7-(dimethoxymethyl)camptothecin | 84017-99-2

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 喜树碱
• 英文名称: 7-(dimethoxymethyl)camptothecin
• 英文别名: 7-dimethoxymethyl camptothecin；7-Dimethoxymethylcamptothecin；(4S)-11-(dimethoxymethyl)-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione；7-formyl-camptothecin dimethylacetal；7-dimethyl-acetal camptothecin；(S)-11-Dimethoxymethyl-4-ethyl-4-hydroxy-1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]fluorene-3,13-dione；(19S)-10-(dimethoxymethyl)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaene-14,18-dione
• CAS: 84017-99-2
• 化学式: C₂₃H₂₂N₂O₆
• 分子量: 422.437
• InChiKey: REONBJNSUPDLMU-QHCPKHFHSA-N

物化性质

• 熔点：
  201 °C (decomp)
• 沸点：
  742.3±60.0 °C(Predicted)
• 密度：
  1.45±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  98.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  7-(dimethoxymethyl)camptothecin 在 甲酸 、 水 、 双氧水 、 溶剂黄146 作用下， 反应 17.5h， 生成 Camptothecin-7-carboxylic acid
  参考文献：
  名称：

  Electron Paramagnetic Resonance (EPR) Study of Spin-Labeled Camptothecin Derivatives: A Different Look of the Ternary Complex

  摘要：

  Camptothecin (CPT) derivatives are clinically effective poisons of DNA topoisomerase I (Top 1) able to form a ternary complex with the Top1 DNA complex. The aim of this investigation was to examine the dynamic aspects of the ternary complex formation by means of site-directed spin labeling electron paramagnetic resonance (SDSL-EPR). Two semisynthetic CPT derivatives bearing the paramagnetic moiety were synthesized, and their biological activity was tested. A 22-mer DNA oligonucleotide sequence with high affinity cleavage site for Top1 was also synthesized. EPR experiments were carried out on modified CPT in the presence of DNA, of Top1, or of both. In the last case, a slow motion component in the EPR signal appeared, indicating the formation of the ternary complex. Deconvolution of the EPR spectrum allowed to obtain the relative drug amounts in the complex. It was also possible to demonstrate that the residence time of CPT "trapped" in the ternary complex is longer than hundreds of microseconds.

  DOI：

  10.1021/jm101232t
• 作为产物：
  描述：

  甲醇 、 喜树碱 在 iron(II) sulfate manganese(IV) oxide 、 硫酸 、 双氧水 作用下， 以83%的产率得到7-(dimethoxymethyl)camptothecin
  参考文献：
  名称：

  E环修饰的7-氧亚氨基甲基喜树碱：合成及初步的体内外生物学评估。

  摘要：

  与五元E环类似物相反，高喜树碱的7-氧亚氨基甲基衍生物具有与DNA和拓扑异构酶I形成稳定的三元复合物的能力。高喜树碱的7-氧亚氨基甲基衍生物被评估为外消旋混合物。在分离出两种对映异构体之后，20（R）-羟基异构体证实了最佳活性。通过使用一组人类肿瘤细胞，所有测试的同型喜树碱均显示出有效的抗增殖活性，与可裂解复合物的持久性相关。在天然支架和相应的喜树碱同系物之间没有观察到显着差异。该系列的选定化合物对人胃肠道肿瘤异种移植物表现出优异的抗肿瘤活性。

  DOI：

  10.1016/j.bmcl.2008.03.074

文献信息

• Chemical Modification of an Antitumor Alkaloid Camptothecin: Synthesis and Antitumor Activity of 7-C-Substituted Camptothecins.
  作者：Seigo SAWADA、Ken-ichiro NOKATA、Tomio FURATA、Teruo YOKOKURA、Tadashi MIYASAKA

  DOI：10.1248/cpb.39.2574

  日期：——

  derivatives (10), acid (11), esters (12) and amides (13) were synthesized starting from 2. 7-Ethyl- (4b) and 7-propylcamptothecin (4c), acyloxymethyl compounds 6a, 6c and ethyl ester (12b) exhibited higher antitumor activity than 1 against L1210 in mice.

