methyl 4-[(10-dihydroartemisininoxy)methyl]benzoate | 216963-48-3

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: methyl 4-[(10-dihydroartemisininoxy)methyl]benzoate
• 英文别名: methyl p-<(10-dihydroartemisininoxy)methyl>benzoate；artelinic acid methyl ester；methyl p-[(10-dihydroartemisininoxy)methyl]benzoate；methyl p-[(12-dihydroartemisininoxy)methyl]benzoate；4-[(10-dihydroartemisininoxy)-methyl]benzoate methyl ester；methyl 4-[[(1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-yl]oxymethyl]benzoate
• CAS: 216963-48-3
• 化学式: C₂₄H₃₂O₇
• 分子量: 432.514
• InChiKey: LMZFUTLREPSZGJ-LRVLTPSZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  72.4
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl 4-[(10-dihydroartemisininoxy)methyl]benzoate 在 potassium hydroxide 作用下， 以 甲醇 为溶剂， 反应 72.0h， 生成 N-[2-(tert-butylamino)-2-oxoethyl]-N-[2-[(7-chloroquinolin-4-yl)amino]ethyl]-4-[[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-yl]oxymethyl]benzamide
  参考文献：
  名称：

  Effects of highly active novel artemisinin–chloroquinoline hybrid compounds on β-hematin formation, parasite morphology and endocytosis in Plasmodium falciparum

  摘要：

  4-Aminoquinolines were hybridized with artemisinin and 1,4-naphthoquinone derivatives via the Ugi-four-component condensation reaction, and their biological activities investigated. The artemisinin-containing compounds 6a-c and its salt 6c-citrate were the most active target compounds in the antiplasmodial assays. However, despite the potent in vitro activities, they also displayed cytotoxicity against a mammalian cell-line, and had lower therapeutic indices than chloroquine. Morphological changes in parasites treated with these artemisinin-containing hybrid compounds were similar to those observed after addition of artemisinin. These hybrid compounds appeared to share mechanism(s) of action with both chloroquine and artemisinin: they exhibited potent beta-hematin inhibitory activities; they caused an increase in accumulation of hemoglobin within the parasites that was intermediate between the increase observed with artesunate and chloroquine; and they also appeared to inhibit endocytosis as suggested by the decrease in the number of transport vesicles in the parasites. No cross-resistance with chloroquine was observed for these hybrid compounds, despite the fact that they contained the chloroquinoline moiety. The hybridization strategy therefore appeared to be borrowing the best from both classes of antimalarials. (C) 2011 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2011.04.018
• 作为产物：
  描述：

  青蒿素 在 sodium tetrahydroborate 、 三氟化硼乙醚 作用下， 以 甲醇 、 乙醚 为溶剂， 反应 26.0h， 生成 methyl 4-[(10-dihydroartemisininoxy)methyl]benzoate
  参考文献：
  名称：

  Antimalarial activity of new water-soluble dihydroartemisinin derivatives

  摘要：

  The usefulness of sodium artesunate (3), a water-soluble derivative of artemisinin (1), is impaired by its poor stability in aqueous solution. To overcome the ease of hydrolysis of the ester group in 3, a new series of derivatives of dihydroartemisinin (2) was prepared in which the solubilizing moiety, which contains a carboxylate group, is joined to dihydroartemisinin by an ether rather than an ester linkage. The new derivatives were prepared in good yield by treatment of dihydroartemisinin with an appropriate alcohol under boron trifluoride etherate catalysis at room temperature. All major condensation products are the beta isomer. Hydrolysis of the esters with 2.5% KOH/MeOH gave the corresponding potassium salts, which were converted to free acids (8b-d) by acidification. The derivatives were tested in vitro against two clones of human malaria, Plasmodium falciparum D-6 (Sierra Leone clone) and W-2 (Indochina clone). No cross-resistance to the antimalarial agents mefloquine, chloroquine, pyrimethamine, sulfadoxine, and quinine was observed. In general, the new compounds are more effective against the W-2 than the D-6 strain. Esters (5a-d) possess activity comparable to that of the parent compounds 1 and 2; however, conversion of the esters to their corresponding carboxylates (7a-d) or acids (8b-d), with the exception of artelinic acid (8d), drastically decreases the antimalarial activities in both cell lines. Artelinic acid, which is both soluble and stable in 2.5% K2CO3 solution, possesses superior in vivo activity against Plasmodium berghei than artemisinin or artesunic acid.

