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Antineoplastic sulfur-containing alkannin and naphthoquinones derivatives

A derivative, shikonin technology, applied in the field of derivatives in the field of medical technology, can solve the problems of limited application, toxicity, side effects, etc., and achieve the effect of inhibiting the growth of tumor cells

Inactive Publication Date: 2008-08-13
SHANGHAI JIAO TONG UNIV +1
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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 The use of these compounds is limited because of their toxicity
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 prior art literature, it is found that the structural modification of shikonin compounds is mainly to modify the hydroxyl on the side chain (Chinese patent, publication number: CN1420111) (Chinese patent, publication number: CN1112363), but The oxygen of the side chain hydroxyl is replaced by the electron isostere sulfur to modify it, but there is no report

Method used

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  • Antineoplastic sulfur-containing alkannin and naphthoquinones derivatives
  • Antineoplastic sulfur-containing alkannin and naphthoquinones derivatives
  • Antineoplastic sulfur-containing alkannin and naphthoquinones derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 2-(1-Hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene V1

[0037] Under nitrogen protection, activated zinc powder (5 g, 0.077 mol) was placed in dry 100 ml tetrahydrofuran, 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.

[0038] 1,4,5,8-Tetramethoxynaphthalene-2-carbaldehyde (1.38g, 0.005mol) was dissolved in dry 50ml tetrahydrofuran, and the isopentenyl zinc bromide prepared above was added, and stirred at room temperature for 1 hour, Add 10ml of hexamethylphosphoric triamide, distill off tetrahydrofuran, and react 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 was separated by column chromatography (ether: n-h...

Embodiment 2

[0040] 2-(1-Mercapto-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene VI1

[0041]2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene V1 (0.87g, 0.025mol), thiourea (0.38g, 0.005mol) and 48% hydrobromic acid (0.56ml) were dissolved in 30ml of ethanol, and after reflux for 2 hours, the ethanol was evaporated, and 20ml of ether and 20ml of water were added. Under the protection of nitrogen, 10 ml of 40% NaOH solution was added dropwise to the aqueous layer, and after the addition was completed, it was refluxed for 2 h. Cool to room temperature, acidify with 6M hydrochloric acid, extract with dichloromethane (3×15ml), combine the organic layers, wash with saturated brine, dry over anhydrous magnesium sulfate, distill off the solvent to obtain a crude product, separate by column chromatography (ether: n-hexane alkane=1:5) to obtain 0.79 g of 2-(1-mercapto-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene (VI1), with a yield of 87%. 1 H NMR (CDCl 3 )δ: 7.01(...

Embodiment 3

[0043] Synthesis of 2-(1-alkanoylthio-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene VII1-VII15

[0044] 0.50mmol of 2-(1-mercapto-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene VI1 and 0.60mmol of carboxylic acid were dissolved in 10ml of dichloromethane, added DCC 0.75mmol and DMAP 0.25mmol were stirred overnight at room temperature under nitrogen. After the white precipitate was filtered off, the solvent was distilled off, and the crude product was separated by column chromatography to obtain a pale yellow oil.

[0045] 3.1.2-(1-acetylthio-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene VII1

[0046] Yield 94%. 1 H NMR (CDCl 3 )δ: 6.81(m, 3H), 5.29(t, J=7.2Hz, 1H), 5.05(t, J=7.2Hz, 1H), 3.92(s, 6H), 3.88(s, 3H), 3.78( s, 3H), 2.69 (m, 2H), 2.31 (s, 3H), 1.59 (s, 6H).

[0047] 3.2.2-(1-propionylthio-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene VII2

[0048] Yield 92%. 1 H NMR (CDCl 3 )δ: 6.80(m, 3H), 5.30(t, J=7.2Hz, 1H), 5.05(t, J=7.2Hz, 1H)...

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Abstract

The invention relates to an antineoplastic derivative of the medical technology field, which contains sulfur alkannin and naphthaquinone, i. e., 6-substituted 5, 8-dimethoxy-1, 4-naphthaquinone derivative and 2-substituted 5, 8-dimethoxy-1, 4-naphthaquinone derivative having a structure formula, wherein, R1 is 3-methyl-2-butenyl, methyl, n-propyl, n-pentyl; R2 is alkanoylindoles, aroyl and alkyl. The formula I is 6-substituted 5, 8-dimethoxy-1, 4-naphthaquinone and the formula II is 2-substituted 5, 8-dimethoxy-1, 4-naphthaquinone.

Description

technical field [0001] The invention relates to a derivative in the technical field of medicine, in particular to a class of sulfur-containing shikonin and naphthoquinone 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 use of such compounds is limited because of their toxicity. 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 s...

Claims

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Application Information

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IPC IPC(8): C07C327/06C07C323/22A61K31/255A61K31/122A61P35/00
Inventor 李绍顺赵立明谢天培何玉琴郭晓娟
Owner SHANGHAI JIAO TONG UNIV
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