  20（S）-喜树碱（1）与甲醇的自由基取代反应提供了7-羟甲基喜树碱（2）。1与高于甲醇的伯醇反应生成7-烷基喜树碱（4），其中烷基比所用的醇少1个碳，并且7-羟烷基喜树碱（5）。为了制备7-烷基喜树碱（4），使用醛作为自由基来源，并合成了几种烷基化衍生物。由2. 7-乙基-（4b）和7开始合成7-酰氧基甲基衍生物（6），7-甲醛（7），亚氨基甲基衍生物（10），酸（11），酯（12）和酰胺（13）。丙基喜树碱（4c），酰氧基甲基化合物6a，6c和乙酯（12b）在小鼠中对L1210的抗肿瘤活性高于1。
• [EN] CRYSTALLINE FORM II OF 7-(DIMETHOXY-METHYL) CAMPTOTHECIN, ITS USE AS INTERMEDIATE AND PRODUCTS OBTAINED THEREFROM<br/>[FR] FORME CRISTALLINE II DE LA 7-(DIMÉTHOXY-MÉTHYL)CAMPTOTHÉCINE, SON UTILISATION COMME INTERMÉDIAIRE ET PRODUITS OBTENUS À PARTIR DE CELLE-CI
  申请人：SIGMA TAU IND FARMACEUTI

  公开号：WO2009016068A1

  公开（公告）日：2009-02-05

  This invention relates to a process for preparing a crystalline form of (4S)-11-(dimethoxymethyl)-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]qui-no line-3,14(4H,12H)-dione (also named 7-(dimethoxy-methyl)camptothecin). With the provision of a particular crystallization step, in appropriate way, a new crystalline form of the above compound is obtained. The process for the preparation of the polymorph Form II comprises transforming camptothecin to the corresponding 7-(dimethoxy-methyl)-camptothecin, and crystallizing it from methanol.

  这项发明涉及一种制备(4S)-11-(二甲氧甲基)-4-乙基-4-羟基-1H-吡喃并[3',4':6,7]吲哚并[1,2-b]喹诺啉-3,14(4H,12H)-二酮（又名7-(二甲氧甲基)喜树碱）的晶型的方法。通过提供特定的结晶步骤，以适当的方式，得到了上述化合物的新晶型。制备多形式II的方法包括将喜树碱转化为相应的7-(二甲氧甲基)-喜树碱，并从甲醇中结晶化。
• Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors
  作者：Raffaella Cincinelli、Loana Musso、Roberto Artali、Mario Guglielmi、Erminia Bianchino、Francesco Cardile、Fabiana Colelli、Claudio Pisano、Sabrina Dallavalle

  DOI：10.1016/j.ejmech.2017.11.021

  日期：2018.1

  compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473

  最近的研究表明，由喜树碱衍生物和HDAC抑制剂组成的联合疗法具有增强的抗癌作用。为了在单一活性化合物中发挥这种协同作用，我们设计了同时靶向拓扑异构酶I和HDAC的新型双作用多价分子。特别地，包含喜树碱和psaMMaplin A支架的所选化合物显示出广谱的抗增殖活性，IC 50值在纳摩尔范围内。初步的体内结果表明对CD-1裸鼠原位异种移植的人间皮瘤原代细胞MM473有很强的抗肿瘤活性，并且具有很高的耐受性。
• Hybrid topoisomerase I and HDAC inhibitors as dual action anticancer agents
  作者：Raffaella Cincinelli、Loana Musso、Roberto Artali、Mario B. Guglielmi、Ilaria La Porta、Carmela Melito、Fabiana Colelli、Francesco Cardile、Giacomo Signorino、Alessandra Fucci、Martina Frusciante、Claudio Pisano、Sabrina Dallavalle

  DOI：10.1371/journal.pone.0205018

  日期：——

  hybrid molecules targeting simultaneously topoisomerase I and HDAC were designed. In particular, a selected multivalent agent containing a camptothecin and a SAHA-like template showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted

  最近的研究表明，在联合疗法中，HDAC抑制剂与喜树碱衍生物具有协同作用。为了利用这种协同作用，设计了同时靶向拓扑异构酶I和HDAC的新杂合分子。特别是，含有喜树碱和SAHA样模板的选定多价药物表现出广谱的抗增殖活性，IC50值在纳摩尔范围内。初步的体内结果表明对CD-1裸鼠原位异种移植的人间皮瘤原代细胞MM473有很强的抗肿瘤活性，并且具有很高的耐受性。
• STEREOSELECTIVE PROCESS AND CRYSTALLINE FORMS OF A CAMPTOTHECIN
  申请人：Carminati Paolo

  公开号：US20090239893A1

  公开（公告）日：2009-09-24

  A stereoselective process for preparing 7-[(E)-t-butyloxyiminomethyl]-camptothecin (also known as gimatecan) is herein disclosed. With the addition of further dissolution and precipitation steps carried out in appropriate different solvent mixtures, four new crystalline forms of gimatecan are also obtainable by using the same stereoselective process.

  本文披露了一种用于制备7-[(E)-t-丁氧基亚胺甲基]-喜树碱（也称为吉马替康）的立体选择性过程。通过在适当的不同溶剂混合物中进行进一步的溶解和沉淀步骤，还可以使用相同的立体选择性过程获得四种新的吉马替康晶体形式。