  DOI：

  10.1021/jm00394a037

文献信息

• CONJUGATES OF ARTEMISININ-RELATED ENDOPEROXIDES AND HYDRAZONE DERIVATIVES FOR THE TREATMENT OF CANCER
  申请人：Sasaki Tomikazu

  公开号：US20080103192A1

  公开（公告）日：2008-05-01

  Compounds having an artemisinin-related endoperoxide moiety covalently coupled to a hydrazone moiety through a linker. Compositions and methods for treating cancer using the compounds.

  具有与联接剂通过连接剂共价耦合的肟基的青蒿素相关内过氧化物基团的化合物。使用这些化合物治疗癌症的组合物和方法。
• Process for one pot conversion of artemisinin into artelinic acid
  申请人：Bhakuni Singh Rajendra

  公开号：US20070270598A1

  公开（公告）日：2007-11-22

  The present invention relates to an improved process for one pot conversion of artemisinin into artelinic acid, which reduces the three step (three pot) conversion of artemisinin to artelinic acid in one step (one pot). The process of preparation of artelinic acid involves stirring of artemisinin with sodium borohydride, catalyst, polyhydroxy compound or chlorotrimethylsilane or amberlyst-15 resin and methyl p-(hydroxymethyl) benzoate, filtration of undissolved, unwanted reaction products and finally stirring of the filtrate with alcoholic or aqueous alkali hydroxide.

  本发明涉及一种改进的工艺，用于将青蒿素一锅法转化为艾替尼酸，该工艺将青蒿素的三步（三锅）转化为艾替尼酸的一步（一锅）。制备艾替尼酸的过程涉及将青蒿素与硼氢化钠、催化剂、多羟基化合物或氯三甲基硅烷或琥珀酸树脂和甲基对羟甲基苯甲酸酯搅拌，过滤未溶解的、不需要的反应产物，最后将滤液与酒精或水溶性碱氢化物搅拌。
• Bhakuni, Rajendra S.; Jain, Dharam C.; Sharma, Ram P., Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1995, vol. 34, # 6, p. 529 - 530
  作者：Bhakuni, Rajendra S.、Jain, Dharam C.、Sharma, Ram P.

  DOI：——

  日期：——
• LIN, AI JENG;KLAYMAN, DANIEL L.;MILHOUS, WILBUR K., J. MED. CHEM., 30,(1987) N 11, 2147-2150
  作者：LIN, AI JENG、KLAYMAN, DANIEL L.、MILHOUS, WILBUR K.

  DOI：——

  日期：——
• Effects of artemisinin-tagged holotransferrin on cancer cells
  作者：Henry Lai、Tomikazu Sasaki、Narendra P. Singh、Archna Messay

  DOI：10.1016/j.lfs.2004.08.020

  日期：2005.1

  Artemisinin reacts with iron to form free radicals that kill cells. Since cancer cells uptake relatively large amount of iron than normal cells, they are more susceptible to the toxic effect of artemisinin. In previous research, we have shown that artemisinin is more toxic to cancer cells than to normal cells. In the present research, we covalently attached artemisinin to the iron-carrying plasma glycoprotein transferrin. Transferrin is transported into cells via receptor-mediated endocytosis and cancer cells express significantly more transferrin receptors on their cell surface and endocytose more transferrin than normal cells. Thus, we hypothesize that by tagging artemisinin to transferrin, both iron and arternisinin would be transported into cancer cells in one package. Once inside a cell, iron is released and can readily react with arternisinin close by tagged to the transferrin. This would enhance the toxicity and selectivity of artemisinin towards cancer cells. In this paper, we describe a method to synthesize such a compound in which transferrin was conjugated with an analog of artemisinin artelinic acid via the N-glycoside chains on the C-domain. The resulting conjugate ('tagged-compound') was characterized by MALDI-MS, UV/Vis spectroscopy, chemiluminescence, and HPLC. We then tested the compound on a human leukemia cell line (Molt-4) and normal human lymphocytes. We found that holotransferrin-tagged artemisinin, when compared with artemisinin, was very potent and selective in killing cancer cells. Thus, this 'tagged-compound' could potentially be developed into an effective chemotherapeutic agent for cancer treatment. (C) 2004 Elsevier Inc. All rights reserved.