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CN-119119150-B - Icariside II derivative with anti-liver cancer activity and preparation method and application thereof

CN119119150BCN 119119150 BCN119119150 BCN 119119150BCN-119119150-B

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an icariside II derivative with anti-liver cancer activity, and a preparation method and application thereof. The invention provides a series of icariside II (ICA-II) derivatives with higher anti-liver cancer activity, and further provides a pharmaceutical composition containing the derivatives or pharmaceutically acceptable salts thereof, and a preparation method of the derivatives or pharmaceutically acceptable salts thereof. In addition, the application of the derivative or the pharmaceutically acceptable salt or the pharmaceutical composition thereof in preparing medicines for treating primary liver cancer is also provided.

Inventors

  • SONG SHAOJIANG
  • LIU QINGBO
  • LUO TIANYU
  • YAO GUODONG
  • WANG XINYE
  • NIU JIAQI
  • WANG JIAYIN
  • LIU YAN

Assignees

  • 沈阳药科大学

Dates

Publication Date
20260512
Application Date
20240912

Claims (9)

  1. 1. The icariside II derivative or pharmaceutically acceptable salt thereof with the anti-liver cancer activity is characterized in that the icariside II derivative is an icariside II oxadiazole derivative, wherein the icariside II oxadiazole derivative has a chemical structure shown in a formula (I) or a formula (II): , R in the formula (I) is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) ; R in the formula (II) is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  2. 2. A icariside II derivative with anti-liver cancer activity or a pharmaceutically acceptable salt thereof is characterized in that the icariside II oxadiazole derivative is selected from the following compounds: 。
  3. 3. The method for preparing icariside II derivative or pharmaceutically acceptable salt thereof according to claim 2, which is characterized by comprising the steps of: , Taking a2-a22, a31 and a33-a34 as starting materials, obtaining intermediates b2-b22, b31 and b33-b34 through a step (i), obtaining fragments c2-c22, c31 and c33-c34 through a step (II), and finally obtaining compounds YYYH 2-22, YYH31 and YYH33-34 through a step (iii) replacing icariside II.
  4. 4. The method according to claim 3, wherein the method comprises the steps of: (i) b2-b22, b31, b33-b34, namely dissolving a2-a22, a31, a33-a34 in a solvent, adding 1.5-3 equivalents of HOBt and 1.5-3 equivalents of EDCI, stirring for 0.5-4 hours, dropwise adding 2-4 equivalents of 80% hydrazine hydrate, reacting at room temperature, removing the solvent, extracting, washing, drying, filtering and purifying; (ii) C2-C22, C31, C33-C34, namely, b2-b22, b31, b33-b34 are dissolved in a solvent, 1-3 equivalents of trimethoxy chloroethane and 3-5 equivalents of acetic acid are added for reaction at 110-130 ℃, and the post-treatment mode is the same as that of the step (i); (iii) Synthesis of YYH2-22, YYH31 and YYH33-34 by dissolving icariside II and 1-2 equivalents K 2 CO 3 , 0.5-1 equivalents KI in a solvent, stirring at room temperature, adding the corresponding fragments, reacting at 60℃and post-treating in the same manner as in step (i).
  5. 5. The process according to claim 4, wherein the solvent is selected from the group consisting of anhydrous acetonitrile, N, N-dimethylaminoformamide, 1, 4-dioxane, toluene and acetone.
  6. 6. A pharmaceutical composition comprising the icariside II derivative or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2 and a pharmaceutically acceptable carrier.
  7. 7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is in the form of an oral dosage form or an injectable dosage form.
  8. 8. The pharmaceutical composition of claim 7, wherein the oral dosage form is a capsule, a tablet, a granule, an oral liquid, a sustained release preparation or a controlled release preparation, and the pharmaceutically acceptable carrier is one or more selected from a diluent, a lubricant, a binder, a disintegrant, a stabilizer or a solvent.
  9. 9. Use of the icariside II derivative according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 6 to 8 in the preparation of a medicament for treating primary liver cancer.

