Tetravalent platinum naphthalimide complex, preparation method and application thereof

A platinum naphthalimide and naphthalimide technology, applied in the field of tetravalent platinum naphthalimide complexes, can solve the problems of weak anti-tumor metastasis activity, immunosuppression, lack of targeting, etc., and achieve enhanced drug resistance. effect on cells, enhancing effective binding, enhancing bioavailability

Active Publication Date: 2020-07-10
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Lack of targeting, drug resistance, weak anti-metastatic activity and immunosuppression are the main reasons for the failure of platinum-based drugs such as cisplatin and oxaliplatin in the treatment of cancer (including advanced cancer)

Method used

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  • Tetravalent platinum naphthalimide complex, preparation method and application thereof
  • Tetravalent platinum naphthalimide complex, preparation method and application thereof
  • Tetravalent platinum naphthalimide complex, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1: 6h (p=0)

[0080]

[0081] 1 H NMR (300MHz, Chloroform-d)δ8.45(s,1H),7.79(d,J=8.5Hz,1H),7.71(s,1H),7.41(s,2H),6.43(s,2H) ,3.21(d,J=6.7Hz,5H),2.44(s,2H),2.19(d,J=18.3Hz,2H),1.56(d,J=26.2Hz,3H),1.28(d,J= 19.4Hz,28H),0.85(s,3H). 13C NMR (75MHz, Chloroform-d) δ184.11,181.13,175.16,166.47–163.55(m),138.96,128.45,127.35,126.40,123.36–121.12(m),118.26,116.21,111.78,6472.932(d, , J=6.9Hz), 31.89, 29.26(d, J=12.6Hz), 26.88–21.83(m), 14.08, 8.76.

[0082] Its preparation method is as follows:

[0083] 1) The divalent platinum compound oxaliplatin Oxp. was oxidized with hydrogen peroxide for 4 hours at 60-70°C to prepare the tetravalent platinum compound Oxide-Oxp.; the tetravalent oxaliplatin compound Oxide-Oxp. (1equiv) and palmitic acid (4equiv) were dissolved in DMF, reacted at 70°C for one week under nitrogen protection, and then the oil pump was pumped dry. After adding dichloromethane to precipitate a solid, the compound Oxp(Ⅳ) was prepared by washing wit...

Embodiment 2

[0095] Example 2: 6g (p=0)

[0096]

[0097] 1 H NMR (300MHz, Chloroform-d) δ8.45 (d, J = 7.3Hz, 1H), 8.22 (dd, J = 15.6, 8.3Hz, 2H), 7.52 (t, J = 7.9Hz, 1H), 6.76 (d, J=8.3Hz, 1H), 4.13(t, J=7.0Hz, 2H), 3.74(s, 8H), 2.37(t, J=7.5Hz, 2H), 2.02–1.92(m, 2H) ,1.17(s,16H),0.79(t,J=6.5Hz,3H). 13 CNMR (75MHz, Methanol-d 4 )δ173.95,164.42,151.22,134.31,131.60,128.09,124.46,122.29,119.84,109.91,109.03,77.58,77.16,76.73,51.57,39.20,31.64,29.61,29.57,29.42,29.27,29.23,23.42,22.60,13.96 .

[0098] The difference between the preparation method of embodiment 2 and embodiment 1 is that In place of step 2) in Others are the same as embodiment 1.

[0099] in, The synthetic route of is:

[0100]

[0101] Reaction reagents and conditions in the formula: (a) Na 2 CrO 3 ,CH 3 COOH, 118℃, 12h; (b) HNO 3 ;Pd / c,H 2 (c)K 2 CO 3 ,CH 3 CN, 85°C, 5h.

Embodiment 3

[0102] Example 3: 6h (p=1)

[0103]

[0104] 1 H NMR (300MHz, Chloroform-d) δ8.06–7.93(m,1H),7.83(dd,J=6.3,2.8Hz,1H),7.76–7.71(m,1H),7.50–7.44(m,2H ),4.10(s,6H),3.25–3.09(m,4H),2.66(s,2H),2.47–2.16(m,4H),1.52(d,J=93.6Hz,6H),1.33(d, J=7.3Hz, 24H), 0.88(t, J=6.5Hz, 3H). 13 CNMR (75MHz, Chloroform-d) δ172.38–165.15(m), 154.93, 144.21, 138.17, 132.29, 131.63, 130.69, 120.79, 114.96, 50.80, 46.05, 43.80, 42.41, 35.82, 30.440, 33.3 ,29.69,26.57,17.94,12.59.

[0105] The difference between the preparation method of embodiment 3 and embodiment 1 is that In place of step 2) in Others are the same as embodiment 1.

[0106] in, The synthetic route of is:

[0107]

[0108] Reaction reagents and conditions in the formula: (a) Na 2 CrO 3 ,CH 3 COOH, 118℃, 12h; (b) HNO 3 ;Pd / c,H 2 (c)K 2 CO 3 ,CH 3 CN, 85°C, 5h.

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a tetravalent platinum naphthalimide complex, a preparation method and application thereof. The tetravalent platinum naphthalimide complex has good anti-tumor activity, which is better than that of cis-platinum and oxaliplatin, and the tetravalent platinum naphthalimide complex has better stability than bivalent platinum like cis-platinum, carboplatin and oxaliplatin. According to the invention, the naphthalimide modified tetravalent platinum has good targeting performance on tumor cells, high selectivity on tumor cells is improved, and different from a classic divalent platinum drug, the complex provided by the invention regulates and controls subcellular organelles and cell nucleus functionsto reverse drug resistance by targeting a tumor high polyamine microenvironment, and relieves immunosuppression of T cells around tumors at the same time. The complex provided by the invention also solves the problems of poor solubility, tedious clinical compatibility, poor patient immunity in clinical application of chemotherapeutic drugs and the like of previous bivalent platinum antitumor drugs, and has good fat solubility and water solubility.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a tetravalent platinum naphthalimide complex, its preparation method and application. Background technique [0002] Lack of targeting, drug resistance, weak anti-metastatic activity and immunosuppression are the main reasons for the failure of platinum drugs such as cisplatin and oxaliplatin in the treatment of cancer (including advanced cancer). In recent years, tetravalent platinum-based antineoplastic drugs as prodrugs of divalent platinum-based drugs have become the focus of research and development of platinum-based drugs. The tetravalent platinum center platinum ion belongs to d 6 electron configuration, in d 2 sp 3 The hybridized orbitals are bonded to form a stable inner orbital complex, which not only retains the broad-spectrum and high-efficiency anti-tumor properties of divalent platinum-based drugs, but also has high stability, less accumula...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00A61P35/00
CPCA61P35/00C07F15/0093Y02P20/55
Inventor 马静王佳佳方东孙华谢松强李迎光李林容岳柯欣
Owner HENAN UNIVERSITY
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