doxazolidine | 193743-49-6

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 蒽环类药物
• 英文名称: doxazolidine
• 英文别名: (7S,9S)-7-[[(3aS,4S,6R,7aS)-4-methyl-2,3a,4,6,7,7a-hexahydro-1H-pyrano[4,3-d][1,3]oxazol-6-yl]oxy]-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
• CAS: 193743-49-6
• 化学式: C₂₈H₂₉NO₁₁
• 分子量: 555.538
• InChiKey: DMROAWTZXCKQPT-PODHPLMESA-N

物化性质

• 沸点：
  799.7±60.0 °C(Predicted)
• 密度：
  1.60±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  40
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  181
• 氢给体数：
  5
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  doxazolidine 生成 阿霉素
  参考文献：
  名称：

  Doxazolidine, a Proposed Active Metabolite of Doxorubicin That Cross-links DNA

  摘要：

  A crystal structure establishes doxoform as a dimeric formaldehyde conjugate of the oxazolidine of doxorubicin. Doxoform is a prodrug of doxazolidine, a monomeric doxorubicin formaldehyde-oxazolidine. Both doxoform and doxazolidine inhibit the growth of cancer cells at 1-4 orders of magnitude lower concentration than doxorubicin. They also inhibit the growth of cancer cells better than doxsaliform, a prodrug for an acyclic doxorubicin-formaldehyde conjugate. Doxoform rapidly hydrolyzes to doxazolidine, which then hydrolyzes to doxorubicin with a half-life of 3 min in human serum at 37 degrees C. Both doxoform and doxazolidine are taken up by multidrug-resistant MCF-7/Adr cells 3- to 4-fold better than doxorubicin. A molecular model suggests that doxazolidine can cross-link DNA by direct reaction with a G-base in a tautomeric form with synchronous ring opening of the oxazolidine. These results point to doxoform being a prodrug for doxazolidine that is the reactive species that directly cross-links DNA.

  DOI：

  10.1021/jm050678v
• 作为产物：
  描述：

  盐酸多柔比星 在 4 Å molecular sieves 作用下， 以 氘代氯仿 为溶剂， 反应 168.0h， 生成 doxazolidine
  参考文献：
  名称：

  WO2007/102888

  摘要：

  公开号：

文献信息

• Design, Synthesis, and Preliminary Evaluation of Doxazolidine Carbamates as Prodrugs Activated by Carboxylesterases
  作者：David J. Burkhart、Benjamin L. Barthel、Glen C. Post、Brian T. Kalet、Jordan W. Nafie、Richard K. Shoemaker、Tad H. Koch

  DOI：10.1021/jm060597e

  日期：2006.11.30

  The synthesis and tumor cell growth inhibition by doxazolidine carbamate prodrugs are reported. The carbamates were designed for selective hydrolysis by one or more human carboxylesterases to release doxazolidine (Doxaz), the formaldehyde-oxazolidine of doxorubicin that cross-links DNA to trigger cell death. Simple butyl and pentyl, but not ethyl, carbamate prodrugs inhibited the growth of cancer cells

  报道了多沙唑烷氨基甲酸酯前药的合成和肿瘤细胞生长抑制。氨基甲酸酯被设计用于通过一种或多种人类羧酸酯酶选择性水解以释放多沙唑烷 (Doxaz)，多柔比星的甲醛-恶唑烷交联 DNA 以引发细胞死亡。简单的丁基和戊基，但不是乙基，氨基甲酸酯前药抑制过度表达羧酸酯酶 CES1 (hCE1) 和 CES2 (hiCE) 的癌细胞的生长。相对 CES1 和 CES2 表达水平通过各自 mRNA 的逆转录，然后进行聚合酶链式反应扩增来确定。具有对氨基苯甲醇 (PABA) 自消除间隔物的更复杂结构显示出更好的生长抑制作用（对 Hep G2 肝癌细胞的 IC50=50 nM），同时对大鼠心肌细胞的毒性降低，相对于母体药物阿霉素。待进一步研究的先导化合物 4-(N-doxazolidinylcarbonyloxymethyl)phenylcarBAmate 似乎在表达 CES1 和 CES2 的 Hep G2
• [EN] ANTHRACYCLINE PRODRUGS AND METHODS OF MAKING AND USING THE SAME<br/>[FR] PROMÉDICAMENTS D'ANTHRACYNE ET PROCÉDÉS DE PRODUCTION ET D'UTILISATION DE CES DERNIERS
  申请人：UNIV COLORADO REGENTS

  公开号：WO2016176332A1

  公开（公告）日：2016-11-03

  Therapeutically effective prodrug compounds for the prevention and treatment of cancer and pharmaceutical compositions containing these compounds as well as methods of making and using these compounds.

