O-[6-azidohexyl]-N-[4-(diethylcarboxamido)phenyl]-N-chloromethylcarbamate | 1346434-65-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: O-[6-azidohexyl]-N-[4-(diethylcarboxamido)phenyl]-N-chloromethylcarbamate
• 英文别名: 6-azidohexyl N-(chloromethyl)-N-[4-(diethylcarbamoyl)phenyl]carbamate
• CAS: 1346434-65-8
• 化学式: C₁₉H₂₈ClN₅O₃
• 分子量: 409.916
• InChiKey: ALJANEMROVWPCX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  28
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  64.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  O-[6-azidohexyl]-N-[4-(diethylcarboxamido)phenyl]-N-chloromethylcarbamate 在 吡啶 、 potassium tert-butylate 、 溶剂黄146 、 三甲基膦 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.25h， 生成
  参考文献：
  名称：

  Macromolecular Prodrug That Provides the Irinotecan (CPT-11) Active-Metabolite SN-38 with Ultralong Half-Life, Low C_max , and Low Glucuronide Formation

  摘要：

  We have recently reported a chemical approach for half-life extension that utilizes β-eliminative linkers to attach amine-containing drugs or prodrugs to macromolecules. The linkers release free drug or prodrug over periods ranging from a few hours to over 1 year. We adapted these linkers for use with phenol-containing drugs. Here, we prepared PEG conjugates of the irinotecan (CPT-11) active metabolite SN-38 via a phenyl ether that release the drug with predictable long half-lives. Pharmacokinetic studies in the rat indicate that, in contrast to other SN-38 prodrugs, the slowly released SN-38 shows a very low C(max), is kept above target concentrations for extended periods, and forms very little SN-38 glucuronide (the precursor of enterotoxic SN-38). The low SN-38 glucuronide is attributed to low hepatic uptake of SN-38. These macromolecular prodrugs have unique pharmacokinetic profiles that may translate to less intestinal toxicity and interpatient variability than the SN-38 prodrugs thus far studied.

  DOI：

  10.1021/jm401644v
• 作为产物：
  描述：

  在 吡啶 、 三甲基氯硅烷 作用下， 以 四氢呋喃 为溶剂， 反应 43.0h， 生成 O-[6-azidohexyl]-N-[4-(diethylcarboxamido)phenyl]-N-chloromethylcarbamate
  参考文献：
  名称：

  β-Eliminative Releasable Linkers Adapted for Bioconjugation of Macromolecules to Phenols

  摘要：

  We recently reported a chemical approach for half-life extension that utilizes sets of releasable linkers to attach drugs to macromolecules via a cleavable carbamate group (Santi et al., Proc. Nat. Acad. Sci. U.S.A. 2012, 109, 6211-6216). The linkers undergo a beta-elimination cleavage to release the free, native amine-containing drug. A limitation of the technology is the requirement for an amino group on the drug in order to form the carbamate bond, since most small molecules do not have an amine functional group. Here, we describe an approach to adapt these same beta-elimination carbamate linkers so they can be used to connect other acidic heteroatoms, in particular, phenolic hydroxyl groups. The approach utilizes a methylene adaptor to connect the drug to the carbamate nitrogen, and an electron-withdrawing group attached to carbamate nitrogen to stabilize the system against a pH-independent spontaneous cleavage. Carbamate cleavage is driven by beta-elimination to give a carboxylated aryl amino Mannich base which rapidly collapses to give the free drug, an aryl amine, and formaldehyde.

  DOI：

  10.1021/bc4002882

文献信息

• A Very Long-Acting PARP Inhibitor Suppresses Cancer Cell Growth in DNA Repair-Deficient Tumor Models
  作者：Shaun D. Fontaine、Gary W. Ashley、Peter J. Houghton、Raushan T. Kurmasheva、Morgan Diolaiti、Alan Ashworth、Cody J. Peer、Ryan Nguyen、William D. Figg、Denis R. Beckford-Vera、Daniel V. Santi

  DOI：10.1158/0008-5472.can-20-1741

  日期：2021.2.15

  These findings demonstrate that a single injection of a long-acting prodrug of the PARP inhibitor talazoparib in murine xenografts provides tumor suppression equivalent to a month of daily dosing of talazoparib.

  摘要 PARP 抑制剂已被批准用于治疗有 BRCA1 或 BRCA2 缺陷的癌症。在这项研究中，我们制备并鉴定了一种长效 PARP 抑制剂。通过共价键合到 PEG40kDa 载体上，再通过β-消除性可释放连接体合成了一种 TalazoPARib（TLZ）的大分子原药。在抑制小鼠异种移植中同源重组缺陷肿瘤的生长方面，单次注射 PEG∼TLZ 共轭物与每天口服 30 次 TLZ 同等有效。这些肿瘤包括带有 PALB2 突变的 KT-10 Wilms 肿瘤、BRCA1 缺陷的 MX-1 三阴性乳腺癌和 BRCA2 缺陷的 DLD-1 结肠癌；该原药对带有野生型 BRCA2 的同源 DLD-1 肿瘤没有抑制作用。虽然 PEG∼TLZ 和释放的 TLZ 在小鼠体内的半衰期只有 1 天，但单次安全有效剂量的原药释放的 TLZ 暴露量超过了一个月内每天口服 TLZ 的暴露量。μPET/CT 成像显示，PEG∼TLZ 的 89Zr 标记替代物在 MX-1 BRCA1 缺失型肿瘤中的摄取量高且保留时间长。这些数据表明，该原药的长效抗肿瘤作用是由其较长的 t1/2、原药释放的 TLZ 的高暴露量、持续暴露后肿瘤敏感性的增加以及肿瘤蓄积等因素共同作用的结果。利用TLZ在人体中的药代动力学参数，我们设计了一种长效PEG∼TLZ，其疗效可能优于每日口服的TLZ，可用于治疗不能耐受口服药物的对PARP抑制剂敏感的癌症。 意义重大： 这些研究结果表明，在小鼠异种移植中注射一次PARP抑制剂talazoPARib的长效原药，其抑制肿瘤的效果相当于每天服用一个月的talazoPARib。