report on the design, synthesis and biochemical characterization of multifunctional bioconjugates containing GnRH‐III as a targeting moiety and daunorubicin as a chemotherapeutic agent. Two different drug design approaches were pursued. The first one was based on the bifunctional [4Lys]‐GnRH‐III (Glp‐His‐Trp‐Lys‐His‐As

  包含GnRH-III激素十肽作为靶向部分的生物共轭物能够将化学治疗剂专门递送至表达GnRH受体的癌细胞，从而提高其局部功效，同时限制了外周毒性。但是，癌细胞上GnRH受体的数量是有限的，并且在连续激素治疗下它们会脱敏。一种提高受体介导的肿瘤靶向性并因此增加生物缀合物的细胞抑制作用的可能方法是将一种以上的化学治疗剂附着到一个GnRH-III分子上。在这里我们报告了包含GnRH-III作为靶向部分和柔红霉素作为化学治疗剂的多功能生物共轭物的设计，合成和生化特性。追求两种不同的药物设计方法。4 Lys] -GnRH-III（Glp-His-Trp-Lys-His-Asp-Trp-Lys-Pro-Gly-NH 2），在4和8位含有两个赖氨酸残基，其amino-氨基用于柔红霉素的偶联。在第二种药物设计中，天然GnRH-III（Glp-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH
• Enhanced Enzymatic Stability and Antitumor Activity of Daunorubicin-GnRH-III Bioconjugates Modified in Position 4
  作者：Marilena Manea、Ulrike Leurs、Erika Orbán、Zsuzsa Baranyai、Peter Öhlschläger、Andreas Marquardt、Ákos Schulcz、Miguel Tejeda、Bence Kapuvári、József Tóvári、Gábor Mező

  DOI：10.1021/bc100547p

  日期：2011.7.20

  Here, we report on the synthesis, enzymatic stability, and antitumor activity of novel bioconjugates containing the chemotherapeutic agent daunorubicin attached through an oxime bond to various gonadotropin-releasing hormone-III (GnRH-III) derivatives. In order to increase the enzymatic stability of the bioconjugates (in particular against chymotrypsin), 4Ser was replaced by N-Me-Ser or Lys(Ac). A

  在这里，我们报道了新型生物共轭物的合成，酶稳定性和抗肿瘤活性，该生物共轭物包含通过肟键与各种促性腺激素释放激素III（GnRH-III）衍生物连接的柔红霉素。为了提高生物缀合物的酶促稳定性（特别是针对胰凝乳蛋白酶），将4 Ser替换为N-Me -Ser或Lys（Ac）。为了研究游离的ε-氨基对生化特性的影响，还制备了其中4 Lys没有被乙酰化的化合物。在体外通过3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴化物测定法确定了生物缀合物对MCF-7人乳腺癌，HT-29人结肠和LNCaP人前列腺癌细胞的抑制作用。通过液相色谱与质谱联用分析了它们的稳定性/降解（1）在人血清中，（2）在大鼠肝溶酶体匀浆存在下，（3）在消化酶（胰蛋白酶，胰凝乳蛋白酶和胃蛋白酶）存在下。光谱法。结果表明：（1）所有合成的生物缀合物均具有体外抑制细胞的作用，（2）它们在人血清中至少稳定24小时，（3）在溶酶体匀
• Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids
  作者：Eszter Lajkó、Sarah Spring、Rózsa Hegedüs、Beáta Biri-Kovács、Sven Ingebrandt、Gábor Mező、László Kőhidai

  DOI：10.3762/bjoc.14.226

  日期：——

  chemotherapeutic drug directly to the tumor cells. In this study our aim was (i) to analyze the effects of GnRH-drug conjugates on melanoma cell proliferation, adhesion and migration, (ii) to study the mechanisms of tumor cell responses, and (iii) to compare the activities of conjugates with the free drug. Results: In the tested conjugates, daunorubicin (Dau) was coupled to 8Lys of GnRH-III (GnRH-III(Dau=Aoa))

  背景：基于肽激素的靶向肿瘤治疗是一种选择性阻断肿瘤生长和扩散的公认策略。在不同肿瘤（例如黑色素瘤）上过度表达的促性腺激素释放激素受体（GnRH-R）可通过应用GnRH类似物作为载体将共价连接的化疗药物直接递送至肿瘤细胞而用于药物靶向。在这项研究中，我们的目的是（i）分析GnRH-药物偶联物对黑素瘤细胞增殖，粘附和迁移的影响，（ii）研究肿瘤细胞应答的机制，以及（iii）比较偶联物的活性。免费药物。结果：在测试的结合物中，将柔红霉素（Dau）偶联到8Lys的GnRH-III（GnRH-III（Dau = Aoa））或由短链脂肪酸酰化的4Lys修饰的衍生物上（[4Lys（Ac）]-GnRH-III（ [4Lys（Bu）]-GnRH-III（Dau = Aoa））中的丁酰基。A2058黑色素瘤模型细胞对结合物的摄取被证明是时间依赖性的。用xCELLigence SP系统进行的基于阻抗的增殖测量表