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Metal complex containing tridentate ligand and xanthine derivative ligand and preparation method and medical application of metal complex

A technology of metal complexes and xanthines, which is applied in platinum-based organic compounds, medical preparations containing active ingredients, and compounds containing elements of group 1/11 of the periodic table, can solve toxic and side effects and limit the overall curative effect of combination therapy And other issues

Active Publication Date: 2020-09-25
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the simultaneous use of multiple drugs will cause more serious side effects, and the different pharmacokinetic properties of the drugs limit the overall efficacy of combined therapy

Method used

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  • Metal complex containing tridentate ligand and xanthine derivative ligand and preparation method and medical application of metal complex
  • Metal complex containing tridentate ligand and xanthine derivative ligand and preparation method and medical application of metal complex
  • Metal complex containing tridentate ligand and xanthine derivative ligand and preparation method and medical application of metal complex

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Synthesis of complex 1:

[0061]

[0062] Add compound 1,3-bis(2'-pyridyl) benzoplatinum chloride (II) (50mg, 0.11mmol) and CH in a 50mL three-necked flask 3 CN (8mL), add AgCF at reflux at 80°C 3 SO 3 (28mg, 0.11mmol), react in the dark for 1h and filter to remove insoluble matter. Add compound 1,3,7,9-tetramethylxanthine iodide (44mg, 0.13mmol) and CH in another 50mL three-necked flask 3 CN (5mL), dissolved completely under heating in 80℃ water bath, add AgCF 3 SO 3 (33mg, 0.13mmol), reacted at room temperature in the dark for 30min, then filtered to remove insoluble matter. The two filtrates were combined, t-BuOK (18mg, 0.16mmol) was added, and reacted at room temperature for 2.5h under the protection of nitrogen, then refluxed at 80°C for 18h. Cool to room temperature, filter to obtain a yellow clear filtrate, evaporate the solvent under reduced pressure, add 2 mL of CH to the crude product 3 Dissolve CN, add 6mL ether to form a precipitate, let the precip...

Embodiment 2

[0068] Synthesis of complex 2:

[0069]

[0070] With reference to the method of Example 1, 1,3,7,9-tetramethylxanthine iodide was replaced by 1-(2-hydroxyethyl)-3,7,9-trimethylxanthine iodide to obtain Complex 2, yield 14.4%.

[0071] 1 H-NMR (300MHz, DMSO-d 6 ): δ (ppm) 8.31 (d, J = 5.6Hz, 2H, ArH ),8.29-8.19(m,4H, ArH ),7.90(d,J=7.7Hz,2H, ArH ),7.44-7.31(m,3H, ArH ),4.90(t,J=5.8Hz,1H, Oh ),4.33(s,3H,N CH 3 ),4.14(s,3H,N CH 3 ),4.07(t,J=6.6Hz,2H,N CH 2 ),3.84(s,3H,N CH 3 ),3.60(q,J=6.4Hz,2H,HO CH 2 ).

[0072] Anal. Calcd for C 27 h 25 f 3 N 6 o 6 PtS: C 39.86, H 3.10, N 10.33. Found: C 39.28, H 3.10, N 10.38.

[0073] HR-MS(ESI)m / z[M] + Calcd for C 26 h 25 N 6 o 3 Pt, 664.1636; Found: 664.1631.

[0074] IR (cm -1 ):3442.94, 2966.52, 1701.22, 1664.57, 1539.20, 1257.59, 1159.22, 1029.99, 767.67, 636.51.

Embodiment 3

[0076] Synthesis of complex 3:

[0077]

[0078] With reference to the method of Example 1, 1,3,7,9-tetramethylxanthine iodide is replaced by 1-(5-oxohexyl)-3,7,9-trimethylxanthine iodide to obtain Complex 3, yield 19.7%.

[0079] 1 H-NMR (300MHz, CD 3 CN): δ(ppm)8.29-8.16(m,2H, ArH ),8.14(d,J=1.7Hz,1H, ArH ),8.12(d,J=1.6Hz,1H, ArH ),8.04-7.94(m,2H, ArH ),7.75(d,J=7.7Hz,2H, ArH ),7.41(t,J=7.7Hz,1H, ArH ),7.26(ddd,J=7.4,5.7,1.5Hz,2H, ArH ),4.33(s,3H,N CH 3 ),4.20(s,3H,N CH 3 ),4.03(t,J=6.9Hz,2H,N CH 2 ),3.83(s,3H,N CH 3 ), 2.55(t, J=6.7Hz, 2H, CO CH 2 ),2.12(s,3H,CO CH 3 ),1.72-1.55(m,4H,COCH 2 CH 2 CH 2 ).

[0080] Anal. Calcd for C 31 h 31 f 3 N 6 o 6 PtS: C 42.91, H 3.60, N 9.68. Found: C 42.96, H 3.38, N 9.81.

[0081] HR-MS(ESI)m / z[M] + Calcd for C 30 h 31 N 6 o 3 Pt, 718.2105; Found: 718.2104.

[0082] IR (cm -1 ):3460.30, 2935.66, 1707.00, 1662.64, 1541.12, 1261.45, 1145.72, 1031.92, 771.53, 636.51.

[0083] Wherein, ...

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Abstract

The invention discloses a metal complex containing a tridentate ligand and a xanthine derivative ligand and a preparation method and medical application of the metal complex. Specifically, the metal complex containing the tridentate ligand and the xanthine derivative ligand is shown as a formula I. The complex has inhibitory activity on tumor cells, tumor stem cells and angiogenesis at the same time, and can be used for preparing drugs for treating various malignant tumors, especially drugs for treating malignant tumors resistant to existing chemotherapeutic drugs. The metal complex disclosedby the invention has the characteristic of multiple anti-tumor effects, overcomes drug resistance caused by tumor stem cells and cancer cell metastasis caused by vascular proliferation, and improves the anti-tumor curative effect.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to a class of metal complexes containing tridentate ligands and xanthine derivative ligands, a preparation method and medical application thereof. Background technique [0002] Malignant tumors have high morbidity and mortality, and are the leading cause of death and an important public health problem worldwide. Tumor recurrence and metastasis are the main causes of high mortality in malignant tumors. Studies have found that the high drug resistance of tumor stem cells and the metastasis of cancer cells are important reasons for the high recurrence rate of tumors, and angiogenesis is a key factor causing cancer cell metastasis. [0003] Metal-based antitumor drugs, due to their structural diversity and specificity caused by their variable geometric coordination configurations, as well as the interaction with biomolecules through redox reactions and ligand exchange reactions to produce antitum...

Claims

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Application Information

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IPC IPC(8): C07F15/00C07F1/00A61K31/555A61P35/00A61P9/00
CPCA61P9/00A61P35/00C07F1/00C07F15/006C07F15/0086
Inventor 张晶晶王致斌于春秋张婉婉徐云根张磊孙泽人
Owner CHINA PHARM UNIV
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