CN112110818B - Malus spectabilis ketone 3-position modified derivative and application thereof in preparation of antitumor drugs - Google Patents
Malus spectabilis ketone 3-position modified derivative and application thereof in preparation of antitumor drugs Download PDFInfo
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Abstract
The structure of the modified derivatives at the 3-position of the begonine is shown as a formula (I), and X is selected from
Or R' - (I-2), R is selected from C 1 ～C 4 Saturated alkyl, allyl, phenyl, 4-chlorophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl; r' is selected from methyl, ethyl and benzyl. Also provides the application of any of the crabapple ketone 3-position modified derivatives in preparing antitumor drugs.
Description
Technical Field
The invention relates to abietane diterpenoid compounds and application thereof in preparation of medicines.
Background
Tripterygium hypoglaucum
Hutch) is a plant of the genus Tripterygium of the family Celastraceae, and the rhizome of Tripterygium is used as a medicine, so that the medicine has the effects of dispelling wind-dampness, removing blood stasis, dredging collaterals and promoting reunion of fractured bones. The medicinal part of the compound contains various abietyl diterpenoid compounds, and the research on the chemical composition of the rhizome of the Begonia kunming, which is a certain Chinese literature on the anti-tumor activity of the abietyl diterpenoid compounds in the report of the prior art (Song Jiang and the like, journal of Chinese herbal medicines, 11 months in 2019, 5395-5399) discloses the abietyl diterpenoid compounds-3β -hydroxy-4 hydroxymethyl-abietyl-8, 11, 13-trien-7-one (named as begonia ketone in this document) having the following structural formula:
Disclosure of Invention
In order to solve the problems, a series of novel compounds are obtained by carrying out chemical modification on the 3-position substituent group of the maltulin. The invention also provides a technical scheme based on the finding that the compound has a certain inhibition activity on various tumor cells and a very strong inhibition effect on certain specific tumors, and the technical scheme provided by the invention is as follows:
the 3-modified derivative of the crab apple ketone has the structure shown in the following formula (I):
The 3-position modified derivative of the begonia ketone is selected from the following compounds:
3β -oxy- (acetyl) -4 hydroxymethyl-ajoene-8, 11, 13-trien-7-one (I-a)
3β -oxy- (pivaloyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-b)
3β -oxy- (isovaleryl) -4 hydroxymethyl-ajoene-8, 11, 13-trien-7-one (I-c)
3β -oxy- (acryl) -4 hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-d)
3β -oxy- (benzoyl) -4-hydroxymethyl-ajoene-8, 11, 13-trien-7-one (I-e)
3β -oxy- (4-chloro-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-f)
3β -oxy- (4-methyl-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-g)
3β -oxy- (4-trifluoromethyl-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-h)
3β -oxy- (4-hydroxy-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-I)
3β -oxy- (4-cyano-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-j)
3β -oxy- (4-nitro-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-k)
3β -oxo- (4-methoxy-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-l)
3β -methoxy-4-hydroxymethyl-ajuga-8, 11, 13-trien-7-one (I-m)
3β -ethoxy-4-hydroxymethyl-ajo-rosin-8, 11, 13-trien-7-one (I-n)
3β -benzyloxy-4-hydroxymethyl-abietyl-8, 11, 13-triene-7-one (I-o)
The 3-position modified derivative of the begonia ketone is preferably the following compound:
3β -oxy- (acetyl) -4 hydroxymethyl-ajoene-8, 11, 13-trien-7-one (I-a)
3β -oxy- (benzoyl) -4-hydroxymethyl-ajoene-8, 11, 13-trien-7-one (I-e)
3β -oxy- (4-chloro-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-f)
3β -oxy- (4-hydroxy-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-I)
3β -benzyloxy-4-hydroxymethyl-abietyl-8, 11, 13-triene-7-one (I-o)
The invention also provides application of any of the begonia ketone 3-position modified derivatives in preparation of antitumor drugs.
The application further comprises the steps of enabling the tumor to be non-small cell lung cancer, colorectal cancer and pancreatic cancer, preferably non-small cell lung cancer, wherein the 3-position modified derivative of the begonine is selected from the group consisting of a compound (I-a), a compound (I-e), a compound (I-f), a compound (I-I) and a compound (I-o).
The invention also provides a preparation method of the begonia ketone 3-position modified derivative, which is characterized by comprising the following steps of:
the method comprises the following steps of
1) Dissolving maltulin with pyridine, adding triphenylchloromethane (TrCl) and Dimethylaminopyridine (DMAP) into the reaction solution, stirring the reaction solution at room temperature overnight, and detecting the reaction completion by TLC; concentrating a large amount of pyridine under reduced pressure, adding a large amount of dichloromethane to the residue for dilution, and washing the organic phase with equal volume of 10% citric acid water, saturated sodium bicarbonate water solution and saturated saline water in sequence; drying and concentrating the organic phase to obtain a crude product of the compound (VI);
2) Dissolving the compound (VI) obtained in the step 1) in pyridine, and then adding acetic anhydride and Dimethylaminopyridine (DMAP) into the reaction solution; stirring the reaction solution at room temperature overnight, and detecting that the reaction is complete by TLC; concentrating a large amount of pyridine under reduced pressure, adding a large amount of dichloromethane to the residue for dilution, and washing the organic phase with equal volume of 10% citric acid water, saturated sodium bicarbonate water solution and saturated saline water in sequence; drying and concentrating the organic phase to obtain a crude product of the compound (V);
3) Dissolving a crude product of a compound (V) in tetrahydrofuran, adding a palladium-carbon catalyst into the reaction solution, vacuumizing the reaction solution, introducing hydrogen, and stirring the reaction solution at room temperature overnight; TLC monitoring reaction is complete; the reaction solution was filtered to remove palladium on carbon, and the filtrate was collected and concentrated to give a crude compound (IV). Recrystallizing the crude product of the compound (IV) by a dichloromethane-methanol mixed solvent to obtain the compound (IV);
4) Compound IV was dissolved in N, N-Dimethylformamide (DMF), sodium hydride was added and stirred at room temperature for half an hour, then methoxymethyl chloride (MOMCl) was added to the reaction solution, the reaction solution was stirred at room temperature, and TLC monitored the reaction was complete; to the reaction solution was added methylene chloride to dilute the reaction solution, and the organic phase was washed with 10% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated brine in this order. Drying and concentrating the organic phase to obtain a crude product of the compound III;
5) Dissolving the crude product of the compound III by tetrahydrofuran, adding a sodium hydroxide solution into the reaction solution, stirring at room temperature overnight, and monitoring the reaction by TLC; tetrahydrofuran was concentrated in the reaction solution, and a large amount of methylene chloride was added to the residue, followed by washing the organic phase with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine. Drying and concentrating the organic phase to obtain a crude product of the compound (II); recrystallizing the crude product of the compound (II) by a dichloromethane-methanol mixed solvent to obtain a pure product of the compound (II);
6.1 Compound (II) was dispersed in methylene chloride, condensing agents EDCI, DMAP and RCOOH were added with stirring at room temperature, and the reaction was continued at room temperature overnight. TLC monitored reaction was complete. To the reaction solution, a large amount of methylene chloride was added to dilute the reaction solution, followed by washing the organic phase with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine. Drying, filtering and concentrating the organic phase to obtain a crude product; dissolving the crude product in tetrahydrofuran, then adding dilute hydrochloric acid to react overnight at room temperature, and monitoring the reaction to be complete by TLC; to the reaction solution, a large amount of methylene chloride was added, and the organic phase was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine. The organic phase is dried and concentrated to obtain a crude product of the compound (I-1). Recrystallizing the crude product of the compound (I-1) by a dichloromethane-methanol mixed solvent to obtain a pure product of the compound (I-1);
6.2 Dispersing the compound (II) in anhydrous DMF, adding NaH and R' I under stirring at room temperature, and continuing to react at room temperature overnight, wherein TLC monitors that the reaction is complete; to the reaction solution, a large amount of methylene chloride was added to dilute the reaction solution, followed by washing the organic phase with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine. Drying, filtering and concentrating the organic phase to obtain a crude product; the crude product of the above step is dissolved in tetrahydrofuran, then diluted hydrochloric acid is added, and the reaction is carried out overnight at room temperature. TLC monitoring reaction is complete; to the reaction solution, a large amount of methylene chloride was added, and the organic phase was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine. The organic phase is dried and concentrated to obtain a crude product of the compound (I-2), and the crude product of the compound (I-2) is recrystallized by a mixed solvent of dichloromethane and methanol to obtain a pure product of the compound (I-2).
The 3-position modified derivatives of the begonia ketone provided by the invention are a series of derivatives of compounds (I-a) to (I-o) obtained by modifying 3-position substituent on the basis of 3-carbonyl begonia ketone extracted from Kunming begonia, and the compounds are found to have certain antitumor activity in pharmacological activity research, wherein the compounds (I-a), the compounds (I-e), the compounds (I-f) and the compounds (I-I) show small toxicity to normal cell lines in cell experiments, but have obvious effect of inhibiting tumor cell growth. Especially, the inhibition effect of the compounds (I-a), (I-e), (I-f), (I-I) and (I-o) on lung cancer cells is more remarkable, and in the survival experiment of tumor-bearing mice, the five compounds can obviously inhibit the tumor growth and metastasis of the tumor-bearing mice and obviously prolong the survival period of the tumor-bearing mice.
