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Combined antitumor drug, preparation method and applications thereof

A technology of anti-tumor drugs and combined drugs, which is applied in the field of anti-tumor drugs and preparations, can solve problems such as rapid release, and achieve the effects of inhibiting proliferation, inhibiting tumor growth, and inhibiting the formation of vascular lumens

Inactive Publication Date: 2016-12-21
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, our previous experiments showed that due to its unique chemical structure, it is difficult for SN38 to directly co-assemble with amphiphilic polymer materials to form nanoparticles.
However, CA4 has a problem of rapid release in polymer nanoparticles

Method used

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  • Combined antitumor drug, preparation method and applications thereof
  • Combined antitumor drug, preparation method and applications thereof
  • Combined antitumor drug, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043]Dissolve butyric acid (51.7μL, 0.57mmol), CA4 (180mg, 0.57mmol), EDC·HCl (163mg, 0.855mmol), DMAP (76.6mg, 0.627mmol), DIEA (188.9μL, 1.14mmol) in 4ml of DCM , stirred overnight at room temperature, added ethyl acetate, followed by 5% citric acid, saturated NaHCO 3 , saturated brine to wash the organic phase, the organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure after collecting the filtrate; the solid was separated and purified by column chromatography (ethyl acetate:n-hexane=1:3), to obtain the target The product butyric acid-CA4 conjugate compound 2 (280 mg, yield 93%).

[0044] Product Butyrate-CA4 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0045] 1 H NMR (400MHz, CDCl 3 ):δ1.00-1.04(t,3H),1.73-1.78(m,2H),2.49-2.53(t,2H),3.71(s,6H),3.80(s,3H),3.83(s,3H ),6.45-6.45(d,2H,J=1.2),6.51(s,2H),6.83-6.85(d,1H,J=8.4),7.00-7.01(d,1H,J=1.6),7.10- 7.12(q,1H).

[0046] HR-ESI ...

Embodiment 2

[0048] Heptanoic acid (80.8 μL, 0.57 mmol), CA4 (180 mg, 0.57 mmol), EDC·HCl (163 mg, 0.855 mmol), DMAP (76.6 mg, 0.627 mmol), DIEA (188.9 μL, 1.14 mmol) were dissolved in 4 mL of DCM , stirred overnight at room temperature, added ethyl acetate, followed by 5% citric acid, saturated NaHCO 3 , saturated brine to wash the organic phase, the organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure after collecting the filtrate; the solid was separated and purified by column chromatography (ethyl acetate:n-hexane=1:3), to obtain the target The product heptanoic acid-CA4 conjugate compound 3 (260 mg, yield 85%).

[0049] Product Enanthate-CA4 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0050] 1 H NMR (400MHz, CDCl 3 ):δ0.88-0.91(t,3H),1.26-1.41(m,6H),1.70-1.74(t,2H),2.51-2.54(t,2H),3.71(s,6H),3.80(s ,3H),3.84(s,3H),6.45-6.45(d,2H,J=1.6),6.51(s,2H),6.83-6.85(d,1H,J=8.4),7.00-7.00(d, 1H, J...

Embodiment 3

[0053] The synthesis method of LNA-SN38 conjugate compound 4 refers to the synthesis of SN38 prodrug 7 in the patent document "7-ethyl-10-hydroxycamptothecin prodrug and its preparation method and application", and the patent application number is 201410295432. X.

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Abstract

The invention discloses a combined antitumor drug. The combined antitumor drug comprises an antiangiogenic drug, a drug used for inhibiting tumor cell proliferation, and an amphiphilic high molecular material; the antiangiogenic drug is a prodrug of Combretastatin A4, and the drug used for inhibiting tumor cell proliferation is a camptothecin antitumor drug. The invention also discloses a combined antitumor drug nanoparticle preparation, a preparation method, and applications. It is shown by cytotoxicity test that the combined antitumor drug nanoparticle preparation is capable of inhibiting proliferation of tumour cell HT-29 and human umbilical vein vascular endothelial cells (HUVEC) obviously, and dose-dependent relationship is detected; it is confirmed by scratch injury experiments and lumen formation experiments that the combined antitumor drug nanoparticle preparation is capable of inhibiting migration of HUVEC and vascularization; compared with single medication systems, the combined antitumor drug nanoparticle preparation possesses excellent tumor killing effect in vivo, clinical application value is high, and application prospect is promising.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to an anti-angiogenesis drug and an anti-tumor cell proliferation drug combined with an anti-tumor drug, a preparation method and an application. Background technique [0002] 7-Ethyl-10-hydroxycamptothecin (SN38) is the active product of clinical antineoplastic drug irinotecan (CPT-11). SN38 takes topoisomerase as the target site, inhibits the combination of topoisomerase I-DNA complex, thereby preventing the reconnection of broken single strands, unwinding the DNA double-strand structure and exerting anti-tumor effects. SN38 exhibits higher activity in vitro, which is 100-1000 times that of CPT-11. Therefore, direct use of SN38 molecules, avoiding the way of enzymatic hydrolysis of CPT-11 to release SN38, is expected to effectively improve the anti-tumor effect of the drug. However, SN38 has poor water solubility and is insoluble in pharmaceutically acceptable solvents ...

Claims

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Application Information

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IPC IPC(8): A61K31/4745A61P35/00A61K47/34A61K31/222
CPCA61K31/222A61K31/4745A61K47/34A61K2300/00
Inventor 王杭祥吴佳萍陈建美谢海洋周琳郑树森
Owner ZHEJIANG UNIV
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