Application of zoledronic acid compound in preparation of drugs for treating cancers

A technology of zoledronic acid and compounds, applied in the field of medicinal chemistry, can solve the problems of no cancer cell inhibitory effect, difficult to predict the drug effect of cancer cells, no proposed anti-cancer effect, etc., and achieve the effect of strong cytotoxic effect

Active Publication Date: 2017-09-29
JIANGSU INST OF NUCLEAR MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to very little research in this area, the inhibitory effect and potential mechanism of bisphosphonates such as zoledronic acid on the growth of colorectal cancer cells have not been thoroughly studied, and because the molecular weight of zoledronic acid (Mr=272 ) is relatively small and is greatly affected by the structure, and small differences in structure may have a greater impact on its efficacy. Therefore, the efficacy of bisphosphonates such as zoledronic acid on cancer cells is also difficult to predict. It is a great challenge and practical significance to optimize the structure of bisphosphonates such as zoledronic acid and further discover drugs with high efficiency and low toxicity, and it is of great value to systematically screen pharmacodynamics
However, there is no relevant report on the treatment of cancer with zoledronate compound 1-hydroxyl-2-(4-methyl-1H-imidazolyl)-ethane-1,1-bisphosphonic acid in the prior art, such as "Synthesis of 4-methylimidazole bisphosphoric acid and its 99 Tc m Zoledronate compound 1-hydroxyl-2-(4-methyl-1H-imidazolyl)-ethane-1,1-bisphosphonic acid (M 4 IDP) is only used for 99 Tc m mark, not raised M 4 Whether IDP has an anti-cancer effect, and there is no in-depth study on its inhibitory effect on cancer cells and its underlying mechanism, so about bisphosphonates such as the above-mentioned M 4 The application of IDP in the field of cancer such as colon cancer treatment still needs further development and research

Method used

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  • Application of zoledronic acid compound in preparation of drugs for treating cancers
  • Application of zoledronic acid compound in preparation of drugs for treating cancers
  • Application of zoledronic acid compound in preparation of drugs for treating cancers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The present embodiment provides a kind of method for preparing the compound shown in formula (I), comprises the following steps:

[0045]

[0046] The synthetic route of compound (I) is:

[0047]

[0048] Synthesis of the compound 2-(4-methyl-1H-imidazolyl) ethyl acetate shown in Q1, formula (A-2)

[0049] In a 150mL three-necked flask, add 8.2g (0.1mol) of the compound 4-methylimidazole shown in formula (A-1), 8.4g (0.15mol) of KOH, KOH 2 CO 3 13.8g (0.1mol), tetrabutylammonium bromide 0.7g (2mmol) and CH 2 Cl 2 75mL, after stirring at room temperature for 0.5h, 11.2mL (0.1mol) of ethyl bromoacetate was slowly added dropwise to it, refluxed for 8h and filtered, and the filter cake was washed with CH 2 Cl 2 40mL was washed twice, the filtrate was washed with 150mL saturated NaCl solution, the layers were separated, and the organic phase was washed with anhydrous NaCl 2 SO 4 After drying, the solvent was distilled off to obtain 10.6 g of a brown viscous liq...

Embodiment 2

[0055] This example provides an anticancer drug, which uses the compound represented by the formula (I) prepared in Example 1 as an active ingredient.

[0056] Further, the anticancer drug is a clinically acceptable preparation made by selectively adding conventional excipients according to a conventional process, using the compound represented by the formula (I) as an active ingredient, and the preparation includes a tablet , capsules, granules, syrups, powders, pills, tinctures, liquors, decoctions, freeze-dried powders, lozenges or mixtures.

experiment example

[0058] Compound 1-hydroxyl-2-(4-methyl-1H-imidazolyl)-ethane-1 shown in formula (I) of the present invention, 1-bisphosphonic acid (M 4 IDP) inhibitory effect on cancer cells

[0059] The experimental materials involved in the following experimental examples are as follows:

[0060] Fetal bovine serum (FBS), antibiotics, and DMEM were purchased from Gibco in the United States;

[0061] Hoechst33258, monodansylcadaverine (MDC), MTT, and DMSO were purchased from Sigma, USA;

[0062] Annexin V / PI staining kit was purchased from Roche;

[0063]CCK-8 kit, crystal violet, cell cycle analysis kit, reactive oxygen species (ROS) analysis kit, RIPA lysate, adenovirus expressing mCherry-GFP-LC3B (Ad-mCherry-GFP-LC3B), and p27, Cyclin D1, PARP, active-caspase3, CHOP, Bip, LC3B, PTEN, phospho-GSK-3β(Ser9), GSK-3β, Bad and other antibodies were purchased from Biyuntian Company;

[0064] Antibodies such as phospho-Rb (Ser780), ERO1L, p62, ATG5, and phospho-PDK1 (Ser241) were purchased fr...

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Abstract

The invention provides an application of a zoledronic acid compound in preparation of drugs for treating cancers. The zoledronic acid compound can be used for treating cancers, can be widely applied to treatment of breast cancer, neuroblastoma, osteosarcoma, prostatic cancer, liver cancer, gastric cancer and colon cancer, and especially has a significant effect in treatment of the colon cancer; and through detection, IC50 of existing zoledronic acid (ZOL) acting on an HCT116 cell for 72h is 25.8muM, the IC50 of a zoledronic acid compound (M4IDP) acting on the HCT116 cell for 72h is 0.98muM, and the IC50 of the ZOL is 26.3 times that of the M4IDP, so that the cytotoxic effect of the M4IDP on the HCT116 cell is higher than that of the ZOL and has a relatively low IC50 value, and the M4IDP has great potential to be developed for treatment of the colon cancer.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to the use of a zoledronate compound in the preparation of drugs for treating cancer. Background technique [0002] Bisphosphonates (bisphosphonates, BPs) are organic analogues of inorganic pyrophosphate (PPi), and are organic compounds characterized by P-C-P formed by connecting two P-C bonds on the same carbon atom. Various BPs have been developed by changing the substituents attached to the carbon atoms. Among them, zoledronic acid (ZOL) is the third-generation bisphosphonate, and the carbon atom is connected with a hydroxyl group and an imidazole ring containing 2 nitrogen atoms ( Figure 22 ). [0003] Bisphosphonates such as zoledronic acid can specifically bind to hydroxyapatite in bone and have a strong anti-bone resorption effect. By directly changing the morphology of osteoclasts, inhibiting actin formation and interfering with osteoclasts The adsorption an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/675A61P35/00
CPCA61K31/675
Inventor 彭莹林建国邱玲李珂吕高超徐栋刘清竹
Owner JIANGSU INST OF NUCLEAR MEDICINE
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