doxoform

• 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: doxoform
• 英文别名: DoxF；bis-(3'-N-(3'-N,4'-O-methylenedoxorubicinyl))methane；(7S,9S)-7-[[(3aS,4S,6R,7aS)-1-[[(3aS,4S,6R,7aS)-4-methyl-6-[[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1H-tetracen-1-yl]oxy]-2,3a,4,6,7,7a-hexahydropyrano[4,3-d][1,3]oxazol-1-yl]methyl]-4-methyl-2,3a,4,6,7,7a-hexahydropyrano[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
• 化学式: C₅₇H₅₈N₂O₂₂
• 分子量: 1123.09
• InChiKey: ZZUVBKWGQQCRMJ-XGMHILOMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  81
• 可旋转键数：
  12
• 环数：
  12.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  345
• 氢给体数：
  8
• 氢受体数：
  24

反应信息

• 作为反应物：
  描述：

  doxoform 在 水 作用下， 生成 doxazolidine
  参考文献：
  名称：

  Preclinical Efficacy of a Carboxylesterase 2-Activated Prodrug of Doxazolidine

  摘要：

  Doxazolidine (Doxaz) is a functionally distinct formaldehyde conjugate or doxorubicin (Dox) that induces cancer cell death in Dox-sensitive and resistant cells. Pentyl PABC-Doxaz (PPD) is a prodrug or Doxaz that is activated by carboxylesterase 2 (CES2), which is expressed by liver, non-small-cell lung, colon, pancreatic, renal, and thyroid cancer cells. Here, we demonstrate that in two murine models, PPD was effective at slowing tumor growth and demonstrated markedly reduced cardiotoxic and nephrotoxic effects, as well as better tolerance, relative to Dox. Hepatotoxicity, consistent with liver expression of the murine CES2 homologue, was induced by PPD. Unlike irinotecan, a clinical CES2-activated prodrug, PPD produced no visible gastrointestinal damage. Finally, we demonstrate that cellular response to PPD may be predicted with good accuracy using CES2 expression and Doxaz sensitivity, suggesting that these metrics may be useful its clinical biomarkers for sensitivity of a specific tumor to PPD treatment.

  DOI：

  10.1021/jm900694z
• 作为产物：
  描述：

  阿霉素 在 4 Å molecular sieves 作用下， 以 甲醇 、 氘代氯仿 、 水 为溶剂， 反应 168.0h， 生成 doxoform
  参考文献：
  名称：

  WO2007/102888

  摘要：

  公开号：

文献信息

• Anti-cancer drug aldehyde conjugate drugs with enhanced cytotoxicity compounds, compositions and methods
  申请人：University Technology Corporation

  公开号：US06677309B1

  公开（公告）日：2004-01-13

  Monomeric and dimeric anti-cancer drug aldehyde conjugate compounds and pharmaceutically acceptable salts thereof. Specifically, monomeric and dimeric aldehyde conjugates of 1-2, dihetero-substituted anti-cancer drugs, including monomeric and dimeric aldehyde conjugates of anthracyclines, are provided. Also provided are pro-drugs which, after administration, release monomeric aldehyde conjugates. Further provided are pharmaceutical and therapeutic compositions containing anti-cancer drug aldehyde conjugates and methods of treating cancer using the aldehyde conjugates.

  单体和二聚抗癌药物醛缀合物及其药用可接受的盐。具体包括1-2，二杂原子取代的抗癌药物的单体和二聚醛缀合物，包括蒽环类抗癌药物的单体和二聚醛缀合物。还提供了前药，在给药后释放单体醛缀合物。进一步提供了含有抗癌药物醛缀合物的药用和治疗组合物，以及使用醛缀合物治疗癌症的方法。
• Doxoform and Daunoform:  Anthracycline−Formaldehyde Conjugates Toxic to Resistant Tumor Cells
  作者：David J. Fenick、Dylan J. Taatjes、Tad H. Koch

