Quadrivalent platinum anticancer complex containing ursolic acid ligand derived from cisplatin and its preparation method and application

A complex, tetravalent platinum technology, applied in the direction of steroids, anti-tumor drugs, drug combinations, etc., to achieve low toxicity, excellent anti-tumor effect, and the effect of overcoming cisplatin resistance

Active Publication Date: 2022-05-10
南京菲力康医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the research and development of new tetravalent platinum anticancer drugs is increasing, no tetravalent platinum anticancer complexes have been clinically approved so far. Therefore, it is necessary to further develop new tetravalent platinum anticancer drugs and explore their rules of action

Method used

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  • Quadrivalent platinum anticancer complex containing ursolic acid ligand derived from cisplatin and its preparation method and application
  • Quadrivalent platinum anticancer complex containing ursolic acid ligand derived from cisplatin and its preparation method and application
  • Quadrivalent platinum anticancer complex containing ursolic acid ligand derived from cisplatin and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1 Preparation of Tetravalent Platinum Anticancer Complex Based on Cisplatin Derivation

[0053] All reagents and solvents were purchased from commercial suppliers. With tetramethylsilane as internal standard, record 1H NMR (300 or 500MHz) and 13 C NMR (125 MHz) spectrum. Analytical and preparative thin-layer chromatography was performed on silica gel (200-300 mesh) GF / UV 254 plates, and the chromatograms were visualized under UV light at 254 nm.

[0054] 1.1 Synthesis of intermediates

[0055] 1.1.1 Synthesis of platinum (IV) intermediates

[0056] The preparation of the platinum (IV) intermediate takes the corresponding divalent cisplatin as the raw material and prepares it through the oxidation of N-chlorosuccinimide (NCS) or hydrogen peroxide.

[0057] The synthetic route of platinum (IV) intermediate monochloromonohydroxycisplatin see figure 1 , whose detailed synthesis method is as follows: To an aqueous solution (450 mL) of cisplatin (8.0mmoL, 1eq), N...

Embodiment 2

[0070] Identification of Example 2 Compounds

[0071] 2.1 Identification of compound UM

[0072] ESI-MS:m / z[M+H] + =471.5, the purity is 96%, proton nuclear magnetic spectrum (see Figure 7 ) and carbon spectra (see Figure 8 ). The details are as follows: 1 HNMR (300MHz, CDCl 3):δ=5.21(m,1H,CH(12)),3.58(s,3H,CH3(31)),3.18(dd,J=11.0,4.9Hz,1H,CH(3)),2.21(d ,J=11.3Hz,1H,CH(18)),1.98(ddd,J=13.4,13.4,4.6Hz,1H,Cha(2)),1.89(dd,J=8.9,3.7Hz,2H,CH2( 11)), 1.77 (ddd, J=13.8, 13.8, 4.8Hz, 1H, Cha(15)), 1.65–1.54 (m, 5H, CH2(7)+Cha(1)+CHa(16)+CHb( 2)),1.47(m,5H,CH(9)+Cha(6)+Cha(21)+Cha(22)+CHb(16)),1.36-1.25(m,4H,CH(19)+CHb (6)+CHb(22)+CHb(21)), 1.19–1.09(m,1H,CHb(15)),1.05(s,3H,CH3(27)),1.03–0.97(m,2H,CH (20)+CHb(1)),0.96(s,3H,CH3(23)),0.92(d,J=6.0Hz,3H,CH3(30)),0.90(s,3H,CH3(25)) ,0.83(d,J=6.4Hz,3H,CH3(29)),0.76(s,3H,CH3(24)),0.72(s,3H,CH3(26)),0.71(brd,J=10.4Hz ,1H,CH(5))ppm; 13 CNMR (125MHz, CDCl3): δ = 177.95 (C = 0, C28), 138.14 (C = CH, C13), 125.57 (HC = C, C12), 78.96...

Embodiment 3

[0082] Example 3 Stability and reducibility of tetravalent platinum anticancer complexes derived from cisplatin

[0083] 3.1 Preparation of solution

[0084] 3.1.1 Preparation of ascorbic acid solution

[0085] Accurately weigh a certain mass of ascorbic acid, add PBS to dissolve and prepare ascorbic acid solution with a concentration of 10mM.

[0086] 3.1.2 Preparation of PBS solution containing platinum complex

[0087] Preparation of tetravalent platinum complex PBS solution: Precisely weigh a certain mass of tetravalent platinum complex US-CIS-CL or US-CIS-SU or US-CIS-OH, first add acetonitrile to dissolve and prepare a 10μM solution, and then use Dilute it with PBS solution to obtain a solution with a final concentration of 1 μM, which is used for stability incubation experiments.

[0088] Cisplatin PBS solution preparation: Accurately weigh a certain mass of cisplatin, add PBS solution containing 10% acetonitrile, vortex until fully dissolved, and prepare a cisplatin...

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to a cisplatin-derived tetravalent platinum anticancer complex containing ursolic acid ligands and a preparation method and application thereof. The series of Pt(IV) complexes containing ursolic acid ligands disclosed by the present invention take cisplatin as the basic core, introduce ursolic acid-derived ligands at one axial end, and introduce -Cl or -OH groups at the other end; Alternatively, ursolic acid-derived ligands are introduced at both ends of the axial direction. The raw materials used in the preparation of this series of Pt(IV) complexes are cheap and easy to obtain, the method is simple and easy to operate, and is suitable for large-scale production. In vitro experiments show that the Pt(IV) complexes US‑CIS‑CL and US‑CIS‑OH exhibit high anticancer activity, which is superior to cisplatin, and has good selectivity for cancer cells, while being resistant to cisplatin The cancer cells also show good anticancer activity, and have the potential to be developed as a new anticancer drug with high efficiency and low toxicity and overcome cisplatin resistance.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a cisplatin-derived tetravalent platinum anticancer complex containing ursolic acid ligand for antitumor, a preparation method and an application. Background technique [0002] Since the advent of cisplatin in 1978, platinum-based drugs have been a hot spot in the development of anti-tumor drugs. At present, several platinum-based anticancer drugs have been approved for clinical treatment of various tumors, among which cisplatin, carboplatin and oxaliplatin have been approved for widespread use worldwide. Although the classic divalent platinum drugs are widely used in clinical application and have obvious advantages, they still have certain limitations, and they usually produce certain toxic and side effects. ; The side effects of carboplatin are mainly bone marrow suppression, often manifested as transient thrombocytopenia; while the neurotoxicity of oxaliplatin i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J63/00A61P35/00
CPCC07J63/008A61P35/00
Inventor 陈西敬赵娣秦智莹孙蒙琪边玥莹雷舒月杜茜
Owner 南京菲力康医药科技有限公司
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