Description

Icariside II derivative with anti-liver cancer activity and preparation method and application thereof Technical Field The invention belongs to the technical field of medicines, and particularly relates to an icariside II derivative with anti-liver cancer activity, and a preparation method and application thereof. Background Liver cancer is one of the most common tumors in the world and is also the leading cause of cancer-related death, with primary liver cancer (Hepatocellular carcinoma, HCC) being the most common form of cancer, accounting for about 90% of patients. Causes of liver cancer include (e.g., type b and type c) viral hepatitis, alcohol, obesity, dietary carcinogens, and the like. The current liver cancer treatment modes mainly comprise surgical excision and liver transplantation, but the effects are poor. Targeted treatment of liver cancer is limited to sorafenib, lenvatinib, regorafenib, ramucirumab and cabotinib, which are beneficial for prolonging survival of patients, but which are resistant (European Journal ofMedicinal Chemistry,2021, 224:113690). Therefore, development of alternative therapeutic strategies is urgently needed. Icaritin (Icaritin/ICT) is taken as a main component in Chinese medicinal epimedium herb, is an isopentenyl flavonoid compound, and is currently marketed as a class I innovative medicine (the medicine name is aclacin). However, it is poorly water-soluble and generally has anti-hepatoma activity. Based on the research of the previous structure-activity relationship of the inventor, the inventor discovers that (1) rhamnose is connected at the C3 position, the activity of the rhamnose is greatly improved, (2) isopentenyl is a key group with anti-liver cancer activity, and (3) the proliferation inhibition effect can be enhanced by introducing nitrogen heterocycle at the C7 position. The invention further modifies C7 on the basis of the research so as to further improve the anti-liver cancer cell proliferation activity of icaritin and the structural analogue thereof. 1,3, 4-Oxadiazole derivatives have been successfully used as antimitotic agents in the treatment of cancer. Most antimitotic drugs target microtubules, which are the dynamic elements of the cytoskeleton responsible for the formation of the mitotic spindle, necessary for chromosome segregation during cell division. The oxazole derivatives inhibit tubulin polymerization and prevent tumor cell mitosis, thereby having antitumor activity (Bioorganic & MEDICINAL CHEMISTRY LETTERS,2006, 16:1191-1196). In addition, 1,3, 4-oxadiazole and 1,3, 4-thiadiazole are also popular fragments for anti-tumor research, so the present inventors have attempted to introduce it to increase the anti-hepatoma cell proliferation activity of icariside. Disclosure of Invention To solve the above technical problems, the present inventors have prepared a series of icariside II (ICA-II) derivatives having high anti-liver cancer activity, and further provided pharmaceutical compositions comprising the derivatives or pharmaceutically acceptable salts thereof, and methods for preparing the derivatives or pharmaceutically acceptable salts thereof. In addition, the application of the derivative or the pharmaceutically acceptable salt or the pharmaceutical composition thereof in preparing medicines for treating primary liver cancer is also provided. Specifically, the invention is realized through the following technical schemes: In a first aspect, the invention provides an icariside II derivative or a pharmaceutically acceptable salt thereof with anti-liver cancer activity, wherein the icariside II derivative is an icariside II oxadiazole derivative or an icariside II thiadiazole derivative, the icariside II oxadiazole derivative has a chemical structure shown in a formula (I) or a formula (II), and the icariside II thiadiazole derivative has a chemical structure shown in a formula (III) or a formula (IV): r in the formula (I), (II), (III) or (IV) is selected from: Preferably, the icariside II oxadiazole derivative or the icariside II thiadiazole derivative having anti-liver cancer activity is selected from the following compounds: in a second aspect, the present invention also provides a method for preparing icariside II oxadiazole derivatives or icariside II thiadiazole derivatives having anti-liver cancer activity according to the first aspect, comprising the steps of: Taking a1-a22 and a31-a34 as starting materials, obtaining intermediates b1-b22 and b31-34 through a step (i), obtaining fragments c1-c22 and c31-34 through a step (II), and finally replacing icariside II through a step (iii), thus obtaining compounds YYYH 1-22 and YYH31-34; taking a23-a30 as a starting material, obtaining an intermediate b23-b30 through a step (i), obtaining an intermediate c23-c30 through a step (iv), obtaining a fragment d23-30 through a step (v), and finally replacing icariside II through a step (iii) to obtain a compound YYH23-30. Specifically, the preparat