N-(tert-butoxycarbonyl)-N'-(6-methacrylamidohexanoyl)hydrazine

• 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-(tert-butoxycarbonyl)-N'-(6-methacrylamidohexanoyl)hydrazine
• 英文别名: N-(tert-butoxycarbonyl )-N′-(6-methacrylamidohexanoyl)hydrazine；1-(t-Butoxycarbonyl)-2-(6-methacrylamido hexanoyl)hydrazine；tert-butyl N-[6-(2-methylprop-2-enoylamino)hexanoylamino]carbamate
• 化学式: C₁₅H₂₇N₃O₄
• 分子量: 313.397
• InChiKey: VQUKXMUZQNYKRE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  22
• 可旋转键数：
  9
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  96.5
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  肼基甲酸叔丁酯 、 6-[(2-甲基 -1-氧代烯丙基)氨基]己酸 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 以45.2 %的产率得到N-(tert-butoxycarbonyl)-N'-(6-methacrylamidohexanoyl)hydrazine
  参考文献：
  名称：

  通过 HPMA 共聚物纳米疗法同时递送 STAT3 抑制剂和阿霉素，实现肿瘤的化学增敏，并具有 pH 敏感性激活

  摘要：

  我们合成了三种新型 STAT3 抑制剂 (S3iD1-S3iD3)，它们具有氧代庚酸残基，能够通过 pH 敏感的腙键连接到 HPMA 共聚物载体。合成了含有阿霉素 (Dox) 和我们的 STAT3 抑制剂的 HPMA 共聚物缀合物，以评估 Dox 和 STAT3 抑制剂共同递送到肿瘤中的抗癌效果。 S3iD1–3 及其共聚物结合对应物 (P-S3iD1-P-S3iD3) 在五种小鼠和人类癌细胞系中表现出相当大的体外细胞抑制活性，IC 50分别为 ~0.6–7.9 μM 和 0.7–10.9 μM。 S3iD2 和 S3iD3 被证实可抑制 STAT3 信号通路。 HPMA 共聚物结合的 Dox (P-Dox) 和 P-S3iD3 的组合，其毒性可忽略不计，在 B16F10 黑色素瘤小鼠中表现出显着的抗肿瘤活性，并完全治愈了 15 只小鼠中的 2 只。单独使用 P-Dox 的治疗活性明显较低

  DOI：

  10.1016/j.nano.2023.102730

文献信息

• GRAFTED MACROMOLECULAR CONJUGATES OF DOXORUBICIN WITH ANTICANCER ACTIVITY AND METHOD OF THEIR PREPARATION
  申请人：Etrych Tomas

  公开号：US20090306004A1

  公开（公告）日：2009-12-10

  A polymeric drug, in which a cancerostatic connected via spacers containing hydrolytically cleavable hydrazone bonds is bound to a water-soluble polymeric carrier prepared on the basis of a N-(2-hydroxypropyl)methacrylamide copolymer, wherein the structure of the polymeric drug consists of the main chain of N-(2-hydroxypropyl)methacrylamide carrying the cancerostatic and another chain of N-(2-hydroxypropyl)methacrylamide—a graft, which may also carry a cancerostatic, said grafts being bound to the main chain by a bond that is stable in the body and/or by a bond cleavable in the body, especially by an oligopeptide spacer selected from the series of GlyLeuGly, GlyPheGly, GlyPheLeuGly and GlyLeuPheGly, and a method of its preparation.

  一种聚合物药物，其中包含通过含有水解可断裂的酰肼键的间隔连接的抗癌药物，与基于N-（2-羟基丙基）甲基丙烯酰胺共聚物制备的水溶性聚合物载体结合，其中聚合物药物的结构由携带抗癌药物的N-（2-羟基丙基）甲基丙烯酰胺主链和另一条N-（2-羟基丙基）甲基丙烯酰胺链组成，该支链也可以携带抗癌药物，所述支链通过身体内稳定的键和/或身体内可断裂的键与主链结合，特别是通过选自GlyLeuGly、GlyPheGly、GlyPheLeuGly和GlyLeuPheGly系列的寡肽间隔连接，以及其制备方法。
• Synthesis of Poly[<i>N</i>-(2-hydroxypropyl)methacrylamide] Conjugates of Inhibitors of the ABC Transporter That Overcome Multidrug Resistance in Doxorubicin-Resistant P388 Cells in Vitro
  作者：V. Šubr、L. Sivák、E. Koziolová、A. Braunová、M. Pechar、J. Strohalm、M. Kabešová、B. Říhová、K. Ulbrich、M. Kovář

