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Antineoplastic alkanna tinctoria ketoximes derivatives

A technology of shikonone oxime and derivatives, which is applied in the field of medicine, can solve the problems of side effects, toxicity, poor water solubility, and cytotoxicity, and achieve the effects of reducing cytotoxicity, improving hydrophilicity, and improving water solubility

Inactive Publication Date: 2008-09-17
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Shikonin compounds are a class of natural products that widely exist in nature. Many studies have shown that these compounds have significant anti-tumor activity, but so far no such compounds have been used clinically as anti-tumor drugs. This is mainly because Their application is limited by the toxicity and poor water solubility of these compounds
The toxicity of shikonin may come from two aspects: (1) The alkylation of naphthoquinone under the action of biological reducing agent to remove the hydroxyl group of the side chain leads to extensive cytotoxicity
(2) The complexation of naphthalene structure and metal ions leads to toxic and side effects caused by ion imbalance in organisms
[0003] After searching the existing technical literature, it is found that the structural modification of shikonin compounds is mainly the modification of the hydroxyl esterification on the side chain, such as: Chinese patent, publication number: CN1420111, name: a class of naphthalene derivatives Compounds and their preparation methods and uses, such as Chinese patent, publication number: CN1112363, title: method for preparing 5,8-dihydronaphthoquinone derivatives, new 5,8-dihydronaphthoquinone derivatives and their anti- The use of cancer drugs, these two technologies do not record the content of oxidizing the side chain hydroxyl to a carbonyl group and then introducing an oxime into the shikonin structure

Method used

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  • Antineoplastic alkanna tinctoria ketoximes derivatives
  • Antineoplastic alkanna tinctoria ketoximes derivatives
  • Antineoplastic alkanna tinctoria ketoximes derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] 2-(1-Hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene 2

[0024] Under nitrogen protection, activated zinc powder (5 g, 0.077 mol) was placed in dry tetrahydrofuran (100 ml), bromoisoamyl (4 ml, 0.035 mol) was added dropwise, the reaction solution was stirred at room temperature for 1 hour, and the zinc powder was filtered off for later use.

[0025] 1,4,5,8-Tetramethoxynaphthalene-2-carbaldehyde (1.38g, 0.005mol) was dissolved in dry tetrahydrofuran (50ml), and the isopentenyl zinc bromide prepared above was added, and stirred at room temperature for 1 hour Afterwards, hexamethylphosphoric triamide (10 ml) was added, tetrahydrofuran was distilled off, and the reaction was carried out at 130° C. for 10 hours. After the reaction solution was cooled, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate (30ml×3), washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated to obtain a crude product, which...

Embodiment 2

[0027] 2-(1-oxo-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene 3

[0028] 2-(1-Hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene 2 (3.46 g, 0.01 mol) was dissolved in dichloromethane (100 ml), Dess-Martin oxidant (4.66 g, 0.011 mol) was added, and after stirring at room temperature for 4 hours, the reaction was stopped. Add saturated sodium bicarbonate solution (80ml), stir for 10 minutes, separate the organic layer, extract the aqueous layer with dichloromethane (50ml×3), combine the organic layers, wash with saturated brine, dry over anhydrous magnesium sulfate, evaporate solvent to obtain a crude product, which was separated by column chromatography (ether: n-hexane = 2:1) to obtain 2.66 g of bright yellow oil, with a yield of 77%. 1 H NMR (CDCl 3 )δ: 6.93(m, 3H), 5.48(t, J=7.2Hz, 1H), 3.98(s, 3H), 3.95(s, 3H), 3.90(s, 3H), 3.85(d, J=6.9 Hz, 2H), 3.78(s, 3H), 1.76(s, 3H), 1.65(s, 3H). ESI-MS m / z 399.05 (M+CH 3 OH+Na) + .

Embodiment 3

[0030] 2-(1-Hydroxyimino-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene 4

[0031] 2-(1-oxo-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene 3 (1.72g, 0.005mol) was dissolved in ethanol (70ml), added Hydroxylamine hydrochloride (0.70 g, 0.01 mol) and pyridine (2 ml) were refluxed for 0.5 hours, and the reaction was stopped. Cool to room temperature, distill off ethanol, add dichloromethane (30ml) and water (30ml) to the residue, shake, separate the organic layer, extract the aqueous layer with dichloromethane (30ml×2), combine the organic layers, and wash with saturated salt Wash with water, dry over anhydrous magnesium sulfate, and distill off the solvent to obtain a crude product, which is separated by column chromatography (ether: n-hexane = 1:1) to obtain 1.45 g of a near-colorless oil, with a yield of 81%. 1 H NMR (CDCl 3 )δ: 6.85(s, 2H), 6.72 a , 6.58 b (s, 1H), 5.25 a , 5.16 b (t, J=7.2Hz, 1H), 3.96(s, 3H), 3.93(s, 3H), 3.91(s, 3H), 3.80 a , 3.77 b (s,...

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Abstract

The invention discloses lithospermum ketoxime derivant which can be used for resisting tumour in the technology field of medicine. The lithospermum ketoxime derivant is 5, 8-dimethoxy-1, 4-naphthoquinone derivant which is replaced by 6-, and has the following structural formula, wherein, R is alkyl and aralkyl. The lithospermum ketoxime derivant is synthesized, and the antitumor activity thereof is measured; alkannin is structurally modified and reorganized, so that an antitumor compound with lowered toxicity and increased water-solubility is obtained.

Description

technical field [0001] The invention relates to a class of derivatives in the technical field of medicine, in particular to a class of shikonone oxime derivatives which can be used for antitumor. Background technique [0002] Many antineoplastic drugs currently used clinically are natural products or are derived from natural products, such as camptothecin, vinblastine, and vincristine. Shikonin compounds are a class of natural products that widely exist in nature. Many studies have shown that these compounds have significant anti-tumor activity, but so far no such compounds have been used clinically as anti-tumor drugs. This is mainly because The application of these compounds is limited because of their toxicity and poor water solubility. The toxicity of shikonin may come from two aspects: (1) The alkylation of naphthoquinone under the action of biological reducing agent to remove the hydroxyl group of the side chain leads to extensive cytotoxicity. (2) The complexation o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C251/40C07C249/08A61K31/15A61P35/00
Inventor 李绍顺赵立明
Owner SHANGHAI JIAO TONG UNIV
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