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Jervine steroid alkaloid derivatives and preparation and application thereof

A technology of steroidal alkaloids and derivatives, which is applied in the field of medicine and can solve problems such as high toxicity

Inactive Publication Date: 2009-11-04
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Veratramine, another steroid alkaloid isolated from veratrum, has significant antitumor activity, but the compound is highly toxic. Intravenous and subcutaneous administration to mice, its LD 50 3.1 mg / kg and 4.5 mg / kg, respectively (Kiyoshi Tanaka, J. Pharma. Exp. Therapeutics. 1955, 113(1): 89-99)

Method used

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  • Jervine steroid alkaloid derivatives and preparation and application thereof
  • Jervine steroid alkaloid derivatives and preparation and application thereof
  • Jervine steroid alkaloid derivatives and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Put 25mg (0.06mmol) 3-carbonyl-Δ 4 -Veratramine was dissolved in 15 mL of methanol, and 18 mg (0.25 mmol) of hydroxylamine hydrochloride was added. Reflux for 4h. After the reaction was completed, it was concentrated to 2 mL and placed in a refrigerator. 111 mg of white crystals were precipitated with a yield of 42.4%.

[0032] Compound 1:

[0033] White powder, ESI-MS: m / z 423.3[M+H] + , 1H-NMR (400MHz, CD 3 OD, J / Hz) δ: 7.11 (d, 1H, J=13, H-16), 6.97 (d, 1H, J=13, H-15), 5.85 (s, 1H, H-4), 3.53 (m, 1H, H-20), 3.16 (m, 1H, H-23), 3.05 (t, 1H, J=7, H-6a), 2.98 (t, 1H, H-8), 2.85 (dd , 1H, J=4, H-26a), 2.77(dd, 1H, H-11), 2.48(m, 1H, H-23), 2.31(s, 3H, H-18), 2.08(t, 1H , J=4, H-26b), 2.00 (brs, 1H, H-24a), 1.50 (d, 3H, H-21), 1.18 (s, 3H, H-19), 1.05 (dd, 1H, H -24b) 0.83 (d, 3H, H-27); 13C-NMR (400MHz, CD 3 OD)δ: 157.5(C-5), 154.9(C-3), 144.7(C-12), 143.7(C-14), 141.2(C-17), 133.9(C-13), 126.5(C- 16), 120.5(C-15), 119.7(C-4), 71.7(C-23), 67.9(C-22), 61.5(C-9), 54.5(C-26), ...

Embodiment 2

[0040] Dissolve 100mg (0.24mmol) of veratramine in 10mL of acetone and add 0.3gK 2 CO 3 (2.4mmol) and 0.5mL (5.2mmol) of dimethyl sulfate (DMS), react at 25°C overnight. After the solvent was evaporated, 30 mL of water was added, and the mixture was extracted with 3×30 mL of ethyl acetate. The organic layer was washed with 30 mL of saturated brine and washed with anhydrous Na 2 SO 4 dry. The solvent was evaporated to obtain 102 mg of the crude product, which was separated by silica gel column to obtain compounds 6 (31 mg) and 7 (8 mg).

[0041] Compound 6: White powder, ESI-MS: m / z 438.3 [M+H]+ ;

[0042] Compound 7: White powder, ESI-MS: m / z 452.4 [M+H] + ;

[0043] The same experimental operation, except that the reactants were changed to fenfenamine and cyclopamine, respectively, and 8 and 9 were obtained correspondingly.

[0044] Compound 8: White powder, ESI-MS: m / z 454.3 [M+H] + ;

[0045] Compound 9: white powder, ESI-MS: m / z 440.4 [M+H] + ;

Embodiment 3

[0047] Dissolve 41mg (0.1mmol) veratramine in 8mL pyridine, add SOCl dropwise after cooling in ice water 2 0.2mL (2.8mmol), gradually increase the temperature to 25°C, and react overnight. TLC indicated that the reaction was over, 50mL ethyl acetate was added, washed with 3×30mL water, the organic layer was washed with 30mL saturated brine, and anhydrous Na 2 SO 4 dry. The solvent was evaporated to obtain 40 mg of crude product, which was separated by silica gel column to obtain compound 10 (20 mg).

[0048] The same experimental operation, except that the reactants were changed to fenfenamine and cyclopamine respectively, and 11 and 12 were obtained correspondingly.

[0049] Compound 10: white powder, ESI-MS: m / z 428.3 [M+H] + ;

[0050] Compound 11: white powder, ESI-MS: m / z 444.3[M+H] + ;

[0051] Compound 12: white powder, ESI-MS: m / z 430.4 [M+H] + ;

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Abstract

The invention provides jervine steroid alkaloid derivatives. Steroidal alkaloids, namely veratramine, jervine and cyclopamine are taken as raw materials, and subjected to chemical modification to obtain ninety-three derivatives, which comprise N-hydrocarbon and N-acylate. In the invention, cell lines such as human pancreatic cancer cells B*PC-3 and SW1990, a small cell lung cancer cell NCI-H466, a non-small cell lung cancer cell NCI-H157 and the like are selected, the antitumor activity of all compounds are evaluated by an MTT method, and results show that the derivatives 41, 43 and 58 have obvious antitumor activity, the other eight derivatives 10, 18, 19, 38, 45, 48, 50 and 92 also show medium antitumor activity, and the derivatives can be used for preparing antitumor medicaments.

Description

Technical field [0001] The invention relates to medicines, in particular to novel phenamine steroidal alkaloid derivatives, their preparation and their application in the preparation of anti-tumor medicines. Background technique [0002] Veratrum (Veratrum) is a Liliaceae (Liliaceae) plant, there are about 40 species in the world. Traditional Chinese medicine: V. nigrum L., V. dahuricum (Turcz.) Loes.f., V. Schindleri Loes. f., V. maackii Regel, The roots and rhizomes of Veratrum dali (V..taliense Loes.f.), V.grandiflorum (Maxim.)Loes.f., etc. are used as medicine for phlegm in stroke, epilepsy, blocked throat, and scabies Ringworm and malignant sores (Chinese Materia Medica (8). Shanghai Science and Technology Press, 1999, 183-188). Modern pharmacological studies have shown that veratrum alkaloids have blood pressure lowering and anti-tumor effects (Chinese Medicine Cihai (Volume IV). China Medical Science and Technology Press, 1998, 8-13; Xu Guojun, Xu Luoshan, Wang Zhengtao, e...

Claims

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Application Information

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IPC IPC(8): C07J69/00A61K31/58A61P35/00A61P1/18A61P11/00
Inventor 张卫东李慧梁汤建单磊柳润辉沈云亨苏娟徐希科
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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