CN1526388A - New use of 3,7,3'4'-substituted flavone - Google Patents

Abstract

The present invention discloses the new use of 3, 7, 3', 4'-substituted flavone. The 3, 7, 3', 4'-substituted flavone is prepared with Chinese herbal medicine materials and through extraction and separation. It can inhibit obviously mouse macrophage in secreting tumor necrosis factor, interleukin-1, interleukin-6 and other cell factor and has obvious treating effect on experimental cancer cachexia. Therefore, 3, 7, 3', 4'-substituted flavone may be used in preparing medicine for treating cancer cachexia.

Description

The new purposes of 3,7,3 ', 4 '-replacement flavone

Technical field

The present invention relates to the purposes of 3,7,3 ', 4 '-replacement flavone, the particularly application of 3,7,3 ', 4 '-replacement flavone in the medicine of preparation treatment cancer cachexia.

Background technology

Cancer cachexia (cachexia) is meant the syndrome of performances such as inappetence that the middle and terminal cancer patient occurs, skeletonize, general metabolism change.In a single day cancer develops into cachexia, will make the patient lose the chance of operation, radiotherapy, chemotherapy, and has a strong impact on patient's quality of life and shorten survival time of patients.Lack effective medicine at present clinically, therefore, the medicine of seeking effective antitumor and improving cancer cachexia has great importance.

3,7,3 ', 4 '-replacement flavone of the present invention, its general structure is as follows:

R=H in the formula, CH ₃, CH ₃CO or-C ₆H ₁₁O ₅(glucosyl, glucityl).

Above-mentioned replacement flavone is applied to prepare existing report in the antitumor medicine, but such replacement chromocor compound application in the medicine of preparation treatment cancer cachexia does not appear in the newspapers.

Summary of the invention

The objective of the invention is to, a kind of new purposes of 3,7,3 ', 4 '-replacement chromocor compound is provided.

Inventive concept

The reason that causes cancer cachexia is thought for a long time mostly because of tumor cell Hypersegmentation propagation, increased the consuming excessively of human nutrition material, but mandatory nutrition is taken in and can not be reversed the cancer cachexia state.Studies show that in a large number in recent years, tumor necrosis factor (tumornecrosis factor by immune cell and tumor cell secretion, TNF) and interleukin-6 (interleukin-6, IL-6) etc. cytokine plays an important role in cancer cachexia pathology.There are high-caliber TNF and IL-6 in the tumor patient serum clinically, and are with the development of tumor and are closely related.Laboratory animal is injected TNF or IL-6 or the inoculating cell factor repeatedly and is produced cell, all can induce cachexia; Injection TNF or the antibody of IL-6 or the cachexia that soluble recepter also can be alleviated animal.After TNF I receptor (TNFRI) knock out mice and soluble TNF RI crossed the transgenic mice lotus tumor of expression, the mice of two kinds of models lost weight and fat reduces and blood triglyceride (TG) significantly is lower than normal tumor-bearing mice; Nuclear factor NF κ B antisense nucleotide is the transcriptional activation of external enwergy inhibition cytokine in vivo, reduces the release of cytokine, can significantly improve cachexia states such as tumor-bearing mice body weight, fat, gastrocnemius and food intake minimizing.Above-mentioned clinical and experimental result is pointed out strongly, and medicine may provide effective way for the treatment of cancer cachexia by suppressing production of cytokines and effect.

Used 3,7,3 ', 4 '-replacement flavone is to obtain through chemical modification by extraction in Chinese medicine Spina Gleditsiae, Folium Pistaciae chinensis Germinatus, the catechu or by extract among the present invention, and the method for concrete extraction and chemical modification is referring to Biomed J, 1957,67:239; CA, 1967,67:51047; Whole nation Chinese herbal medicine compilation (on), Beijing: People's Health Publisher, 1976,454, R=CH wherein ₃The substituent of CO is by 3,7, and 3 ', 4 '-kaempferol and excess acetyl chloride are separated preparation through silicagel column sephadex LH-20 again.

Be better understanding content of the present invention, below with 3,7,3 ', 4 '-kaempferol (fisetin, fisetin) be example,, its application in the medicine of preparation treatment cancer cachexia be described by its effect content of the test and result who regulates cytokine activity and improve the tumor-bearing mice cancer cachexia.But given example does not limit protection scope of the present invention.

Test is with mouse melanin tumor cell system (B16), and available from Shanghai cell institute of Chinese Academy of Sciences cell bank, L929 cell and B9.9 cell are provided by immunity teaching and research room of The 2nd Army Medical College.

Test method:

(1) the inducing and measuring of cytokine: preparation Turnover of Mouse Peritoneal Macrophages, add in 24 orifice plates, adding fisetin and LPS (10 μ g/ml) then simultaneously educated 24 hours altogether, the collecting cell supernatant, use cytokine IL-1, IL-6 and the TNF activity of mouse chest cell, B9.9 cell and the release of L929 raji cell assay Raji macrophage respectively.

