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Anti-tumor compound capable of overcoming cis-platinum drug resistance and preparation and application thereof

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

Active Publication Date: 2021-09-28
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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  • Anti-tumor compound capable of overcoming cis-platinum drug resistance and preparation and application thereof
  • Anti-tumor compound capable of overcoming cis-platinum drug resistance and preparation and application thereof
  • Anti-tumor compound capable of overcoming cis-platinum drug resistance and preparation and application thereof

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 invention provides an anti-tumor compound capable of overcoming cis-platinum drug resistance and preparation and application thereof, the anti-tumor compound capable of overcoming cis-platinum drug resistance has a structure as shown in a compound 1 and a compound 2 as shown in a formula I. In view of serious toxicity and drug resistance of cis-platinum in clinical application, the invention aims to solve the technical problem that a novel platinum (II) compound is designed and synthesized by combining a compound with a known platinum (II) compound containing a functional group according to the characteristic that the compound with the activity of inhibiting protein kinase 2 can inhibit DNA (Deoxyribonucleic Acid) damage repair, and the obtained compound has a very strong inhibition effect on cisplatin-sensitive tumors and cisplatin-resistant tumors, is relatively low in toxicity, has the characteristics of high efficiency and low toxicity, and can be used for preparing anti-tumor 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 Applications(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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