Benzo-[k,l]thiaxanthene-3,4-dimethyl anhydride derivative-uridine conjugates, and preparation method and application thereof

A technology of dicarboxylic acid anhydrides and dicarboxylic acid anhydrides is applied in the fields of benzo[k,l]thioxanthene-3,4-dicarboxylic acid anhydride derivatives-uridine conjugates and the fields of preparation and application thereof, and can solve the problem of No use, etc.

Active Publication Date: 2015-05-13
杭州庆正鸿科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Through the retrieval and analysis of the background information related to the present invention, it is found that: up to now, all studies are derivatives with 1,8-naphthalimide as the parent structure As a potential drug for the treatment of tumors, there is no use of 1,8-naphthalimide derivatives-uridine conjugates or benzo[k,l]thioxanthene-3,4-dicarboxylic anhydride d

Method used

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  • Benzo-[k,l]thiaxanthene-3,4-dimethyl anhydride derivative-uridine conjugates, and preparation method and application thereof
  • Benzo-[k,l]thiaxanthene-3,4-dimethyl anhydride derivative-uridine conjugates, and preparation method and application thereof
  • Benzo-[k,l]thiaxanthene-3,4-dimethyl anhydride derivative-uridine conjugates, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: the preparation of compound (I)

[0049] Add 30.43mg (0.1mmol) of benzo[k,l]thioxanthene-3,4-dicarboxylic anhydride and 24.32mg (0.1mmol) of 2-aminouridine into 1.0mL of DMF, under argon protection In the presence of 25.79mg (0.1mmol, excess 25% mol) of DCC (dicyclohexylcarbodiimide), the solution was stirred and reacted at 35.5°C for 25.5 h, and the reaction progress was monitored by TLC (chloroform:methanol=9:1 , v / v) Rf = 0.55, then, naturally cool the reaction solution, filter the resulting precipitate—N,N-dicyclohexyl urea, and wash it with a small amount of acetone, and use the obtained filtrate to preparative thin-layer chromatography (HF254, 20×25 cm silica gel plate, 1.5 mm thick) for purification, using 9:1 volume ratio of chloroform:methanol as the eluent, washing the product band with ethanol, collecting the eluate and removing the ethanol with a rotary evaporator Dry in a vacuum oven at a temperature lower than 30°C to obtain 21.36 mg of a ye...

Embodiment 2

[0050] Embodiment 2: the preparation of compound (II)

[0051] 1) Synthesis of intermediate benzo[k,l]thioxanthene-3,4-dicarboximide-N-propionic acid

[0052] Dissolve 35.80 mg (0.085 mmol) of benzo[k,l]thioxanthene-3,4-dicarboxylic anhydride and 8.91 mg (0.1 mmol) of 3-alanine in 1.2 mL of DMF under the protection of argon , then stirred and refluxed for 6h, and TLC monitored the reaction process (chloroform:methanol=9:1, v / v) R f =0.65. DMF was removed at 60°C with a rotary evaporator, and the resulting residue was dissolved in a mixed solvent (chloroform:methanol=8:1, v / v), and then subjected to silica gel column chromatography, respectively with chloroform:methanol=15:1 , 14:1, and 10:1 were used as eluents, and 15 mg of yellow powder was finally isolated with a yield of 73%. 1 H NMR (600 MHz, DMSO-d 6 ): δ 8.43 (d, J 5,6 = 8.4, 1H, 5-H), 8.42 (d, J 1,2 = 8.4, 1H, 2-H), 7.68-7.71 (m, 2H, 1-H, 6-H), 7.57 (d, J 7,8 =7.2, 1H, 7-H), 7.47-7.52 (m, 3H, 8-H, 9-H, 10-H), ...

Embodiment 3

[0055] Embodiment 3: the preparation of compound (Ⅲ)

[0056] The synthetic route of compound (Ⅲ) was the same as that of compound 2, using 6-aminocaproic acid instead of 3-aminopropionic acid to obtain 36 mg of yellow powder with a yield of 56.0%. 1 HNMR (600 MHz, DMSO-d 6 ): δ 8.47 (d, J 5”,6” = 7.2, 1H, 5”-H), 8.29 (d, J 1”,2” = 7.8, 1H, 2”-H), 7.88 (d, J 6,5 = 8.4, 1H, 6-H), 7.70-7.74 (m, 3H, 1”-H, 6”-H), 7.58 (d, J 7”,8” = 7.8, 1H, 7”-H), 7.47-7.53 (m, 3H, 8”-H, 9”-H, 10”-H), 5.88 (d, J 1’,2’ = 9, 1H, 1’-H), 5.67 (d, J 5,6 = 7.2, 1H, 5-H), 5.17 (d, J 5’,4’ = 5.4, 1H, 5'-OH), 4.48-4.52 (m, 1H, 2'-H), 4.05-4.07 (m, 1H, 3'-H), 3.97-3.99 (m, 1H, ε-H ), 3.915-3.917 (m, 1H, 4'-H), 3.55-3.60 (m, 2H, 5'-H), 2.13-2.15 (m, 2H, α-H), 1.56-1.61 (m, 2H , δ-H), 1.46-1.51 (m, 2H, β-H), 1.23-1.29 (m, 2H, γ-H); FAB-Mass: m / z calculated for C 33 h 30 N 4 o 8 S: 642.18; found: 643[M+H] + .

[0057]In the following examples, Compound 1, Compound 2, and Compound 3 refer to Com...

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Abstract

The invention relates to benzo-[k,l]thiaxanthene-3,4-dimethyl anhydride derivative-uridine conjugates, and a preparation method and application thereof. According to the invention, benzo-[k,l]thiaxanthene-3,4-dicarboamide parent ring having the properties of a DNA intercalator is conjugated with uridine having important biological activity to construct 3 novel target compounds. The above 3 target compounds are applied to research on the selective combining capacity of the promoter activation DNA sequence of the proto-oncogene c-myc highly expressed in some tumor cells at the extracellular molecule level; the above 3 target compounds are applied to research at the cell level, and research results show that all the three compounds have certain effects on killing two tumor cells, wherein compound 1 shows the strongest effect on killing the tumor cells; and the 3 compounds have substantial significance on the research and development of antitumor gene-targeted drugs having down-regulated c-myc gene and mediated by the benzo-[k,l]thiaxanthene-3,4-dimethyl anhydride derivative-uridine conjugates.

Description

technical field [0001] The invention relates to a novel benzo[k,l]thioxanthene-3,4-dicarboxylic anhydride derivative-uridine conjugate and its application in the preparation of antitumor drugs. Background technique [0002] The precursors of benzo[k,l]thioxanthene-3,4-dicarboxylic anhydride derivatives, 1,8-naphthoimides, are a class of small molecules with good antitumor activity and have been widely studied Synthetic compounds, whose main feature is a conjugated planar aromatic structure, have excellent intercalation properties for DNA, and can be embedded in the middle of DNA base pairs, resulting in changes in the topological structure of DNA, thereby affecting the recognition of DNA by topoisomerase II And role, it is often used as a DNA intercalator. In addition, there are coplanar fluorescent chromophores in its structure, which can be used as a specific DNA fluorescent probe after being embedded in DNA. The development of 1,8-naphthalimide compounds began in the ...

Claims

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Application Information

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IPC IPC(8): C07D495/06A61K31/4743A61P35/00
CPCC09B57/08A61K47/54A61K47/549C07H19/06C07D495/06
Inventor 张文吴艳玲李子健刘佳春王岩丽
Owner 杭州庆正鸿科技有限公司
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