(2) mice cachexia model and drug effect: C57BL/6 mouse peritoneal injection B16 melanoma cell 1.5 * 10 ⁶, rose in second day and to irritate stomach and give fisetin, after 11 days, mouse heart is got blood, measure blood triglyceride (TG), non-esterified fatty acid (non-esterified fatty acid, NEFA), glucose and T-CHOL; Measure mice corpse dry weight, epididymal adipose tissues and total body fat.Measure mice food every day and water simultaneously and take in situation.

Result of the test

(1) fisetin produces the influence of cytokine to mouse macrophage

Inflammatory cytokine such as TNF, IL-1 and IL-6 and cancer cachexia are closely related.We have tested fisetin Turnover of Mouse Peritoneal Macrophages have been produced IL-1, the influence of TNF and IL-6.The result shows that fisetin and Turnover of Mouse Peritoneal Macrophages are educated altogether, can induce macrophage to discharge inflammatory cytokine IL-1 by concentration dependence ground inhibition LPS, and IL-6 and TNF the results are shown in Table 1.

Table 1 fisetin discharges the influence of IL-1, TNF and IL-6 to lipopolysaccharide-induced Turnover of Mouse Peritoneal Macrophages

Fisetin (μ mol.L ^-1) IL-1 activity (cpm) TNF activity (U.ml ^-1) IL-6 activity (U.ml ^-1)

0 9862±567 183±21 20.8±2.4

12.5 7425±297 98±12** 10.4±1.9*

25 5894±825* 37±16** 6.8±1.4**

50 4366±637** 18±7** 3.2±2.1**

n＝3， x±s，*P＜0.05，**P＜0.01?vs?0.

Table 2 is the result show, compares with fisetin, and the effect that substituent 1,2 suppresses Turnover of Mouse Peritoneal Macrophages release IL-1, TNF and IL-6 is better than fisetin, and the effect of substituent 3 all is weaker than fisetin.

Table 2 fisetin and analog discharge the influence of IL-1, TNF and IL-6 to Turnover of Mouse Peritoneal Macrophages

Group R1 IL-1 activity (cpm) TNF activity (U.ml ^-IL-6 activity (U.ml ^-

¹) ¹)

Solvent control group 9936 ± 238 189 ± 32 21.6 ± 2.2

Fisetin H 5924 ± 512** 38 ± 11** 7.2 ± 1.2**

Substituent 1 CH ₃4513 ± 524**, 28 ± 8**, 5.6 ± 2.1**

Substituent 2 CH ₃CO 4439 ± 368** 36 ± 10** 4.9 ± 1.8**

Substituent 3 glucosyl 7122 ± 135* 65 ± 22** 10.1 ± 3.8*

The concentration of fisetin and substituent 1-3 is 25 μ mol.L ^-1, compare with the solvent control group, ^*P＜0.05, ^*P＜0.01

(2) fisetin is to the influence of tumor-bearing mice cancer cachexia

Fisetin can significantly improve cachexia states (table 3) such as tumor-bearing mice body weight, epididymal adipose tissues and total body fat minimizing, recovers blood parameters simultaneously and changes (table 4).

Table 3 fisetin is to the cachectic influence of B16 tumor-bearing mice

Fisetin epididymal adipose tissues total body fat corpse dry weight

/mg/kg (mg) (g/mouse) (g)

Normal control 347 ± 53 1.62 ± 0.10 5.5 ± 0.3

Matched group 163 ± 26## 1.10 ± 0.13## 4.2 ± 0.1##

10 170±34 0.98±0.28 4.5±0.2

25 268±65 ^* 1.25±0.34 4.7±0.9

63 318±58 ^* 1.38±0.13 ^* 4.8±0.8

N=10, ##P＜0.01vs normal control, ^*P＜0.05, ^*P＜0.01vs matched group.

Table 4 fisetin is to the influence of B16 tumor-bearing mice blood parameters

Fisetin triglyceride non-esterified fatty acid glucose T-CHOL

/mg/kg (mg/dL) (mEq/L) (mg/dL) (mg/dL)

Normal control 74 ± 3 1.85 ± 0.07 132 ± 6 84 ± 3

Matched group 214 ± 46## 3.04 ± 0.16## 86 ± 10## 106 ± 5##

10 116±20 2.41±0.18 112±4 104±4

25 100±30 ^* 2.55±0.21 121±7 ^** 123±5 ^*

63 98±21 ^* 2.25±0.23 ^* 139±9 ^** 97±4 ^*

N=10, ##P＜0.01vs normal control, ^*P＜0.05, ^*P＜0.01vs matched group.

The invention has the advantages that, find that known compound 3,7,3 ', 4 '-replacement flavones can obviously suppress little Mouse macrophage secreting tumor necrosis factor, interleukin 1 and the cell factors such as-6 are disliked experimental cancer Sick matter has obvious therapeutic action, thereby widens known compound 3,7, the medicinal model of 3 ', 4 '-replacement flavones Enclose.

Claims (1)

1,3,7,3 ', 4 '-replacing flavone, its general structure is as follows:

R=H in the formula, CH ₃, CH ₃CO or-C ₆H ₁₁O ₅

Application in the medicine of preparation treatment cancer cachexia.