Honokiol-chlorambucil co-prodrug with lymphocytic leukemia resisting effect, preparation method and application thereof

A technology of chlorambucil and prodrugs, which is applied in the preparation of organic compounds, medical preparations of non-active ingredients, and preparation of cyanide reactions. It can solve the problems of rare clinical research and achieve enhanced mitochondrial activity. , the effect of delaying the growth in the body

Active Publication Date: 2020-09-22
GUANGDONG FOOD & DRUG VOCATIONAL COLLEGE
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few clinical studies on HN at present.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Honokiol-chlorambucil co-prodrug with lymphocytic leukemia resisting effect, preparation method and application thereof
  • Honokiol-chlorambucil co-prodrug with lymphocytic leukemia resisting effect, preparation method and application thereof
  • Honokiol-chlorambucil co-prodrug with lymphocytic leukemia resisting effect, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] About 180 mg of CBL (0.59 mmol) dissolved in 5 ml of DMF was added to EDCI (~135 mg, 0.70 mmol), then the solution was stirred at room temperature for 10 min; then HN (75 mg, 0.28 mmol) was added, and the reaction mixture was stirred at room temperature Stir overnight; add 50ml of ethyl acetate to the reaction solution, wash once with 50ml of water, dry with sodium sulfate, filter and concentrate; purify the yellow solid by chromatography, which is the co-precursor of honokiol-chlorambucil Drug (HN-CBL), yield 10%. 1H-NMR (400MHz, CDL3): δ1.85-1.86(m, 1H), 2.09-2.12(m, 2H), 2.18-2.19(m, 1H), 2.40-2.42(m, 2H), 2.49-250 (m, 1H), 2.64-2.66(m, 2H), 2.71-2.73(m, 2H), 2.73-2.85(m, 1H), 3.37-3.45(m, 4H), 3.68-3.70(m, 8H) , 3.73-3.76(m, 8H), 5.09-5.71(m, 2H), 6.65-6.71(m, 4h), 6.96-7.00(m, 1H), 7.02-7.08(m, 2H), 7.12-7.22( m, 7H), 7.30-7.31 (m, 2H), 7.37-7.39 (m, 2H). MS (ESI): 839.7 (C 46 h 52 Cl 4 N 2 o 4 )[M+H] + , and the calculated M / z was 838.6. Structural chara...

Embodiment 2

[0041] Example 2: In vitro targeted release pharmacokinetics of HN-CBL in tumor cells

[0042] According to the characteristics of prodrug HN-CBL and carbonate ester cleavage under the catalysis of intracellular esterase, and then release CBL and HN in biological media such as PBS and plasma, especially in the environment with high esterase content and low pH value Released in tumor tissue or cancer cells. To test the above intuitive hypothesis about the prodrug HN-CBL, the release of HN or CBL in different media was evaluated by HPLC-MS. The hydrolytic release of the prodrug HN-CBL was determined at 37°C (pH = 7.4 or 5.5, 10% fresh plasma and 10% cancer cell lysis) in different biological media such as PBS. The degradation of HN-CBL and the generation of HN or CBL were measured by high-performance liquid chromatography-mass spectrometry (HPLC-MS). from figure 1 It can be seen from the results that the hydrolysis rate of HN-CBL in normal isotonic buffer PBS of pH=7.4 is <10...

Embodiment 3

[0043] Example 3: HN-CBL selectively inhibits leukemia cell proliferation

[0044] In this example, the anticancer effect of the prodrug HN-CBL on seven tumor cell lines was studied by MTT colorimetry. Our data show that HN-CBL can effectively reduce the survival rate of seven tested cancer cell lines, namely lymphocytic carcinoma CCRF-CEM (IC50=1.09μM), Jurkat (IC50=1.15μM), U937 (IC50=1.29μM ), MV4-11 (IC50=2.78μM), K562 (IC50=4.86μM), lung cancer A549 (IC50=25.10μM), human liver cancer HepG2 (IC50=24.50μM), there was no significant effect on two normal cells LO2 and NIH3T3 Cytotoxicity. These results indicated that HN-CBL has a broad anti-tumor spectrum, especially selective for leukemia cells. Among the seven human cancer cell lines tested, the IC50 values ​​of HN-CBL were lower than those of CBL and HN, indicating that the synergistic antitumor activity of HN-CBL was stronger than that of HN and CBL (Table 1).

[0045] Table 1 IC50 of HN, CBL and HN-CBL on tumor cell l...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention belongs to the technical field of anti-cancer drugs, and discloses a honokiol-chlorambucil co-prodrug with a lymphocytic leukemia resisting effect, a preparation method and application thereof. The co-prodrug has a structure shown as formula (I) in the specification. The preparation method comprises the following steps of: dissolving chlorambucil in N, N-dimethylformamide, then adding N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride, and then stirring the solution for 10min at room temperature; then adding honokiol, and stirring the reaction mixture overnight at roomtemperature; and adding ethyl acetate into the reaction solution, then performing washing with water, conducting drying with sodium sulfate, and performing filtering, concentrating, and purifying by chromatography to obtain the honokiol-chlorambucil co-prodrug.

Description

technical field [0001] The invention belongs to the technical field of anticancer drugs, and in particular relates to a honokiol-chlorambucil co-prodrug with anti-lymphocytic leukemia effect and its preparation method and application. Background technique [0002] Chlorambucil (CBL) is a DNA alkylating agent belonging to the nitrogen mustard family, and is a chemotherapeutic drug used to treat chronic lymphocytic leukemia (CLL), lymphoma and other solid tumors. The N,N-bis(2-chloroethyl)-amine moiety can covalently react with proteins, nucleic acids and phospholipids to induce the inhibitory function of cell survival, while the alkylation reaction between CBL and DNA is the main form of cytotoxicity. The forms of CBL-modified DNA crosslinks include monofunctional base pair mismatches and bifunctional double-strand DNA breaks, resulting in sustained DNA damage. Due to the high reactivity of CBL with many biomacromolecules (nucleic acids, proteins, phospholipids), resulting i...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/42C07C227/18A61K47/55A61P35/02
CPCC07C229/42C07C227/18A61K47/55A61P35/02
Inventor 夏黎汪小根张雷红沈小钟张树潘李绍林
Owner GUANGDONG FOOD & DRUG VOCATIONAL COLLEGE
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap