Indole alkaloid adduct, and preparation method and application thereof in preparing anti-tumor drug

A technology of indole alkaloids and indole alkaloid hydrazides, which is applied in the application field of indole alkaloid adducts and their preparation, and preparation of antitumor drugs, can solve problems such as limited applications, and achieve reduced toxicity and in vivo Toxicity, mild reaction conditions, and high product purity

Active Publication Date: 2013-09-04
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Like many antitumor drugs, vinblastine drugs also have many serious side effects during treatment, such as myelosuppression, myalgia, malignant vomiting and other adverse reactions (Magnus, P., Ladlow, M., Elliot, J.Models for a hypothetical mechanism of action of the anticancer agent vinblastine. J Am Chem Soc, 1987, 109(25), 7929-7930), which limits its clinical application

Method used

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  • Indole alkaloid adduct, and preparation method and application thereof in preparing anti-tumor drug
  • Indole alkaloid adduct, and preparation method and application thereof in preparing anti-tumor drug
  • Indole alkaloid adduct, and preparation method and application thereof in preparing anti-tumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Preparation and separation and purification of indole alkaloid adducts

[0041]1.1.1 Preparation of the hydrazine hydrolysis product of vinblastine: Weigh 182 mg (0.2 mmol) of vinblastine sulfate into a 35 ml thick-walled pressure-resistant tube, add 8 ml methanol and 0.9 ml 80% hydrazine hydrate (23 mmol), ultrasonicate for 5 minutes, and degas Remove the air contained in the solution, then plug the stopper tightly, cover it with tin foil to avoid light, put it in a 60°C oil bath and stir for 24 hours. After the reaction is completed, add water to dilute, extract with dichloromethane (DCM) several times, and combine organic phase, washed successively with water, saturated NaCl solution, anhydrous NaCl 2 SO 4 After drying, the solvent was evaporated under reduced pressure. The resulting mixture was separated and purified by RP-HPLC (reversed phase preparative high performance liquid chromatography) (mobile phase was MeOH:H 2 O:Et 3 N=70:30:0.005, V / V / V), t...

Embodiment 2

[0061] Example 2 In vitro cytotoxicity test of indole alkaloids and their derivatives

[0062] Experimental method: Cells in the logarithmic growth phase (A549 (human non-small cell lung cancer cells), Lovo (human colon cancer cells), CNE-2 (human nasopharyngeal carcinoma cells), HepG2 (human liver cancer cells), Hela (human cervical cancer cells), MCF-7 (human breast cancer cells), MDA-MB-231 (human breast cancer cells), NCI-N87 (human gastric cancer cells), PC-3 (human prostate cancer cells), DU145 (human Prostate cancer cells), K562 (human leukemia cells), A375 (human melanoma cells), SH-SY5H (human neuroblastoma cells), human promyelocytic leukemia cells (HL-60), BEL-7402 / 5- Fu (fluorouracil-resistant strain of human liver cancer), HepG2 / ADM (doxorubicin-resistant strain of human liver cancer), MCF-7 / ADR (doxorubicin-resistant Bovine serum 10%, penicillin 100U / mL), adjust cell concentration to 5×10 5 cells / mL, inoculated in a 96-well culture plate, and inoculated 100 μL ...

Embodiment 3

[0072] Example 3 In vitro toxicity test of indole alkaloids and their derivatives to normal cells

[0073] Experimental method: detect the effect of indole alkaloids, hydrazinolysis products and indole alkaloid adducts on human normal liver cancer cell LO by the method of embodiment 2 2 and in vitro cytotoxicity of human umbilical vein endothelial cells HUVEC.

[0074] Experimental results: hydrazinolysis products and adducts on LO 2 and HUVEC were much less cytotoxic than the corresponding indole alkaloids (see Table 3). It shows that the cytotoxicity of the compound after targeted modification is significantly reduced.

[0075] Table 3. MTT method to determine the toxic effect of indole alkaloids and their derivatives on normal cells

[0076]

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Abstract

The invention relates to the field of anti-tumor drugs, and specifically discloses an indole alkaloid adduct, and a preparation method and an application thereof in preparing an anti-tumor drug. The indole alkaloid adduct has a structure shown as a formula I, wherein R is formed in the way that an indole alkaloid is subjected to hydrazinolysis and the hydrazinolysis product is bonded with hydrazine group. The indole alkaloid adduct can significantly reduce toxicity to normal cells and in-vivo toxicity and inhibit in-vitro proliferation of various tumor cell lines and the growth of tumor in the nude mouse bearing the tumor.

Description

technical field [0001] The present invention relates to the field of antitumor drugs, more specifically, relates to an indole alkaloid adduct, a preparation method thereof and an application in the preparation of antitumor drugs. Background technique [0002] Cancer is a large class of diseases characterized by abnormal cell proliferation and metastasis. Among urban residents, cancer has become the number one cause of death. Although scientists from all over the world have carried out in-depth research on how to overcome the world problem of cancer from various disciplines for many years, they have proposed a variety of treatment methods. These treatments have a certain therapeutic effect, but usually cause severe systemic toxicity, cancer metastasis and recurrence, and there is still a considerable distance from the cure of cancer. Therefore, research on antitumor drugs with better therapeutic effects is still a hot and difficult point in drug development today. [0003]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00C07D471/20C07D471/22A61K31/475A61K31/55A61P35/00A61P35/02
Inventor 陈河如叶文才张冬梅陈敏锋肖绪枝许男徽雷雪萍胡坚杨
Owner JINAN UNIVERSITY
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