Biotin-podophyllotoxin esterified derivative and pharmaceutical composition thereof, as well as preparation methods and applications of derivative and pharmaceutical composition

A technology of podophyllotoxin and biotin, which is applied in drug combination, pharmaceutical formulation, organic chemistry, etc., can solve the problems of no anti-tumor activity of such compounds, no biotin-podophyllotoxin ester derivatives, etc.

Active Publication Date: 2014-10-15
KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] So far, there are no reports of biotin-podophyllotoxin esterified derivatives in the prior art, let alone reports of such compounds having antitumor activity

Method used

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  • Biotin-podophyllotoxin esterified derivative and pharmaceutical composition thereof, as well as preparation methods and applications of derivative and pharmaceutical composition
  • Biotin-podophyllotoxin esterified derivative and pharmaceutical composition thereof, as well as preparation methods and applications of derivative and pharmaceutical composition
  • Biotin-podophyllotoxin esterified derivative and pharmaceutical composition thereof, as well as preparation methods and applications of derivative and pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Synthetic general formula of the present invention such as figure 2 shown.

Embodiment 2

[0039] The preparation of compound 4β-amino-(biotin)-4-deoxy-4'-demethylpodophyllotoxin: (by figure 2 The fourth step, the fifth step, the sixth step, and the tenth step in the middle)

[0040] the fourth step: Preparation of 4'-O-desmethylpodophyllotoxin (V):

[0041] 2.1 g of podophyllotoxin (5.0 mmol) was dissolved in dry dichloromethane solution, sodium iodide (2.3 g, 15.0 mmol) was added to the above solution, and stirred for 5 minutes. The reaction liquid was cooled to 0° C. in an ice-water bath, and 1.4 g of methanesulfonic acid (15.0 mmol) was slowly added dropwise to the above reaction liquid to continue stirring, and then the reaction was continued at room temperature for 5 hours. Nitrogen protection was used to remove the HI gas generated during the reaction. Then, the solvent in the above reaction was removed under reduced pressure, and the next step was carried out without any treatment. Dissolve the above crude product in acetone-water (25mL-25mL) mixed sol...

Embodiment 16

[0131] In vitro inhibitory effects of biotin-podophyllotoxin ester derivatives on different tumor cells:

[0132] 1. Experimental materials

[0133]Cell lines: human leukemia cell line HL-60, human liver cancer cell line SMMC-7721, human lung cancer cell line A-549, human breast cancer cell line MCF-7, and human colon cancer cell line SW480.

[0134] Detection principle: MTT method to detect cell viability

[0135] 2. Test method

[0136] 1). Inoculate cells: use culture medium (DMEM or RMPI1640) containing 10% fetal bovine serum to prepare a single cell suspension, inoculate 5000–10000 cells per well into a 96-well plate with a volume of 100 μl per well, adherent cells Inoculate the culture 12 hours in advance.

[0137] 2). Add the compound solution to be tested (preliminary screening at a fixed concentration of 40 μM, at which concentration the compound that inhibits tumor cell growth near 50% is set to enter the gradient rescreening at 5 concentrations), the final volume...

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Abstract

The invention provides a biotin-podophyllotoxin esterified derivative represented as the general formula (I), pharmaceutical composition taking compounds as active ingredients, as well as applications of the biotin-podophyllotoxin esterified derivative in preparing antitumor drugs and inhibitors. Activity screening proves that the biotin-podophyllotoxin esterified derivative represented as the general formula (I) has better antitumor activity. Meanwhile, a preparation method of the compounds is provided and comprises the following steps: podophyllotoxin is taken as a lead compound, structures of hydroxyl at the 4 site and methoxyl at the 4' site are modified, and a series of compounds are synthesized through connection of different chains between biotin and podophyllotoxin. According to the invention, biotin which is necessary for cell growth is used for structure modification on podophyllotoxin, cancer cell targeting selectivity of a modifier is improved, selective distribution toward cancer cells is realized, and better treatment effect can be achieved. Meanwhile, biotin is soluble in water, and the water solubility problem of drugs can be solved by introducing biotin into podophyllotoxin molecules.

Description

technical field [0001] The invention belongs to the field of pharmaceutical compounds, specifically, mainly relates to biotin-podophyllotoxin esterified derivatives, pharmaceutical compositions using them as active ingredients, their preparation methods and their use in the preparation of antitumor drugs and inhibitors application. Background technique [0002] Podophyllotoxin belongs to cyclolignan lactone compounds in lignan compounds, which has significant anti-tumor activity. It has a similar anti-tumor mechanism to colchicine, both by preventing the formation of microtubule bundles in the metaphase of cell mitosis To inhibit tumor growth (Russell-Jones, G et al., J. Inorg. Biochem. 2004, 98, 1625-1633.). Due to the toxicity and adverse reactions of podophyllotoxin, the research on the structural modification of podophyllotoxin as the lead compound was prompted. Etoposide (VP-16) and teniposide (VM-26) have become clinically used anticancer drugs, and they have good ef...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00A61K31/4188A61K31/4192A61P35/00
CPCC07D519/00
Inventor 蒋子华字成庭胡江苗周俊丁中涛刘玉清杨柳
Owner KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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