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Water-soluble alpha-naphthoflavone alcohol derivative as well as preparation method and application thereof

A technology of naphthoflavone alcohol and naphthoflavone alcohol hydroxy alkyl ether is applied in the field of water-soluble α-naphthoflavone alcohol derivatives and preparation thereof, and can solve the problems of limited application, poor solubility and the like, and achieves simple operation, easy availability of raw materials, The effect of high reaction yield

Active Publication Date: 2014-09-24
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The inventor used α-naphthoflavone as a precursor to synthesize an inhibitor with strong inhibitory activity and high selectivity to CYP1B1 enzymes (invention patent application publication number: CN 102993157 A); but these compounds are similar to α-naphthoflavone, and they are Poor solubility in water, limiting their use as pharmaceuticals

Method used

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  • Water-soluble alpha-naphthoflavone alcohol derivative as well as preparation method and application thereof
  • Water-soluble alpha-naphthoflavone alcohol derivative as well as preparation method and application thereof
  • Water-soluble alpha-naphthoflavone alcohol derivative as well as preparation method and application thereof

Examples

Experimental program
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Embodiment 1

[0034] This embodiment relates to a preparation method of 6,7,10-trimethoxy-α-naphthalene flavonol (II-1) with structural formula (II), such as figure 1 shown, including the following steps:

[0035] Step 1: Dissolve 2-acetyl-4,5,8-trimethoxy-1-naphthol in anhydrous N,N'-dimethylformamide, add 2.0 equivalents of sodium hydride and 1.6 equivalents Chloromethyl methyl ether, after stirring at room temperature for 3h, adding saturated sodium bicarbonate solution to quench the reaction, CH 2 Cl 2 Extract and combine the organic layers. The organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated, and silica gel column chromatography to obtain 4,5,8-trimethoxy-2-acetyl-1-naphthol methoxymethyl ether, It was a yellow solid with a yield of 92%. 1H NMR (300MHz, CDCl 3 ): δ6.99(s, 1H, H-C(2)), 6.93(d, J=8.7Hz, 1H), 6.88(d, J=8.7Hz, 1H), 5.01(s, 2H, OCH 2 O), 3.96(s, 3H, OCH 3 ), 3.93 (s, 3H, OCH 3 ), 3.90 (s, 3H, OC...

Embodiment 2

[0041] This embodiment relates to a preparation method of 2'-fluoro-6,7,10-trimethoxy-α-naphthalene flavonol (II-2) with structural formula (II), such as figure 1 shown, including the following steps:

[0042] The steps of this example are the same as the steps of Example 1, and in step 2, 2-fluorobenzaldehyde is used instead of benzaldehyde. The product was yellow crystals with a total yield of 15%. 1 H NMR (400MHz, d 6 -DMSO): δ9.49(s, 1H, OH), 7.86(t, J=6.9Hz, 1H), 7.63(m, 1H), 7.43(m, 2H), 7.33(s, 1H, H-C(5 )), 7.27(d, J=8.6Hz, 1H), 7.22(d, J=8.6Hz, 1H), 3.96(s, 3H, OCH 3 ), 3.84(s, 6H, OCH 3 ).

Embodiment 3

[0044] This embodiment relates to a preparation method of 3'-fluoro-6,7,10-trimethoxy-α-naphthalene flavonol (II-3) with structural formula (II), such as figure 1 shown, including the following steps:

[0045] The steps of this example are the same as those of Example 1, and in step 2, 3-fluorobenzaldehyde is used instead of benzaldehyde. The product was yellow crystals with a total yield of 13%. 1 H NMR (400MHz, d 6 -DMSO): δ10.03(s, 1H, OH), 8.33(d, J=7.9Hz, 1H, H-C(2')), 8.23(d, J=11.4Hz, 1H, H-C(6')) , 7.68(dd, J=14.7, 7.9Hz, 1H, H-C(5')), 7.37(m, 1H, H-C(4')), 7.31(s, 2H), 7.30(s, 1H, H-C(5') )), 4.09(s, 3H, OCH 3 ), 3.96 (s, 3H, OCH 3 ), 3.85(s, 3H, OCH 3 ).

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Abstract

The invention relates to a water-soluble alpha-naphthoflavone alcohol derivative as well as a preparation method and application thereof. A structural formula of the water-soluble alpha-naphthoflavone alcohol derivative is shown in a formula (I) shown in the specification, wherein R represents hydrogen or amino carboxylic ester of fatty alcohol and a physiologically acceptable salt thereof, and R1, R2 and R3 are respectively hydrogen or halogen. The invention further relates to a preparation method for the water-soluble alpha-naphthoflavone alcohol derivative and application thereof. The water-soluble alpha-naphthoflavone alcohol derivative can inhibit activity of body CYP1B1 enzyme, so that inhibitory activity of part of the compounds is far higher than that of the alpha-naphthoflavone; the water-soluble alpha-naphthoflavone alcohol derivative can be used for preventing malignant tumors. The water-soluble alpha-naphthoflavone alcohol derivative and anti-tumor drugs are combined for use, so that anti-tumor drug resistance caused by CYP1B1 can be overcome.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a water-soluble α-naphthalene flavonol derivative and a preparation method and application thereof. Background technique [0002] CYP1B1 enzymes are a subtype of the CYP1 family that are mainly expressed outside the liver. It can metabolize estradiol to 4-hydroxyestradiol, which plays a key role in the development of estradiol-induced breast cancer (Cavalieri et al, Proc.Natl.Acad.Sci.US4, 1997 , 94: 10937-10942). In addition, CYP1B1 enzyme is involved in the metabolic activation of polycyclic aromatic hydrocarbon pro-carcinogens such as benzopyrene, and is a factor in inducing tumors. A large number of recent studies have confirmed that CYP1B1 enzymes are highly expressed in tumor tissues such as breast cancer, ovarian cancer, prostate cancer, liver cancer, lung cancer, and kidney cancer, while the expression level in corresponding normal cells is low. The import...

Claims

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Application Information

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IPC IPC(8): C07D311/92A61K31/352A61P35/00A61K31/337
CPCA61K31/337A61K31/352C07D311/92Y02P20/55
Inventor 李绍顺崔庆孟青青崔家华
Owner SHANGHAI JIAO TONG UNIV
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