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Prodrug of compound podophyllotoxin PPT with anti-tumour activity and preparation method thereof

A technology of anti-tumor activity and podophyllotoxin, applied in pharmaceutical formulations, luminescent/biological dyeing preparations, preparations for in vivo tests, etc., to achieve improved biocompatibility and less toxic and side effects

Inactive Publication Date: 2015-09-30
DONGHUA UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Has strong cytotoxicity, so far there is no medicine

Method used

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  • Prodrug of compound podophyllotoxin PPT with anti-tumour activity and preparation method thereof
  • Prodrug of compound podophyllotoxin PPT with anti-tumour activity and preparation method thereof
  • Prodrug of compound podophyllotoxin PPT with anti-tumour activity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] DCM-NH 2 Activation and synthesis of DCM-S:

[0040] Accurately weigh DCM-NH 2 (225mg, 0.72mmol) and triphosgene (860mg, 2.9mmol) were added to a 100mL three-necked flask containing 35mL of dry toluene, and DIEA (1.5g, 11.7mmol) was slowly added dropwise at room temperature under the protection of argon. , the above solution was heated to 111 ° C under the protection of argon for 3h reflux reaction, the activation reaction is as follows image 3 (a) shown. After the reaction, argon was blown in the solution to remove the remaining phosgene, and under argon atmosphere, 2-hydroxyethyl disulfide (1.2g, 90%, 7.2mmol) was added as a solvent with THF / DCM solution, and in DMAP Under catalysis, stirring overnight at room temperature, the addition reaction is as follows image 3 (b) shown. The solvent was removed by rotary evaporation under reduced pressure, and EA / PE (v / v, 1:1) was used as the eluent for column chromatography separation and purification to obtain 96 mg of ...

Embodiment 2

[0042] Synthesis of DCM-S-PPT:

[0043] Weigh DMAP (122mg, 1.0mmol) and vacuum dry it in a 50mL round bottom flask for 15min, then weigh podophyllotoxin (50mg, 0.1mmol) and triphosgene (20mg, 0.07mmol) into the round bottom flask, stopper Put in a round bottom flask, then add 10 mL of dry chloroform with a syringe under the condition of an ice bath and avoid light, and stir magnetically until the solution is clear. Then take the benzopyranonitrile derivative DCM-S (50mg, 0.1mmol) and dissolve it in 5mL of dry chloroform, drop it into the round bottom flask under ice bath and stir to room temperature until the solution turns light yellow, the reaction is as follows Figure 4 shown. The solvent was spin-dried and separated by column chromatography (developer DCM:EA:PE=1:0.8:1.2) to obtain 10 mg of a khaki solid with a yield of 11%. The NMR characterization results are as follows Figure 4 (b) and 4(c), indicating that DCM-S-PPT has been successfully synthesized. 1 H NMR (400...

Embodiment 3

[0045] In vitro GSH response experiment of DCM-S-PPT:

[0046] Prepare a mixed solvent of DMSO / PBS=1:1, take 2mL and add it to a cuvette, then add 2μL of DCM-S-PPT (20mM) mother solution to make the final concentration 10μM, mix well, put into the pre-adjusted in a good 37°C water bath, then add the freshly prepared reduced GSH (0.1M), and react at 37°C for 1 hour, as Figure 5 As shown in (a), the color change of the solution can be observed, and the UV-visible absorption spectrum also has a red shift, which proves that the structure of DCM-S-PPT changes and the disulfide bond may be cut.

[0047] Use high-resolution mass spectrometry (HRMS) to analyze the reaction solution of DCM-S-PPT (10 μM) and GSH (200 μM) at 37 ° C for 1 h, as Figure 5 As shown in (b), the charge-to-mass ratio of 310.1 (DCM-NH 2 ) and 413.2 (PPT) molecular ion peaks, once again proved that the sulfhydryl group on the GSH cut off the disulfide bond in DCM-S-PPT, and then by removing a sulfur-containin...

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Abstract

The invention relates to a prodrug of a compound podophyllotoxin PPT with an anti-tumour activity and a preparation method thereof. The preparation method comprises the following steps: converting the hydroxyl group of C4 of the C-ring of the PPT to chloro-carbonic ester, and reacting the group with the addition product DCM-S of 2-hydroxyethyl disulphide and a benzopyranyl nitrile amino derivative DCM-NH2 to generate a GSH-sensitive PPT-S-DCM prodrug compound. The compound obtained by the preparation method disclosed by the invention has the characteristic of selectively releasing the PPT in vitro and in vivo through tumour cell targeting (GSH sensitivity), and a clinical application prospect; meanwhile, the release behaviour of the PPT prodrug compound can be detected and researched by virtue of the near-infrared fluorophore of benzopyranyl nitrile.

Description

technical field [0001] The invention belongs to the field of prodrugs and preparation thereof, in particular to a prodrug of anti-tumor active compound podophyllotoxin PPT and a preparation method thereof. Background technique [0002] Malignant tumor is a common chronic non-communicable disease that seriously endangers human health, and has become the leading cause of death among Chinese residents. Chemotherapy (chemotherapy) is one of the three major methods for treating malignant tumors. It is a treatment method that directly uses chemical drugs to inhibit the proliferation, invasion, and metastasis of cancer cells until finally killing cancer cells. Compared with surgery alone, the disease-free survival rate of patients treated with chemotherapy combined with surgery has increased from 10-20% to 60-80%. However, insoluble and toxic side effects are currently affecting the bioavailability and An important bottleneck for clinical efficacy. And because of these two shortc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04A61K49/00G01N21/64
CPCC07D493/04A61K49/0021A61K49/0052A61K49/006G01N21/6428G01N2021/6432
Inventor 黄志伟史萍朱绍佳房志家
Owner DONGHUA UNIV
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