An antitumor compound capable of overcoming cisplatin resistance and its preparation and application

A compound, anti-tumor technology, applied in the field of anti-tumor compounds

Active Publication Date: 2022-04-08
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In summary, there is a significant DNA repair phenomenon in cisplatin-resistant cancer cells, and the overexpression of CK2 in drug-resistant cancer cells is one of the main reasons for cisplatin resistance

Method used

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  • An antitumor compound capable of overcoming cisplatin resistance and its preparation and application
  • An antitumor compound capable of overcoming cisplatin resistance and its preparation and application
  • An antitumor compound capable of overcoming cisplatin resistance and its preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Embodiment one: the preparation of compound 1

[0057] Suspend equimolar amounts of compound 3 and compound 4 (2mmol) in 30mL of anhydrous methanol in a 50mL reaction flask, add 2-3 drops of acetic acid, and react at 30-60°C in the dark for 48-72h. TLC monitors the compound 3 complete responses. After cooling and filtering, the filter cake was washed with 30 mL (3×10 mL) of methanol to obtain a yellow solid product with a yield of 96.4%.

[0058] 1 H NMR (600MHz, DMSO-d6) δ11.15(s, 1H), 10.19(s, 1H), 9.67(s, 1H), 8.99(d, J=4.2Hz, 1H), 8.86(d, J= 7.7Hz, 1H), 8.58(d, J=3.8Hz, 1H), 8.26(s, 1H), 8.23(s, 1H), 8.14(d, J=7.2Hz, 1H), 7.93(d, J= 7.3Hz, 1H), 7.45(t, J=7.5Hz, 1H), 7.14(d, J=6.9Hz, 1H), 4.26(s, 6H), 3.74(s, 4H)ppm. 13 C NMR(150MHz,DMSO-d6)δ176.45,176.23,163.28,159.72,150.55,148.18,147.80,143.63,142.33,135.12,133.28,130.62,127.50,126.91,124.23,123.84,122.80,122.69,121.73,120.64,119.68 ,116.83,56.40,49.60,46.96ppm.HR-MS(m / z)(ESI):calcd for C 25 h 23 ClN 7 o ...

Embodiment 2

[0059] Embodiment two: the preparation of compound 2

[0060] Compound 3 and compound 5 were prepared according to the method shown in Example 1 to obtain a yellow solid product with a yield of 95.2%.

[0061] 1 H NMR (600MHz, DMSO-d6) δ10.18(s, 1H), 10.09(s, 1H), 9.68(s, 1H), 8.99(d, J=5.5Hz, 1H), 8.84(d, J= 8.4Hz,1H),8.59(d,J=5.4Hz,1H),8.35(s,1H),8.23(s,1H),8.09(d,J=8.1Hz,1H),7.93(d,J= 8.2Hz, 1H), 7.45(t, J=8.0Hz, 1H), 7.15(d, J=7.7Hz, 1H), 6.01(d, J=8.0Hz, 2H), 5.30(m, 2H), 3.70 -3.79(m,4H),2.07(s,2H),1.83(d,J=11.9Hz,2H),1.44-1.46(m,2H),1.22(d,J=8.8Hz,2H),1.02( t,J=9.5Hz,2H)ppm. 13C NMR(150MHz,DMSO-d6)δ206.07,176.03,165.83,150.48,148.15,147.72,143.76,142.39,134.71,133.28,130.54,127.52,126.26,124.19,123.01,122.86,122.62,121.48,120.56,119.57,116.82 ,62.57,56.35,46.86,31.96,24.50ppm.HR-MS(m / z)(ESI):calcd forC 31 h 31 ClN 7 o 5 Pt[M+H] + :811.1717; found: 811.1158.

Embodiment 3

[0062] Embodiment three: the preparation of compound 3

[0063] Compound 6 (1.09g, 3mmol) was dissolved in 20mL of methanol in a 50mL single-necked bottle, and hydrazine hydrate (6-30mmol) was slowly added dropwise at room temperature, and heated to reflux for 24-72h until the reaction was complete. After cooling, a large amount of solid precipitated out, and was suction filtered, and the filter cake was washed with 3×10 mL ice methanol to obtain 1.05 g of a bright yellow solid product, with a yield of 97.1%. 1 H NMR (600MHz, DMSO-d6) δ10.14(s, 1H), 10.08(s, 1H), 9.63(s, 1H), 8.95(d, J=6.0Hz, 1H), 8.80(d, J= 12.0Hz, 1H), 8.55(d, J=6.0Hz, 1H), 8.33(t, J=1.8Hz, 1H), 8.21(d, J=1.6Hz, 1H), 8.07(d, J=6.0Hz ,1H),7.91(dd,J=12.0,1.6Hz,1H),7.42(t,J=6.0Hz,1H),7.12(dd,J=8.0,1.4Hz,1H),4.63(s,2H) ppm. 13 C NMR(150MHz,DMSO-d6)δ165.77,150.47,148.13,147.69,143.76,142.40,134.73,133.35,130.52,127.52,126.26,124.17,123.00,122.83,122.60,121.47,120.57,119.56,116.79ppm.HR- MS(m / z)(ESI):calcd for...

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Abstract

The present invention provides an anti-tumor compound capable of overcoming cisplatin resistance and its preparation and application. The anti-tumor compound capable of overcoming cisplatin resistance has a structure such as compound 1 and compound 2 shown in formula I. In view of Cisplatin has serious toxicity and drug resistance in clinical application, and the technical problem to be solved by the present invention is to use the compound that inhibits protein kinase 2 activity to be able to inhibit the characteristics of DNA damage repair, and known platinum containing functional groups ( II) Combining compounds, designing and synthesizing a new platinum (II) compound, the obtained compound not only has a strong inhibitory effect on cisplatin-sensitive tumors but also cisplatin-resistant tumors, and has less toxicity and has With the characteristics of high efficiency and low toxicity, it can be used to prepare antitumor drugs.

Description

technical field [0001] The present invention relates to an anti-tumor compound that can effectively overcome cisplatin resistance, in particular to bonding a compound with protein kinase 2 (CK2) inhibitory activity to a platinum (II) compound known to have anti-tumor activity to obtain a compound that can effectively overcome cisplatin A novel platinum-resistant antitumor compound; the invention also relates to a preparation method and application of the compound. Background technique [0002] Since the discovery of cisplatin's antitumor activity in the 1960s, platinum-based drugs such as cisplatin, carboplatin, and oxaliplatin have been on the market, and they have been widely used clinically. After a lot of research, it is generally believed that the mechanism of action of cisplatin antineoplastic drugs is that the platinum (II) compound binds to the guanine N7 target on the DNA of cancer cells to form a DNA cross-linked adduct, which limits DNA replication and thus inhibi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61P35/00A61P35/02A61K31/4375A61K31/5377A61K31/4545A61K31/444
CPCC07D471/04A61P35/00A61P35/02A61K31/4375A61K31/444A61K31/4545A61K31/5377A61K31/282C07F15/00
Inventor 苟少华王心怡
Owner SOUTHEAST UNIV
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