  用于预防和治疗癌症的具有治疗效果的前药化合物，以及含有这些化合物的药物组合物，以及制备和使用这些化合物的方法。
• METHODS OF TREATING CANCER WITH DOXAZOLIDINE AND PRODRUGS THEREOF
  申请人：Koch Tad H.

  公开号：US20110135618A1

  公开（公告）日：2011-06-09

  The invention provides therapeutically effective compounds for the prevention and treatment of cancer and pharmaceutical compositions containing these compounds as well as methods of using and administering these compounds. The invention also includes methods of activating a prodrug of these therapeutically effective compounds by the administration of a peptide-directed targeting construct that delivers a prodrug-activating enzyme to a target activation site.

  本发明提供了预防和治疗癌症的治疗有效化合物，以及含有这些化合物的制药组合物，以及使用和管理这些化合物的方法。本发明还包括通过给靶向肽构造物输送一种前药激活酶到目标激活位点来激活这些治疗有效化合物的前药的方法。
• Anthracycline prodrugs and methods of making and using the same
  申请人：THE REGENTS OF THE UNIVERSITY OF COLORADO

  公开号：US10912767B2

  公开（公告）日：2021-02-09

  The present invention includes compounds of the class anthracycline that have been modified to include photo-activated prodrug anthracycline compounds that are useful in the treatment of cancer. One example composition of the invention may include photodoxazolidine which may be synthesized in two steps from 4,5-dimethoxy-2-nitrobenzyl alcohol and doxazolidine. In this embodiment commercial 4,5-dimethoxyl-2-nitrobenzyl alcohol reacts with p-nitrophenylchloroformate to give the p-nitrophenyl carbonate of the benzyl alcohol derivative. The p-nitrophenyl carbonate is then reacted with doxazolidine to give the exemplary photodoxazolidine composition.

  本发明包括经过修饰的蒽环类化合物，其中包括可用于治疗癌症的光活化原药蒽环类化合物。本发明的一种实例组合物可包括光恶唑烷，它可由 4,5-二甲氧基-2-硝基苯甲醇和多恶唑烷分两步合成。在本实施例中，商用 4,5-二甲氧基-2-硝基苯甲醇与对硝基苯基氯甲酸酯反应，生成苄醇衍生物的对硝基苯基碳酸酯。然后，对硝基苯碳酸盐与多沙唑烷反应，得到示例性光多沙唑烷组合物。
• Photoactivatable Prodrug of Doxazolidine Targeting Exosomes
  作者：Ryo Tamura、Alla Balabanova、Samuel A. Frakes、Austin Bargmann、Jan Grimm、Tad H. Koch、Hang Yin

  DOI：10.1021/acs.jmedchem.8b01508

  日期：2019.2.28

  Natural lipid nanocarriers, exosomes, carry cell-signaling materials such as DNA and RNA for intercellular communications. Exosomes derived from cancer cells contribute to the progression and metastasis of cancer cells by transferring oncogenic signaling molecules to neighboring and remote premetastatic sites. Therefore, applying the unique properties of exosomes for cancer therapy has been expected in science, medicine, and drug discovery fields. Herein, we report that an exosome-targeting prodrug system, designated MARCKS-ED-photodoxaz, could spatiotemporally control the activation of an exquisitely cytotoxic agent, doxazolidine (doxaz), with UV light. The MARCKS-ED peptide enters a cell by forming a complex with the exosomes in situ at its plasma membrane and in the media. MARCKS-ED-photodoxaz releases doxaz under near-UV irradiation to inhibit cell growth with low nanomolar IC50 values. The MARCKS-ED-photodoxaz system targeting exosomes and utilizing photochemistry will potentially provide a new approach for the treatment of cancer, especially for highly progressive and invasive metastatic cancers.