Novel topoisomerase I inhibitor and pharmaceutical compositions thereof as well as preparation methods and applications of novel topoisomerase I inhibitor and pharmaceutical compositions thereof

A technology of topozyme and drug, applied in the direction of drug combination, organic chemical method, separation/purification of carbonyl compound, etc.

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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there is nothing about these six compounds in the prior art as topoisomerase I inhibitors and their pharmaceutical compositions, their application in the preparation of drugs for the treatment of cancer and the complications caused by it, and in the preparation of functional foods reports on applications in

Method used

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  • Novel topoisomerase I inhibitor and pharmaceutical compositions thereof as well as preparation methods and applications of novel topoisomerase I inhibitor and pharmaceutical compositions thereof
  • Novel topoisomerase I inhibitor and pharmaceutical compositions thereof as well as preparation methods and applications of novel topoisomerase I inhibitor and pharmaceutical compositions thereof
  • Novel topoisomerase I inhibitor and pharmaceutical compositions thereof as well as preparation methods and applications of novel topoisomerase I inhibitor and pharmaceutical compositions thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of three compounds of Eucalyptus globulus heteroterpene A (Globulusal A), Macrocarpal A and Macrocarpal B:

[0032]Take blue eucalyptus fruit (6.0kg), crush it, and extract it by cold soaking in ethyl acetate for 3 times, each time for 48 hours, combine the extracts, recover the solvent under reduced pressure to obtain extract (550g). The extract was mixed with silica gel 80-100 mesh, followed by silica gel (200-300 mesh) column chromatography, the eluent was petroleum ether-acetone (30:1→1:1, v / v) gradient elution, TLC Detection combined to obtain nine components Fr.1-Fr.9. Fr.9 (40g) was subjected to Rp-18 reverse phase column chromatography (MeCN–H 2 O, 50:50 → 100:0 v / v) yielded 6 fractions (Fr.9a–Fr.9f). Fr.9d (1.8g) was chromatographed by Sephadex LH-20 (CHCl 3 –MeOH, 1:1v / v) followed by reverse phase semi-preparative HPLC (MeCN–H 2 O, containing 0.01% TFA, 80:20→95:5v / v) was further purified to obtain eucalyptus heteroterpene A (1, 9.0mg). Compou...

Embodiment 2

[0034] Preparation of a compound of Eucalyptin A:

[0035] Take blue eucalyptus fruit (6.0kg), crush it, and extract it by cold soaking in ethyl acetate for 3 times, each time for 48 hours, combine the extracts, recover the solvent under reduced pressure to obtain extract (550g). The extract was mixed with silica gel 80-100 mesh, followed by silica gel (200-300 mesh) column chromatography, the eluent was petroleum ether-acetone (30:1→1:1, v / v) gradient elution, TLC Detection combined to obtain nine components Fr.1-Fr.9. Fr.5 (20g) by Sephadex LH-20 (CHCl 3 -MeOH, 3:2v / v) after removing fatty acid, it was subjected to Rp-18 reverse phase column chromatography (MeCN–H 2 O, 60:40 → 100:0 v / v) yielded 6 fractions (Fr.5a–Fr.5f). Fr.5e (50mg) was reversed phase semi-preparative by HPLC (MeCN–H 2 O, H 2 O containing 0.01% TFA, 75:25→95:5 v / v) was further purified to obtain Eucalyptin A (6, 13 mg).

Embodiment 3

[0037] Preparation of two compounds Eucalrobusone C and Eucarobustol C:

[0038] Take blue eucalyptus fruit (6.0kg), crush it, and extract it by cold soaking in ethyl acetate for 3 times, each time for 48 hours, combine the extracts, recover the solvent under reduced pressure to obtain extract (550g). The extract was mixed with silica gel 80-100 mesh, followed by silica gel (200-300 mesh) column chromatography, the eluent was petroleum ether-acetone (30:1→1:1, v / v) gradient elution, TLC Detection combined to obtain nine components Fr.1-Fr.9. Fr.4 (30g) by Sephadex LH-20 (CHCl 3 -MeOH, 3:2v / v) after removing fatty acid, it was subjected to Rp-18 reverse phase column chromatography (MeCN–H 2 O, 60:40 → 100:0 v / v) yielded 5 fractions (Fr.4a–Fr.4e). Fr.4d (128mg) was reversed phase semi-preparative by HPLC (MeCN–H 2 O, H 2 O containing 0.01% TFA, 90:10→99:1 v / v) was further purified to give Eucalrobusone C (2, 8.2 mg) and Eucarobustol C (3, 6.5 mg).

[0039]

[0040] Phys...

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Abstract

The invention relates to formyl phloroglucinol hetero terpenoids separated out from fruit of eucalyptus globulus, pharmaceutical compositions taking the formyl phloroglucinol hetero terpenoids as active components, preparation methods of the formyl phloroglucinol hetero terpenoids and the pharmaceutical compositions as well as applications of the formyl phloroglucinol hetero terpenoids and the pharmaceutical compositions in preparation of medicines for treating tumors and in preparation of functional health care products. The methods provided by the invention are easy in obtaining of raw materials, simple and easy to operate; biological experiments prove that the obtained compounds have better activity of inhibiting the growth of tumor cells; furthermore, the compounds 1, 2, 3 and 5 have aDNA inhibiting topoisomerase I (TOP1) activity similar to camptothecin, and the compounds 1 and 4 have a better activity of promoting cancer cell apoptosis.

Description

Technical field: [0001] The invention belongs to the field of medicines, and in particular relates to formylphloroglucinol heteroterpenes isolated from Eucalyptus globulus and pharmaceutical compositions thereof, their application in preparing medicines for treating cancer, and their use in preparing functional foods in the application. Background technique: [0002] Cancer is a disease that seriously threatens human health and life. In recent years, the morbidity and mortality of cancer have shown a sharp increase. According to the report of the World Health Organization, by 2030, the number of cancer patients worldwide is expected to increase by 21 million, and the annual number of cancer deaths will reach 13.2 million (Wong A.S.T., et al. Nat. Prod. Res. 2015,32:256–272 ). At present, most of the chemotherapy drugs used clinically are cytotoxic components, which have obvious selectivity to various cancer cells; in the process of eliminating cancer cells, such component...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/78C07C45/79C07C45/80C07C45/81C07C49/86C07C49/583C07C47/57A61K31/12A61K31/11A61P35/00A61P35/02
CPCA61K31/11A61K31/12C07B2200/07C07C47/57C07C49/583C07C49/86
Inventor 刘海洋倪伟金玲钰严欢刘晖
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