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Synthesis of benzimidazole-containing naphthalimide derivatives and applications of benzimidazole-containing naphthalimide derivatives on cancer resistance

A technology of benzimidazole and naphthalimide, applied to medical preparations containing active ingredients, antineoplastic drugs, drug combinations, etc., to achieve good tumor inhibitory activity and cell selectivity

Inactive Publication Date: 2013-06-19
DALIAN UNIV OF TECH
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  • Abstract
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Problems solved by technology

The most famous derivatives that have been used clinically are amonafide (N-(β-dimethylaminoethyl)-3-amino-1,8-naphthalimide) and mitonafide (N-(β-di Methylaminoethyl)-3-nitro-1,8-naphthalimide), but did not enter clinical phase III because of its neurotoxic side effects

Method used

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  • Synthesis of benzimidazole-containing naphthalimide derivatives and applications of benzimidazole-containing naphthalimide derivatives on cancer resistance
  • Synthesis of benzimidazole-containing naphthalimide derivatives and applications of benzimidazole-containing naphthalimide derivatives on cancer resistance
  • Synthesis of benzimidazole-containing naphthalimide derivatives and applications of benzimidazole-containing naphthalimide derivatives on cancer resistance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Synthesis of N-butyl-4-(1H-benzo[d]imidazole-2-y1)-1,8-naphthalimide (derivative 3)

[0018] (1) Synthesis of 1,2-dihydroacenaphthylene-5-carbonaldehyde (2)

[0019]

[0020] In a zero-degree ice-water bath, add 10 mL (1.3 mol) of anhydrous DMF (treated with calcium hydride) to a 100 mL dry two-necked bottle, and slowly add 10 mL (1.0 mol) of DMF (treated with calcium hydride) to the reaction system with a constant pressure dropping funnel under magnetic stirring. POC13, remove the ice-water bath, react at room temperature for 1 hr, dissolve 4.0 g (26.0 mmol) of acenaphthene in 15 mL of anhydrous DMF, add dropwise into the reaction system, raise the temperature to 100 °C after the dropwise addition, continue the reaction for 8 hr, and trace to The response is complete. Cooled to room temperature, slowly poured into 200 mL of ice water under vigorous stirring, precipitated gray precipitate, filtered, dried to obtain 4.2 g of gray needle-like solid, yield: 88.9%. The...

Embodiment 2

[0033] N-(N',N'-dimethylaminoethyl)-4-(1H-benzo[d]imidazole-2-y1)-1,8-naphthalimide (derivative 1)

[0034]

[0035] Except using N,N-dimethylethylenediamine instead of n-butylamine, other preparation and purification methods are the same as in Example 1. Separated by silica gel column chromatography (column chromatography eluent: CH 2 Cl 2 :CH 3 OH=20:1) to obtain compound M1 as a yellow solid, yield: 88.9%. Melting point: 93.2-93.8°C.

[0036] HR-MS (m / z): C 23 h 20 N 4 o 2 , calculated value: 384.1586, measured value: 384.1588.

[0037] 1 HNMR(d 6 -DMSO, 400MHz): δ(ppm): 13.35(s, 1H), 8.76(d, J=8.8Hz, 1H), 8.63(d, J=7.6Hz, 1H), 8.58(d, J=6.8Hz , 1H), 8.37(d, J=7.6Hz, 1H), 8.00(dd, J 1 =6.0Hz,J 2 =5.6Hz, 1H), 7.74(m, 2H), 7.33(m, 2H), 4.19(t, J=7.2Hz, 2H), 2.60(t, J=7.2Hz, 2H), 2.27(s, 3H ).

Embodiment 3

[0039] N-(N'N'-diethylaminoethyl)-4-(1H-benzo[d]imidazole-2-y1)-1,8-naphthalimide (derivative 2)

[0040]

[0041] Except using N, N-diethylethylenediamine instead of n-butylamine, other synthesis and purification methods are the same as example 1, separated through silica gel column (column chromatography eluent is CH 2 Cl 2 :CH 3 OH=20:1) to obtain the target compound M2 as a yellow-green solid with a yield of 81.7% and a melting point of 149.9-150.6°C.

[0042] HR-MS (m / z): C 25 h 24 N 4 o 2 , calculated value: 412.1899, measured value: 412.1895.

[0043] 1 HNMR(d 6 -DMSO, 400MHz): δ(ppm): 13.22(s, 1H), 9.75(d, J=8.0Hz, 1H), 8.63(d, J=8.0Hz, 1H), 8.58(d, J=8.0Hz , 1H), 8.37(d, J=7.6Hz, 1H), 7.99(dd, J 1 =J 2 =8.0Hz, 1H), 7.84(d, J=7.6Hz, 1H), 7.66(d, J=7.6Hz, 1H), 7.32(m, 2H), 4.16(t, J=8.0Hz, 2H), 2.73(t, J=8.0Hz, 2H), 2.60(m, 4H), 0.99(s, 6H).

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Abstract

The invention relates to synthesis of benzimidazole-containing naphthalimide derivatives and applications of the benzimidazole-containing naphthalimide derivatives on cancer resistance, and belongs to the field of organic synthesis and pharmaceutical chemistry technology. The benzimidazole-containing naphthalimide derivatives are obtained through a method that a benzimidazole group is introduced into a fourth position of a naphthalene ring of naphthalimide. Experiments of proliferation inhibiting effects of the benzimidazole-containing naphthalimide derivatives on cancer cells adopt a microculture tetrozolium (MTT) reduction method and aim at MCF-7 human breast cancer cells, Hela human cervical cancer cells and PC12 rat adrenal medullary pheochromocytoma differentiated cells. Results of the experiments show that the benzimidazole-containing naphthalimide derivatives have the advantages of good inhibitory activity against cancer cells and good selectivity on cancer cells.

Description

technical field [0001] The invention relates to the synthesis of a 4-(1H-benzimidazole-2-y1)-1,8-naphthalimide compound and its application in tumor cells, belonging to the technical fields of organic synthesis and medicinal chemistry. Background technique [0002] Naphthalimide is a good precursor of DNA intercalator, and it is a research hotspot in recent years. The most famous derivatives that have been used clinically are amonafide (N-(β-dimethylaminoethyl)-3-amino-1,8-naphthalimide) and mitonafide (N-(β-di Methylaminoethyl)-3-nitro-1,8-naphthalimide), but because of its neurotoxic side effects, it has not entered clinical phase III. In order to improve the toxic and side effects and enhance the antitumor activity, the active site of naphthalimide is modified to synthesize new naphthalimide derivatives. The foreign Brana research group has reported a series of imidazonaphthimide derivatives, and the inhibitory activity of these derivatives to human colon cancer cells (...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04A61K31/496A61K31/473A61P35/00
Inventor 李晓莲林彦杰
Owner DALIAN UNIV OF TECH
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