  DOI：10.1021/jm970237e

  日期：1997.8.1

  DNA via catalytic production of formaldehyde prompted the synthesis of derivatives bearing formaldehyde. Reaction of the parent drugs with aqueous formaldehyde at pH 6 produced in 40-50% yield conjugates consisting of two molecules of the parent drug as oxazolidine derivatives bound together at their 3'-nitrogens by a methylene group. The structures were established as bis(3'-N-(3'-N,4'-O-methylenedoxorubicinyl))

  最近发现，临床上重要的抗肿瘤药物阿霉素和柔红霉素烷基化DNA通过催化甲醛的产生促使合成带有甲醛的衍生物。母体药物与pH为6的甲醛水溶液反应，可产生40-50％的结合物，该结合物由母体药物的两个分子组成，它们是恶唑烷衍生物，在3'-氮处通过亚甲基结合在一起。该结构被确定为双（3'-N-（3'-N，4'-O-亚甲基二氧杂丁酰））甲烷（Doxoform）和双（3'-N-（3'-N，4'-O-亚甲基二柔红霉素） ））光谱数据中的甲烷（Daunoform）。两种衍生物对于母体药物的水解都是不稳定的。3'-N，4'-亚甲基阿霉素和3'-N，4'-O-亚甲基柔比星是水解的中间体。与给定药物-DNA加合物等价的浓度的柔红霉素和甲醛的组合相比，金牛菊与自身互补的脱氧寡核苷酸（GC）4的反应速度更快。尽管水解不稳定，Doxoform对MCF-7人乳腺癌细胞的毒性要高150倍，对MCF-7 / ADR耐药细胞的
• 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.
• Doxazolidine, a Proposed Active Metabolite of Doxorubicin That Cross-links DNA
  作者：Glen C. Post、Benjamin L. Barthel、David J. Burkhart、John R. Hagadorn、Tad H. Koch

  DOI：10.1021/jm050678v

  日期：2005.12.1

  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.
• Nuclear Targeting and Nuclear Retention of Anthracycline−Formaldehyde Conjugates Implicates DNA Covalent Bonding in the Cytotoxic Mechanism of Anthracyclines
  作者：Dylan J. Taatjes、David J. Fenick、Tad H. Koch

  DOI：10.1021/tx990008q

  日期：1999.7.1

  The anthracycline, antitumor drugs doxorubicin (DOX), daunorubicin (DAU), and epidoxorubicin (EPI) catalyze production of formaldehyde through induction of oxidative stress. The formaldehyde then mediates covalent bonding of the drugs to DNA. Synthetic formaldehyde conjugates of DOX, DAU, and EPI, denoted Doxoform (DOXF), Daunoform (DAUF), and Epidoxoform (EPIF), exhibit enhanced toxicity to anthracycline-sensitive and -resistant tumor cells. Uptake and retention of parent anthracycline antitumor drugs (DOX, DAU, and EPI) relative to those of their formaldehyde conjugates (DOXF,DAUF, and EPIF) were assessed by flow cytometry in both drug-sensitive MCF-7 cells and drug-resistant MCF-7/ADR cells. The MCF-7 cells took up more than twice as much drug as the MCF-7/ADR cells, and both cell lines took up substantially more of the formaldehyde conjugates than the parent drugs. Both MCF-7 and MCF-7/ADR cells retained fluorophore from DOXF, DAUF, and EPIF hours after drug removal, while both cell Lines almost completely expelled DOX, DAU, and EPI within 1 h. Longer treatment with DOX, DAU, and EPI resulted in modest drag retention in MCF-7 cells following drug removal but poor retention of DOX DAU, and EPI in MCF-7/ADR cells. Fluorescence microscopy showed that the formaldehyde conjugates targeted the nuclei of both sensitive and resistant cells, and remained in the nucleus hours after drug removal. Experiments in which [H-3]Doxoform was used, synthesized from doxorubicin and [H-3]formaldehyde, also indicated that Doxoform targeted the nucleus. Elevated levels of 3H were observed in DNA isolated from [H-3]Doxoform-treated MCF-7 and MCF-7/ADR cells relative to controls. The results implicate drug-DNA covalent bonding in the tumor cell toxicity mechanism of these anthracyclines.