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Acenaphthene heterocyclic compounds and application thereof

A compound and heterocyclic technology, applied in the field of acenaphthoheterocyclic Bcl-2 family protein inhibitors, can solve the problems of insufficient BH3 similarity, complex apoptosis signaling pathway, toxic and side effects, etc.

Inactive Publication Date: 2012-01-18
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But they all have shortcomings: Gossypol and Obatoclax have insufficient BH3 similarity, and are not absolute BH3 analogs, that is, they have cytotoxicity independent of BAX / BAK, indicating that there are other targets, so they have toxic side effects
However, as a potential anti-tumor drug based on apoptosis, its development also faces difficulties in the development of such drugs: the complexity of the apoptosis signaling pathway, the potential strong cytotoxicity and the blindness of drug use that will inevitably result. This is an important reason for the failure of the development of such drugs

Method used

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  • Acenaphthene heterocyclic compounds and application thereof
  • Acenaphthene heterocyclic compounds and application thereof
  • Acenaphthene heterocyclic compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: 3-(4-sec-butylphenoxy)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (compound 1) and 4-(4-sec-butyl Synthesis and Characterization of Phenoxy)phenoxy-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (Compound 2)

[0054]

[0055] Weigh 0.99g of 5-(4-sec-butylphenoxy)acenaphthenequinone, dissolve 0.33g of malononitrile in dichloromethane, add to the silica gel column, rinse quickly, spin dry after passing through the column to obtain a red solid. Weighed 1.07g, yield 94%. Get 0.77g gained red solid, add 0.05g K 2 CO 3 , 20ml of acetonitrile was heated to reflux for 3 hours, and the reaction solution was spin-dried after the reaction was completed. Chromatographic column separation (CH 2 Cl 2 : petroleum ether=1:1) to obtain two isomers.

[0056] Compound 1: M.p.219-220°C. 1 H NMR (400M, CDCl 3 ): δ8.92(d, J=8.0Hz, 1H), 8.65(d, J=8.8Hz, 1H), 8.46(d, J=8.0Hz, 1H), 7.87(t, J=8.0Hz, 1H ), 7.33(d, J=8.4Hz, 2H), 7.14(d, J=8.4Hz, 2H), 7.04(d, J=8.0Hz,...

Embodiment 2

[0058] Example 2: 3-(4-isobutylphenoxy)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (compound 3) and 4-(4-isobutyl Synthesis and Characterization of Phenoxy)phenoxy-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (Compound 4)

[0059]

[0060] Weigh 0.99g of 5-(4-isobutylphenoxy)acenaphthenequinone, dissolve 0.33g of malononitrile in dichloromethane, add to a silica gel column, rinse quickly, spin dry after passing through the column to obtain a red solid. Weighed 1.07g, yield 94%. Get 0.77g gained red solid, add 0.05g K 2 CO 3 , 20ml of acetonitrile was heated to reflux for 3 hours, and the reaction solution was spin-dried after the reaction was completed. Chromatographic column separation (CH 2 Cl 2 : petroleum ether=1:1) to obtain two isomers.

[0061] Compound 3: M.p.214-215°C. 1 H NMR (400M, CDCl 3 ): δ8.78(d, J=7.6Hz, 1H), 8.60(d, J=8.0Hz, 1H), 8.43(d, J=7.6Hz, 1H), 7.67(t, J=8.0Hz, 1H ), 7.29(d, J=8.0Hz, 2H), 7.12(d, J=8.0Hz, 2H), 6.95(d, J=8.0Hz, 1H),...

Embodiment 3

[0063] Example 3: Synthesis and characterization of 3-(4-isopropylphenoxy)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (compound 5)

[0064]

[0065] 1g of 8-oxo-8H acenaphtho[1,2-b]pyrrole-9-carbonitrile and 0.54g of p-isopropylphenol were added to 50 ml of acetonitrile, refluxed for 3 hours, the solvent was distilled off, and compound 5 was obtained by column chromatography. rate 30%.

[0066] Compound 5: M.p.272-274°C; 1 H NMR (400M, CDCl 3 ): δ8.92(d, J=8.0Hz, 1H), 8.25(d, J=8.8Hz, 2H), 8.44(d, J=8.0Hz, 1H), 7.86(t, J=8.0Hz, 1H ), 7.38(d, J=8.4Hz, 2H), 7.14(d, J=8.4Hz, 2H), 7.04(d, J=8.8Hz, 1H), 3.01(m, 1H), 1.32(d, J =8.0Hz, 6H); TOF MS EI + (m / z): C 24 h 16 N 2 o 2 , calculated value: 364.1212, measured value: 364.1215.

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Abstract

The invention relates to new acenaphthene heterocyclic compounds and application of the compounds in preparation of BH3 analogues Bcl-2 family protein inhibitors. The acenaphthene heterocyclic compounds have the structure of a general formula I as shown in the specification. The acenaphthene heterocyclic compounds are prepared by introducing various oxides, sulfides and carbonyl group, ester group and acyl group compounds on 3, 4 and 6 positions of 8-oxy-8-hydro-acenaphtho[1,2-b]pyrrole-9-nitrile or further replacing 9-nitrile as acid, ester, amido compounds. According to the invention, the acenaphthene heterocyclic compounds can perform in vitro and intracellular competitive bonds and antagonisms with Bcl-2 and Mcl-1 proteins through stimulating a BH3-only protein, thereby inducing apoptosis. The acenaphthene heterocyclic compounds can be used for preparing anticancer compounds.

Description

technical field [0001] The present invention relates to a series of novel acenaphthocyclic Bcl-2 family protein inhibitors and their analog BH3-only proteins in vivo and in vitro, which competitively bind and antagonize Bcl-2 and Mcl-1 proteins, thereby inducing cell apoptosis Apoptosis and application as an anticancer compound. Background technique [0002] Molecularly targeted antineoplastic drugs are becoming a hot spot in new drug development and a new generation of market-oriented products after cytotoxic antineoplastic drugs. Bcl-2 family proteins are the most important molecular targets for antagonizing and reversing the immortality of malignant tumors. Therefore, drugs that specifically antagonize Bcl-2 family proteins will achieve the goal of anti-cancer with high selectivity, safety, high efficiency, and no toxic side effects by specifically inducing tumor cell apoptosis. Among the Bcl-2 inhibitors, highly specific BH3 analogs (BH3mimetics) have the most signific...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/56A61K31/403A61P35/00
Inventor 张志超吴桂叶
Owner DALIAN UNIV OF TECH
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