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Beta-carboline alkaloid and application thereof in preparation of antitumor drugs

An alkaloid and carboline technology, applied in the field of cyclin-dependent kinase 4 inhibitors, can solve the problems of high toxicity and side effects, limited clinical application, high cytotoxicity, etc., and achieve the effect of low toxicity

Inactive Publication Date: 2016-07-13
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, fascaplysin is a compound with a planar structure that can be embedded in DNA molecules, and its effect is similar to that of DNA intercalating agents basalpine and ellipticine. limit its clinical application

Method used

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  • Beta-carboline alkaloid and application thereof in preparation of antitumor drugs
  • Beta-carboline alkaloid and application thereof in preparation of antitumor drugs
  • Beta-carboline alkaloid and application thereof in preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1 Preparation of carboline alkaloids represented by formula (I)

[0037] 1. Instrument

[0038] (1) Melting point is measured with WRS-2 microcomputer melting point measuring instrument (Shanghai Shengyan Ultrasonic Instrument Co., Ltd.);

[0039] (2) IR × spectrum was measured with a NicoletImpact410 infrared spectrometer, and pressed into KBr tablets;

[0040](3) 1HNMR is measured with a JEOLFX90Q Fourier transform nuclear magnetic resonance instrument;

[0041] (4) MS was determined by Nicolet2000 Fourier transform mass spectrometer and MAT-212 mass spectrometer.

[0042] 2. Preparation method

[0043]

[0044] The preparation process of the carboline alkaloid of formula (I) is as follows:

[0045]

[0046] (1) 1-Formic acid-1,2,3,4-tetrahydro-β-carboline (Ⅰ-1)

[0047] Weigh 5.00g of tryptamine and place it in a 250mL three-necked bottle, add 60.00mL of water, add an appropriate amount of concentrated hydrochloric acid under stirring until the ...

Embodiment 2

[0076] Example 2 Toxicity assessment of carboline alkaloids represented by formula (I)

[0077]

[0078] Choose the 2-phenyl-1-formic acid methyl ester group-9H-β-carboline bromide (I-4) (R 1 = Methoxycarbonyl, R 2 = phenyl) and fascaplysin (formula (II)) were simulated by chem3D software for dihedral angle data, and then their planarity was compared.

[0079] Table 1 Comparison of the dihedral angle data of Fascaplysin and 2-phenyl-1-formyl-9H-β-carboline bromide salt

[0080]

[0081]

[0082] According to the data simulated by computer drug design software, the most planar 2-phenyl-1-formic acid methyl ester group-9H-β-carboline bromide (I-4) (R 1 = methyl formate, R 2 =Phenyl) structure is less planar than fascaplysin, but the planar structure of fascaplysin allows it to be embedded in DNA and has higher cytotoxicity.

[0083] Therefore, the designed compound of the present invention is more effective than 2-phenyl-1-formic acid methyl group-9H-β-carboline bro...

Embodiment 3

[0085] Example 3 Verification experiment of CDK4 inhibitory activity of carboline alkaloids represented by formula (I)

[0086] 1. Materials

[0087] Instrument TECAN Safire2 measuring instrument, black wall and black bottom 384-well plate (CORNING, USA), plate shaker (Jiangsu Guangming Experimental Instrument Factory), reagent CDK4 / clyclinD, pRb protein substrate, DMSO (Sigma)

[0088] 2. Experimental method

[0089] (1) Take 133ul of 5× buffer and add it to 367ul of water to obtain 500ul of 1.33× kinase buffer;

[0090] (2) Add 0.2ul of CDK4 / clyclinD and 0.8ul of substrate to 199ul of 1.33×kinase buffer to obtain 200ul of kinase / substrate mixture;

[0091] (3) Take 6ul10mMATP and add it to 144ul1.33 kinase buffer to obtain 150ul4×ATP solution;

[0092] (4) Add 0.2ul of phosphorylated peptide to 49.8ul of 1.33×kinase buffer to obtain 50ul of phosphorylated peptide solution;

[0093] (5) Take the synthetic compound Ⅰ-1——Ⅰ-7 and configure it into 2ul10 -2 The aqueous solut...

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Abstract

The invention relates to the field of pharmaceutical chemistry, and discloses a beta-carboline alkaloid represented by formula (I), and an application thereof in the preparation of antitumor drugs. The beta-carboline alkaloid has an inhibition effect on cyclin-dependent kinase 4, can be used to prepare the antitumor drugs, and provides more medicine choices for tumor treatment.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a β-carboline alkaloid and its application in the preparation of antitumor drugs, especially the application as a cyclin-dependent kinase 4 inhibitor. Background technique [0002] Cyclin-dependent kinases (CDKs) are a class of serine (Ser) / threonine (Thr) kinases with a molecular weight of about 35-40kD, which were first discovered in Schizosaccharomyces saccharomyces and Saccharomyces pombe. More than 40% homogenic and named Cdc28 and Cdc2. In mammals, 10 members have been found, Cdc2 (CDK1), CDK2-10. CDKs play a central role in the cell cycle regulatory network. It is generally believed that CDK2, CDK4, and CDK6 in CDKs are closely related to tumorigenesis, and are often overexpressed in tumor cells, such as breast cancer, esophageal cancer, and primary liver cancer. The regulation of cell cycle G1 / S phase restriction point is very important. In the regulatory network of G1...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P35/00
Inventor 贺殿孙晓飞杨竹青侯猛
Owner LANZHOU UNIVERSITY
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