Application of Bufalin-3beta-N-methoxyl-N-beta-D-heteroside in preparing cardiotonic drug

A technology of glucoside and bufalin, which is applied in the field of preparation of cardiotonic drugs, can solve the problems of weak inhibitory effect, and achieve the effect of strong cardiotonic effect, high yield and high safety

Inactive Publication Date: 2015-11-11
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The results of anti-tumor activity evaluation show that this type of compound has strong inhibitory activity on tumor cells, but weak inhibitory effect on normal cells (Chinese invention patent number: CN103288911B)

Method used

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  • Application of Bufalin-3beta-N-methoxyl-N-beta-D-heteroside in preparing cardiotonic drug
  • Application of Bufalin-3beta-N-methoxyl-N-beta-D-heteroside in preparing cardiotonic drug
  • Application of Bufalin-3beta-N-methoxyl-N-beta-D-heteroside in preparing cardiotonic drug

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0024] Experimental example 1: Synthesis of bufalin-3β-N-methoxy-N-β-D-glucoside

[0025] (1) The C3 hydroxyl of the reaction substrate Bufalin is oxidized by the oxidant pyridinium chlorochromate hydrochloride (PCC) to generate the Bufalone of the C3 ketone. This step can be reacted at room temperature and the yield is higher (90 %); (2) the latter reacts with methoxylamine hydrochloride through affinity addition-elimination reaction to generate bufalone derivatives 2a / b, Bufaloneoximes, which have a methoxyl imine structure at the C3 position, and the reaction is comparatively Thoroughly, the yield is higher (yield 90%); (3) oxime mixture Bufaloneoximes is reduced by reducing agent tert-butylamine borane hydrochloride, generates C3 position configuration different isomer compound 3α and 3β, reacts in Carried out under ice-bath cooling, the yield is about 60%, wherein, the intermediate molar ratio is about 3α:3β=2:1, and the two isomers can be separated by silica gel column; ...

Embodiment 2

[0030] Embodiment 2: Bufalin-3β-N-methoxyl-N-β-D-glucoside (compound 1) and bufalin-3α-N-methoxyl-N-beta-D-glucoside ( Compound 2) Na + / K + -ATPase inhibitory activity.

[0031] The test method can be found in literature (Zhang, R.R.; Tian, ​​H.Y.; Tan, Y.F.; Chung, T.Y.; Sun, X.H.; Xia, X.; Ye, W.C., Middleton, M.A.; NatalyaF.; EsmannM.; Tzen, J.T.C.; Jiang, R.W.Structures, chemotaxonomic significance, cytotoxic and Na+, K+-ATPase inhibitory activities of new cardenolides from Asclepiascurassavica.Org.Biomol.Chem.2014, 12(44), 8919-8929.), activity evaluation of compounds 1 and 2, the specific steps are as follows:

[0032] (1) Add the activity test solution to a 96-well plate, 100 μL per well, containing 100mMNaCl, 20mMKCl, 1mMMgCl 2 , 1mMEGTA, 20mMTris-HCl, pH7.4, and 0.2μgofpurifiedNa + / K + - ATPase alpha 1 or alpha 2 subtype.

[0033] (2) After adding different concentrations of compounds 1 and 2, the 96-well plate was incubated at 37° C. for 15 min.

[0034] (3)...

Embodiment 3

[0037] Example 3: Cardiotonic effect of bufalin-3β-N-methoxy-N-β-D-glucoside (compound 1) on zebrafish

[0038] The present invention uses the zebrafish model with green fluorescence (easy to observe) in the heart to study its cardiotonic effect (Huang, C.C.; Monte, A.; Cook, J.M.; Kabir, M.S.; Peterson, K.P. Zebrafish Heart Failure Models for the Evaluation of Chemical Probes and Drugs. Assay Drug Dev. Technol. , 11(9-10), 561-572.).

[0039] Tg(cmlc2:GFP) transgenic zebrafish (University of Macau) was used, and the fertilized eggs were obtained from mating of male and female fish in the early morning. The fertilized eggs were divided into four groups (medication group, positive control group, negative control group, and vehicle control group), and then the fertilized eggs of each group were placed in the culture medium and hatched at 28°C. After 24 hours, doxorubicin (0.3 μM) was added to the culture medium, and the culture was continued for 24 hours to establish the model)...

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PUM

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Abstract

The invention belongs to the technical field of preparation of cardiotonic drugs, and discloses an application of Bufalin-3beta-N-methoxyl-N-beta-D-heteroside in preparing a cardiotonic drug. The Bufalin-3beta-N-methoxyl-N-beta-D-heteroside in preparing cardiotonic drug has the structure as shown in the formula I (the formula I is in the description). The researches made in the invention shows that Bufalin-3beta-N-methoxyl-N-beta-D-heteroside has obvious activity in inhibiting Na<+> / K<+>-ATP enzyme, higher cardiotonic activity than that of positive medicine digoxin, and higher selectivity index for alpha2 subtype than that of positive medicine digoxin. The Bufalin-3beta-N-methoxyl-N-beta-D-heteroside is high in safety, strong in cardiotonic effect and good officinal prospect, and the preparation technology is simple, low in cost and high in yield.

Description

technical field [0001] The invention belongs to the technical field of preparation of cardiotonic drugs, and in particular relates to the application of bufalin-3β-N-methoxy-N-β-D-glucoside in the preparation of cardiotonic drugs. Background technique [0002] With the acceleration of the aging process of the world's population, the incidence of common cardiovascular diseases such as hypertension and coronary heart disease is increasing year by year, so the prevalence of heart failure is also gradually increasing. According to statistics, there are about 10,000 heart failure patients in my country every year. Na + / K + -ATPase is the target of cardiotonic steroids. Cardiophenone inhibits Na + / K + -ATPase, making intracellular Na + Concentration rises, starting Na + -Ca + Exchange, so that intracellular Ca + The concentration rises, thereby exerting a cardiotonic effect. Commonly used cardiotonic steroids include digoxin, digitoxin, ouabain C, ouabain K, and total ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7048A61P9/00A61P9/04A61P9/06
Inventor 江仁望郭锦华唐红进田海妍黄超刘灿群
Owner JINAN UNIVERSITY
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