6-position derivatives of phenanthrene and indolizidine alkaloids and their preparation, anti-plant virus and anti-cancer activities

A technology for phenanthroindolizidine and alkaloids, which is applied to the 6-position derivatives of phenanthroindolizidine alkaloids and the fields of their preparation, anti-plant virus and anti-cancer activities, and can solve the problem of 6-position substituents. The lack of reports on the application of anti-cancer activity, the lack of reports on the effect of the 6-position substituent activity, and the unfavorable practical application, etc., achieve the effects of excellent anti-plant virus activity, high in vitro anti-TMV activity, and good in vivo activity

Active Publication Date: 2020-08-07
NANKAI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the reported synthesis method cannot be prepared in large quantities, there is a lack of reports on the impact of the 6-position substituent of 6-O-demethylantorphine (2) on the activity. The previous patent (CN 103923134 A) and the paper ( Wu Meng. Synthesis, structural modification, biological activity and structure-activity relationship of phenanthrene and indolizidine alkaloids. Doctoral dissertation. School of Chemistry, Nankai University. 2012.) published 6-O-demethylation Antoin The preparation and anti-plant virus activity of the 6-base glycosylation product of fen (2), but the complex synthetic route is not conducive to practical application, and there is also a lack of reports on the anti-cancer activity of the 6-position substituent and its application in medicine

Method used

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  • 6-position derivatives of phenanthrene and indolizidine alkaloids and their preparation, anti-plant virus and anti-cancer activities
  • 6-position derivatives of phenanthrene and indolizidine alkaloids and their preparation, anti-plant virus and anti-cancer activities
  • 6-position derivatives of phenanthrene and indolizidine alkaloids and their preparation, anti-plant virus and anti-cancer activities

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: phenanthrene and indolizidine alkaloid 6-position carboxylic acid derivative (I a )Synthesis

[0027]

[0028] Compound (R / S)-6-O-desmethylantorphine was dissolved in anhydrous dichloromethane, EDCI, TEA, different acids and DMAP were added respectively, and reacted at room temperature for 10 h. After the reaction was detected by TLC, saturated ammonium chloride was added, separated, the organic phase was washed with saturated NaCl, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound Ia.

[0029] Compound I a -1

[0030] Yield: 80%. Pale yellow solid. Melting point: 218-219°C. 1 H NMR (400MHz, CDCl 3)δ8.16(d, J=2.4Hz, 1H), 7.89-7.87(m, 2H), 7.30-7.27(m, 2H), 4.69(d, J=14.8Hz, 1H), 4.13(s, 3H ), 4.08(s, 3H), 3.69(d, J=14.8Hz, 1H), 3.51-3.46(m, 1H), 3.34(dd, J=16.0Hz, 2.4Hz, 1H), 2.93-2.87(m , 1H), 2.71-2.65(m, 1H), 2.48-2.42(m, 2H), 2.29-2.18(m, 3H), 2.10-2.00(m, 1H), 1.97-1.88(m, 3H), 1.82 -1.66(m, 4H),...

Embodiment 2

[0071] Embodiment 2: the phenanthrene and indolizidine alkaloid derivative (I b )Synthesis

[0072]

[0073] Dissolve 6-O-(2-hydroxyethyl) desmethylantorphine in anhydrous dichloromethane, add EDCI (2equiv), TEA (2equiv), Boc protected amino acid (lequiv) and DMAP (0.2equiv ), react at room temperature for 10h. After the reaction was detected by TLC, saturated ammonium chloride was added, separated, the organic phase was washed with saturated NaCl, dried over anhydrous sodium sulfate, and separated by column chromatography (CH 2 Cl 2 :MeOH=40:1) to obtain the compound, the compound was dissolved in dichloromethane (20mL), TFA (20equiv) was added dropwise, reacted at room temperature for 1h, and the reaction solution was poured into saturated NaHCO 3 middle, liquid separation, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with NaCl, dried over anhydrous sodium sulfate, and spin-dried to obtain compound I b .

[0074] Comp...

Embodiment 3

[0094] Embodiment 3: the assay of anti-tobacco mosaic virus activity, assay procedure is as follows:

[0095] 1. Virus purification and concentration determination:

[0096] Virus purification and concentration determination were carried out in accordance with the SOP specification for tobacco mosaic virus compiled by the Bioassay Laboratory of the Institute of Elements, Nankai University. After the crude virus extract was centrifuged twice with polyethylene glycol, the concentration was measured and refrigerated at 4°C for later use.

[0097] 2. Compound solution preparation:

[0098] After weighing, the original drug was dissolved in DMF to prepare 1×10 5 μg / mL mother solution, and then diluted with 1‰ Tween 80 aqueous solution to the required concentration; Ningnanmycin preparation was directly diluted with water.

[0099] 3. In vitro effect:

[0100] Rub inoculation of leaves of Shanxi tobacco at the right age, rinse with running water, the virus concentration is 10 μg...

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Abstract

The invention relates to 6-position derivatives of phenanthroindolizidine alkaloids, preparation of the 6-position derivatives and applications of the 6-position derivatives to anti-plant-virus and anti-cancer aspects. Each group in a formula is defined in the description. The 6-position derivatives of the phenanthroindolizidine alkaloids show particularly excellent anti-plant-virus activity, can well inhibit TMV (tobacco mosaic virus), show good anti-cancer activity and can well inhibit human lung adenocarcinoma A-549 and human hepatoma BEL-7402.

Description

technical field [0001] The invention relates to 6-position derivatives of phenanthrene and indolizidine alkaloids, a preparation method thereof, and anti-plant virus and anti-cancer applications. Background technique [0002] In 1935, the first phenanthrene and indolizidine alkaloid - tylophorine (tylophorine) was isolated and identified .Indian J.Med.Res., 1935, 22:433-441.], due to its unique chemical structure, significant biological activity, it has been widely concerned by chemists at home and abroad. Phenanthrene and indolizidine alkaloids mainly exist in four families of plants: Asclepiadaceae, Moraceae, Acanthaceae and Lauraceae. Among them, the most important ones are the plants of the Romoaceae. In this family, five genera of plants have been found to contain phenanthroindolizidine alkaloids, namely: Tylophora, Cyanchum, The genera Pergularia, Vinceto-xicum and Antitoxicum. Phenanthrene and indolizidine alkaloids have been found to have a wide range of biologica...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A01N43/90A01P1/00A61K31/4745A61P35/00
CPCA01N43/90C07D471/04
Inventor 汪清民韩贵芳刘玉秀王兹稳宋红健陈琳伟谢佳林吴萌
Owner NANKAI UNIV
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