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Anti-tumor medicine conjugate, preparation method, preparation and application

A technology of anti-tumor drugs and conjugates, which is applied in the direction of anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., to achieve the effect of low preparation cost, high stability, and simple steps

Inactive Publication Date: 2017-01-11
ZHEJIANG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] So far, there is no report on the combination of camptothecins and paclitaxel antineoplastic drugs and the preparation and application of nanomicelles

Method used

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  • Anti-tumor medicine conjugate, preparation method, preparation and application
  • Anti-tumor medicine conjugate, preparation method, preparation and application
  • Anti-tumor medicine conjugate, preparation method, preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] The synthetic route of SN38-PTX conjugate is as follows figure 1 As shown, the specific steps are as follows:

[0062] PTX (500mg, 0.59mmol) and succinic anhydride (176mg, 1.77mmol) were added to a 100mL round bottom flask, dissolved in 8mL of anhydrous pyridine, then DMAP (7.2mg, 0.06mmol) was added, stirred at 25°C for 3h, and the oil pump Remove pyridine, wash once with 0.1N HCl and saturated saline; dry the organic phase with anhydrous sodium sulfate, filter, collect the filtrate and remove the solvent under reduced pressure; separate and purify the solid by column chromatography (DCM:MeOH=80:1) The product 5 (550 mg, yield 98%) was obtained.

[0063] product 5 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0064] 1 H NMR (400MHz, CDCl 3 ): δ1.14(s,3H),1.23(s,3H),1.69(s,3H),1.89-1.92(d,4H,J=11.2),2.20-2.22(d,4H,J=9.6) ,2.44(s,3H),2.54-2.64(m,4H),2.67-2.70(t,2H),3.68(s,2H),3.80-3.82(d,2H,J=6.8),4.20-4.23( d,1H,J=8.8),4.30-4.32(d,1H,...

Embodiment 2

[0071] The synthetic route of SN38-DTX conjugate is as follows figure 2 As shown, the specific steps are as follows:

[0072] Add DTX (500mg, 0.62mmol) and succinic anhydride (186mg, 1.86mmol) into a 100mL round-bottomed flask, dissolve in 8mL of anhydrous pyridine, then add DMAP (7.2mg, 0.06mmol), stir at 25°C for 3h, oil pump Remove pyridine, wash once with 0.1N HCl and saturated saline; dry the organic phase with anhydrous sodium sulfate, filter, collect the filtrate and remove the solvent under reduced pressure; separate and purify the solid by column chromatography (DCM:MeOH=80:1) The product 6 (500 mg, yield 91%) was obtained.

[0073] product 5 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0074] 1 H NMR (400MHz, CDCl 3 ):δ1.08-1.13(t,3H),1.20(s,3H),1.32-1.34(d,9H,J=7.2),1.74-1.76(d,3H,J=6.4),1.83-1.86( d,2H,J=10.0),1.89-1.91(d,3H,J=7.2),2.27-2.28(t,2H),2.37-2.39(d,2H,J=8.4)2.53-2.64(m,5H ),2.77-2.83(m,2H),3.89-3.92(t,1H),4.17-4.20(t...

Embodiment 3

[0081] The synthetic route of SN38-CTX conjugate is as follows image 3 As shown, the specific steps are as follows:

[0082] Add CTX (500mg, 0.60mmol) and succinic anhydride (180mg, 1.80mmol) into a 100mL round-bottom flask, dissolve in 8mL of anhydrous pyridine, then add DMAP (7.2mg, 0.06mmol), stir at 25°C for 3h, oil pump Remove pyridine, add DCM to dissolve, and wash with 0.1N HCl and saturated brine successively; the organic phase is dried with anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure after collecting the filtrate; the solid is separated and purified by column chromatography (DCM :MeOH=80:1) to obtain product 7 (549 mg, yield 98%).

[0083] product 7 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0084] 1 H NMR (400MHz, CDCl 3 ): δ1.21-1.22(s,6H),1.36(s,9H),1.57(s,7H),1.72(s,3H),1.87-1.88(d,3H,J=1.2),2.25-2.27 (d,1H,J=9.2),2.66-2.73(m,5H),3.30(s,3H),3.45(s,4H),3.80-3.88(m,2H),4.16-4.18(d,1H, ...

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Abstract

The invention discloses an anti-tumor medicine conjugate, a preparation method, nano-micelle preparation thereof and application. The structural formula of the conjugate provided by the invention is represented by the formula (I), and the conjugate is formed by connecting 7-ethyl-10-hydroxy camptothecin with a paclitaxel anti-tumor medicine through a connection bond, wherein L is the connection bond, R1 is phenyl or tert-butoxy, R2 is acetyl, H or methyl, and R3 is H or methyl. The steps are simple, the preparation cost is low, the stability is high, and the safety is high; the requirement on clinical medication is met; the anti-tumor medicine conjugate is suitable for large-scale industrial production. The invention further discloses nano-micelle consisting of the anti-tumor medicine conjugate represented by the formula (I) and an amphiphilic polymer and application of the nano-micelle in tumor resistance; an in-vitro test shows that the nano-micelle is good in tumor resisting effect and has relatively high market prospect and value.

Description

technical field [0001] The invention belongs to the technical field of research and development of anti-tumor drugs, and in particular relates to an anti-tumor drug conjugate, a preparation method, a preparation and an application. Background technique [0002] Cancer is a common disease that seriously threatens the safety of human life. In the current tumor treatment, drug-based chemotherapy plays an irreplaceable role, but long-term monotherapy can easily make the human body resistant to specific drugs. The combined drug regimen can improve the anti-tumor efficacy of the drug, delay the generation of drug resistance in the body, and reduce adverse reactions and side effects (Ma L, Kohli M, Smith A. Nanoparticles for Combination Drug Therapy. ACSnano.2013, 7: 9518 -25.) At present, the treatment of tumors has changed from the initial single drug to combination drug. [0003] 7-Ethyl-10-hydroxycamptothecin (SN38) is the active ingredient of the clinical antitumor drug irin...

Claims

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Application Information

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IPC IPC(8): C07D491/22A61K31/4745A61K9/107A61P35/00
CPCA61K9/1075A61K31/4745A61K47/34C07D491/22
Inventor 王杭祥
Owner ZHEJIANG UNIV
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