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Nitrogen-containing derivatives of lamellarin d, their preparation methods and their use in the treatment of tumor diseases

A technology for tumors and drugs, applied in the field of nitrogen-containing derivatives of orcin D and its preparation, can solve the problems of increased lysosomal membrane penetration, cell apoptosis, etc., and achieve improved selectivity, high tumor selectivity, and targeting strong effect

Active Publication Date: 2019-04-30
SHANDONG UNIV
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  • Description
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Problems solved by technology

[0005] Recent studies have found that the amine-methylated derivatives of orcin D have good anti-tumor activity, and further studies on the mechanism of action have found that this kind of weakly basic derivatives of orcin D can be oriented and enriched in tumor cell lysosomes. collection, further causing an increase in lysosomal membrane permeability, leading to apoptosis

Method used

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  • Nitrogen-containing derivatives of lamellarin d, their preparation methods and their use in the treatment of tumor diseases
  • Nitrogen-containing derivatives of lamellarin d, their preparation methods and their use in the treatment of tumor diseases
  • Nitrogen-containing derivatives of lamellarin d, their preparation methods and their use in the treatment of tumor diseases

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Embodiment 1: the preparation of compound I-1 to I-4

[0068]

[0069] Preparation of Compound I-1

[0070] A solution of nitric acid (5.3 μL) in acetic acid (0.5 mL) was slowly added dropwise to dichloromethane (0.7 mL) of phyllonin D (50 mg) at 0°C. Stir at room temperature for 24 hours. After the reaction, pour the reaction system into ice water, extract with dichloromethane, combine the organic phases, wash with water three times, dry over sodium sulfate, filter, evaporate the solvent, and purify by silica gel column chromatography to obtain compound I- 1. MS m / z 470(M+1); 1 H NMR (600MHz, CDCl 3 )δ10.72(s,1H),7.63(s,1H),7.38(t, J=7.8Hz,1H),7.28(s,1H),7.10(d,J=7.7Hz,1H),6.96( d,J=8.1Hz,1H),6.93(d,J=8.0Hz,1H),6.88(m,3H),6.84(d,J=8.1Hz,1H),6.56(s,1H),6.38( d,J=7.6Hz,1H),5.81(s,1H),4.96(s,1H),4.94(s,1H),3.06-2.57(m,8H).

[0071] Preparation of Compound I-2

[0072] Dissolve compound I-1 (98mg) in ethyl acetate (5mL), add palladium carbon (5mg), and stir magne...

Embodiment 2

[0077] Embodiment 2: the preparation of compound 1-5

[0078]

[0079] Dissolve phyllonin D (0.5mmol), potassium carbonate (1.5mmol) and 2-chloro-N,N-dimethylethylamine (0.5mmol) in acetone (10mL) solution, heat to reflux, stir for 24 hours, react After completion, filter and remove the solvent, and the obtained product is purified by silica gel column chromatography to obtain the pure compound I-5. MS m / z 496(M+1); 1 H NMR (CDCl 3 ) δ7.35(t, J=7.9Hz, 1H), 7.12(d, J=7.8Hz, 1H), 7.02(d, J=7.9Hz, 1H), 6.96-6.93(m, 2H), 6.89( d,J=7.6Hz,1H),6.86-6.77(m,3H),6.75(dd,J=8.1,1.6Hz,1H),6.65(d,J=7.6Hz,1H), 6.21(s,1H ),5.38(d,J=1.6Hz,1H),4.17-4.02(m,2H),3.07-2.96(m,2H),2.96-2.80(m,4H),2.70-2.61(m,1H), 2.61-2.53 (m, 2H), 2.42 (t, J=12.0Hz, 1H), 2.29 (s, 6H).

Embodiment 3

[0080] Embodiment 3: the preparation of compound 1-6

[0081]

[0082] Dissolve phyllonin D (0.5mmol), potassium carbonate (1.5mmol) and 2-chloro-N,N-diethylethylamine (0.5mmol) in acetone (10mL) solution, heat to reflux, stir for 24 hours, react After completion, filter and remove the solvent, and the obtained product is purified by silica gel column chromatography to obtain the pure compound I-6. MS m / z 524(M+1); 1 H NMR (CDCl 3 ) δ7.38(t, J=7.9Hz, 1H), 7.16(d, J=7.7Hz, 1H), 6.99(d, J=7.3Hz, 1H), 6.93(d, J=7.9Hz, 2H) ,6.94-6.82(m,4H),6.74(d,J=7.5Hz,1H),6.51(d,J=6.1Hz,1H),6.28(s,1H),5.40(s,1H),4.30- 4.20(m, 2H), 2.98-2.90(m, 4H), 2.82(d, J=10.5Hz, 2H), 2.70(s, 4H), 2.63(t, J=11.1Hz, 1H), 2.50(t , J=11.1Hz, 1H), 1.27(s, 6H).

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Abstract

The invention discloses a riccardia multifida D nitrogenous derivative as well as a preparation method and application thereof in treating tumor diseases. The structure of the riccardia multifida D nitrogenous derivative is as shown in formula I, in the formula, R1, R2 and R3 are respectively selected from hydrogen atoms, nitryl, amino, acylamino or (C1-C10) alkyl amino; and R4, R5 and R6 are respectively selected from hydrogen atoms or (C1-C10) alkyl amino with different substituent groups. After structural modification and improvement, the anti-tumor activity of the riccardia multifida D nitrogenous derivative disclosed by the invention is remarkably improved when being compared with that of riccardia multifida D, and the derivative has a good prospect of being developed into a novel anti-tumor medicine.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a nitrogen-containing derivative of orcin D, a preparation method thereof, and an application in treating tumor diseases. Background technique [0002] Tumor is a kind of disease that seriously endangers human health and quality of life. The discovery and development of anti-tumor drugs has always been the focus and focus of drug researchers. At present, there are two major challenges in cancer chemotherapy. The first is poor drug selectivity, that is, it causes damage to normal tissues during tumor treatment, leading to treatment failure; the second is tumor drug resistance. After drug resistance, resistance to other drugs is often produced, that is, multidrug resistance, which eventually leads to the failure of chemotherapy. Finding the Achilles' heel of tumors to design antitumor drugs is a long-term pursuit of medicinal chemists. Compared with normal...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D313/00A61K31/335A61K31/4025A61K31/4523A61K31/55A61K31/4545A61K31/5377A61P35/00A61P35/02
CPCC07D313/00
Inventor 娄红祥孙斌高云郑泓波李琳
Owner SHANDONG UNIV
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