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NQO1-targeted indolequinone 23-hydroxybetulinic acid derivatives, preparation method and use

A technology for indole quinones and derivatives, applied in the field of medicinal chemistry, can solve the problems of unclear mechanism, poor pharmacokinetic properties, etc., and achieve the effects of good activity, good inhibitory effect and low toxicity

Active Publication Date: 2022-03-08
CHINA PHARM UNIV
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

23-HBA has unique antitumor activity, but its clinical application is limited due to its unclear mechanism and poor pharmacokinetic properties

Method used

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  • NQO1-targeted indolequinone 23-hydroxybetulinic acid derivatives, preparation method and use
  • NQO1-targeted indolequinone 23-hydroxybetulinic acid derivatives, preparation method and use
  • NQO1-targeted indolequinone 23-hydroxybetulinic acid derivatives, preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] 3-O-[(5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole)-3-methoxyacyl)-propionyl)] -23-Acetyl-lupine-20(29)-en-28-oic acid

[0039] The targeting group indoloquinone was dissolved in dichloromethane (10mL), succinic anhydride (309mg, 2.71mmol) and DMAP (110mg, 0.91mmol) were added thereto, heated to 45°C, reacted for 1.5h, added water, Dichloromethane (50mL×3) was extracted, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and column chromatography (dichloromethane:methanol=100:1) gave yellow intermediate 1;

[0040] The 23-HBA derivative (50mg, 0.083mmol) protected by acetyl group at the 23rd position was dissolved in anhydrous DCM (4mL), and Intermediate 1 (39.8mg, 0.13mmol), EDCI (24mg, 0.13mmol) and DMAP (17mg, 0.13mmol), reacted at room temperature for 5h, extracted with EA (20mL×3), added 1N hydrochloric acid (2mL), combined organic layers, washed with saturated NaHCO3 solution...

Embodiment 2

[0042]

[0043] 3-O-[(5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole)-3-methoxyacyl)-butyryl)] -23-Acetyl-lupine-20(29)-en-28-oic acid

[0044] The synthesis method refers to the synthesis of Example 1, 30.5%. 1 H NMR (300MHz, Chloroform-d) δ 6.86(s, 1H), 5.66(s, 1H), 5.33(s, 2H), 4.77(s, 1H), 4.64(s, 1H), 3.94(s, 3H ), 3.85(s, 4H), 3.73(s, 1H), 3.62-3.51(m, 1H), 3.09-3.02(s, 1H), 2.45-2.34(m, 5H), 2.27-2.19(m, 2H ), 1.72(s, 1H), 1.33(s, 3H), 0.99(s, 3H), 0.90(s, 3H), 0.80(s, 3H); 13 C NMR (125MHz, Chloroformm-d) δ179.0, 177.4, 171.9, 160.3, 152.5, 129.5, 121.5, 119.4, 106.8, 72.2, 67.1, 58.4, 58.3, 58.0, 56.5, 50.7, 49.2, 48.2, 46.9, 43.6 , 42.5, 42.2, 40.8, 38.5, 37.1, 36.3, 36.0, 34.0, 31.4, 30.2, 29.7, 29.7, 25.5, 23.5, 22.6, 20.9, 19.4, 16.6, 15.1, 14.7, 11.8. / z: calculated for C 48 h 65 NO 11 Na[M+Na] + :854.4450, found: 854.4458.

Embodiment 3

[0046]

[0047] 3-Hydroxy-23-O-[(5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole)-3-methoxyacyl)- Butyryl)]-lupine-20(29)-en-28-oic acid

[0048] The synthetic method refers to the synthesis of Example 1, 33.7%. 1 H NMR (300MHz, Chloroform-d) δ6.84(s, 1H), 5.70(s, 1H), 5.28(d, J=2.7Hz, 2H), 4.75(s, 1H), 4.62(s, 1H) , 3.96(s, 3H), 3.84(s, 4H), 3.49-3.35(m, 1H), 3.02-2.99(m, 1H), 2.47-2.39(m, 4H), 2.30-2.17(m, 2H) , 2.02-1.95(m, 5H), 1.70(s, 3H), 1.30(s, 3H), 0.94(s, 3H), 0.89(s, 3H), 0.87(s, 3H); 13 C NMR (75MHz, Chloroform-d) δ 195.3, 179.1, 177.4, 173.3, 172.7, 162.1, 160.4, 150.4, 137.7, 129.6, 121.5, 119.5, 106.8, 72.4, 61.9, 58.1, 58.0, 56.6, 52.3, 49 47.0, 44.0, 42.4, 42.1, 40.7, 38.4, 37.1, 36.9, 36.4, 33.6, 33.2, 31.5, 30.2, 29.7, 28.2, 25.5, 20.2, 19.4, 16.8, 16.0, 14.2, 11.8; HR-MS(ESI) m / z: calculated for C 46 h 63 NO 10 Na[M+Na] + :812.4344, found: 812.4351.

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Abstract

The invention discloses quinone oxidoreductase (NQO1)-targeted indole quinone 23-hydroxybetulinic acid derivatives, a preparation method and application. The compound of the invention has good activity and low toxicity, has significant inhibitory effect on tumor cell growth, especially has better inhibitory effect on tumor cells with high expression of NQO1, and can be used to further prepare new anti-tumor drugs. Preferred neoplastic diseases for treatment are lung cancer, liver cancer, melanoma and colon cancer.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to quinone oxidoreductase (NQO1) targeted indole quinone 23-hydroxy betulinic acid derivatives, preparation method and application. It specifically relates to 23-hydroxybetulinic acid derivatives (I), (II) and (III), which are novel derivatives of indolequinone 23-hydroxybetulinic acid targeted by NQO1. Background technique [0002] Targeted anti-tumor prodrugs refer to compounds that can specifically transform or release the original drug with anti-tumor activity in tumor cells. Targeted anti-tumor prodrugs can greatly improve the shortcomings of chemotherapy drugs such as high toxicity and poor selectivity, and play a vital role in targeted tumor therapy. DTD (DT-diaphorase, EC 1.6.99.2) is a homodimeric protein with a 27kda subunit, which has two, three and four phenotypes in mice, rats and humans, respectively. In humans, the predominant phenotype present is NAD(P)H:quinone oxidoreductas...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J63/00A61K31/56A61P35/00
CPCC07J63/008A61P35/00
Inventor 徐进宜朱华健徐盛涛刘洁鲁丽雪姚鸿陈哲生杨冬华叶文才
Owner CHINA PHARM UNIV
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