  DOI：10.1021/bm500649q

  日期：2014.8.11

  The effects of novel polymeric therapeutics based on water-soluble N-(2-hydroxypropyl)methacrylamide copolymers (P(HPMA)) bearing the anticancer drug doxorubicin (Dox), an inhibitor of ABC transporters, or both, on the viability and the proliferation of the murine monocytic leukemia cell line P388 (parental cell line) and its doxorubicin-resistant subline P388/MDR were studied in vitro. The inhibitor derivatives 5-methyl-4-oxohexanoyl reversin 121 (MeOHe-R121) and 5-methyl-4-oxohexanoyl ritonavir ester (MeOHe-RIT), showing the highest inhibitory activities, were conjugated to the P(HPMA) via the biodegradable pH-sensitive hydrazone bond, and the ability of these conjugates to block the ATP driven P-glycoprotein (P-gp) efflux pump was tested. The P(HPMA) conjugate P-Ahx-NH-N═MeOHe-R121 showed a dose-dependent increase in the ability to sensitize the P388/MDR cells to Dox from 1.5 to 24 μM, and achieved an approximately 50-fold increase in sensitization at 24 μM. The P(HPMA) conjugate P-Ahx-NH-N═MeOHe-RIT showed moderate activity at 6 μM (∼10 times higher sensitization) and increased sensitization by 50-fold at 12 μM. The cytostatic activity of the P(HPMA) conjugate P-Ahx-NH-N═MeOHe-R121(Dox) containing Dox and the P-gp inhibitor MeOHe-R121, both bound via hydrazone bonds to the P(HPMA) carrier, was almost 30 times higher than that of the conjugate P-Ahx-NH-N═Dox toward the P388/MDR cells in vitro. A similar result was observed for P-Ahx-NH-N═MeOHe-RIT(Dox), which exhibited almost 10 times higher cytostatic activity than P-Ahx-NH-N═Dox.
• Polymer-ritonavir derivate nanomedicine with pH-sensitive activation possesses potent anti-tumor activity in vivo via inhibition of proteasome and STAT3 signaling
  作者：Ladislav Sivák、Vladimír Šubr、Jiřina Kovářová、Barbora Dvořáková、Milada Šírová、Blanka Říhová、Eva Randárová、Michal Kraus、Jakub Tomala、Martin Studenovský、Michaela Vondráčková、Radislav Sedláček、Petr Makovický、Jitka Fučíková、Šárka Vošáhlíková、Radek Špíšek、Libor Kostka、Tomáš Etrych、Marek Kovář

  DOI：10.1016/j.jconrel.2021.03.015

  日期：2021.4
• Overcoming resistance to rituximab in relapsed non-Hodgkin lymphomas by antibody-polymer drug conjugates actively targeted by anti-CD38 daratumumab
  作者：Ondřej Lidický、Pavel Klener、Daniela Machová、Petra Vočková、Eva Pokorná、Karel Helman、Cory Mavis、Olga Janoušková、Tomáš Etrych

  DOI：10.1016/j.jconrel.2020.08.042

  日期：2020.12

  B-cell non-Hodgkin lymphomas (B-NHL) represent the most common type of hematologic malignancies in the Western hemisphere. The therapy of all B-NHL is based on the combination of different genotoxic cytostatics and anti-CD20 monoclonal antibody (mAb) rituximab. Unfortunately, many patients relapse after the mentioned front-line treatment approaches. The therapy of patients with relapsed/refractory (R/R) B-NHL represents an unmet medical need. We designed, developed and tested novel actively targeted hybrid mAb-polymer-drug conjugate (APDC) containing anti-CD20, anti-CD38 or anti-CD19 mAbs. Biocompatible copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) with cytostatic agent doxorubicin attached via stimuli-sensitive hydrazone bond were employed for the mAb grafting. Anti-lymphoma efficacy of the APDC nanotherapeutics was evaluated in vivo on a panel of three patient-derived lymphoma xenografts derived from two patients with R/R B-NHL and one patient with so far untreated B-NHL. In both PDX models derived from patients with R/R B-NHL, the targeting with anti-CD38 antibody daratumumab demonstrated highly improved anti-lymphoma efficacy compared to the targeting with anti-CD20 rituximab, two experimental anti-CD19 antibodies and non-targeted controls. The results represent a proof-of-concept of a new algorithm of personalized anti-tumor therapy based on highly innovative APDC biomaterials.
• US8603990B2
  申请人：——

  公开号：US8603990B2

  公开（公告）日：2013-12-10