Drawings
FIG. 1 is a typical image of the results of fluorescence microscopy of the induction of autophagy of A549-GFP-LC3 by the hydroxy derivative of Begonia ketone 3 of example 8;
FIG. 2 is a graph of typical results of photomicrographs of the ability of the begonia ketone 3 hydroxy derivative of example 9 to inhibit HUVEC cell tube formation.
Detailed Description
Extraction of begonia ketone
Pulverizing root and stem of Tripterygium wilfordii, percolating with 50 times of 95% ethanol, and concentrating under reduced pressure to obtain extract. Mixing the extract with diatomite according to a mass ratio of 1:2, performing solid-liquid extraction, eluting with petroleum ether and dichloromethane sequentially, taking dichloromethane eluent, concentrating under reduced pressure to obtain dichloromethane extract, preparing a coarse product of the maltulip ketone according to a method reported in chemical composition research (Song Jiang and the like, journal of Chinese herbal medicines, 11 month in 2019, 5395-5399) of rhizomes of the maltulip in literature, recrystallizing the coarse product of the maltulip ketone by using a mixed solvent of dichloromethane and methanol (volume ratio of 1:1) to obtain the pure product of the maltulip ketone, wherein the purity is 98.5 percent.
Example 1
Preparation of Compound (IV)
Mallotus ketone 632mg (2.0 mmol,1.0 eq) was weighed into a reaction flask, 4ml pyridine was added to dissolve the sample, followed by 667mg triphenylchloromethane (2.4 mmol,1.2 eq) and 293mg dimethylaminopyridine (DMAP, 2.4mmol,1.2 eq) to the reaction solution. The reaction was stirred overnight at room temperature and the reaction was complete by TLC. The pyridine was concentrated under reduced pressure, and the residue was diluted with dichloromethane, and the organic phase was washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated brine. The organic phase is dried and concentrated to obtain a crude product of the compound (VI).
The crude compound (VI) was dissolved in 4ml of pyridine, followed by addition of 245mg of acetic anhydride (2.4 mmol,1.2 eq) and 293mg of dimethylaminopyridine (DMAP, 2.4mmol,1.2 eq) to the reaction solution. The reaction was stirred overnight at room temperature and the reaction was complete by TLC. The pyridine was concentrated under reduced pressure, and the residue was diluted with dichloromethane, and the organic phase was washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated brine. The organic phase is dried and concentrated to obtain a crude product of the compound (V).
The crude product of the compound (V) was dissolved in 5ml of tetrahydrofuran, 60mg of palladium on carbon catalyst was added to the reaction solution, and then the reaction solution was evacuated and then purged with hydrogen, and the reaction solution was stirred at room temperature overnight. TLC monitored reaction was complete. The reaction solution was filtered to remove palladium on carbon, and the filtrate was collected and concentrated to give a crude compound (IV). And recrystallizing the crude product of the compound (IV) by a mixed solvent of dichloromethane and methanol to obtain 593mg of pure product of the compound (IV).
The NMR spectrum data of compound (IV) are: 1 H NMR(500MHz，DMSO-d 6 )：δ1.53(1H，m)，2.34(1H，m)，1.75(1H，m)，1.83(1H，m)，3.13(1H，m)，1.80(1H，m)，2.88(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，2.13(3H，s).HR-ESI-MS m/z：found 359.2231，calculated 359.2238[M+H] + 。
example 2
Preparation of Compound (II)
591mg of compound (IV) (1.65 mmol,1.0 eq) was weighed into a reaction flask, 5ml of anhydrous DMF was added to dissolve it, 43.6mg of sodium hydride (1.82 mmol,1.1 eq) was added to the reaction system and stirred at room temperature for half an hour, then 147mg of methoxymethyl chloride (1.82 mmol,1.1eq, MOMCl) was added to the reaction solution, the reaction solution was stirred at room temperature and TLC was monitored to be complete. To the reaction solution was added methylene chloride to dilute the reaction solution, and the organic phase was washed with 10% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated brine in this order. The organic phase is dried and concentrated to obtain a crude product of the compound III.
The crude compound (III) was dissolved in tetrahydrofuran, and a 4N sodium hydroxide solution was added to the reaction mixture, followed by stirring at room temperature overnight. TLC monitored reaction was complete. Tetrahydrofuran was concentrated in the reaction solution, and a large amount of methylene chloride was added to the residue, followed by washing the organic phase with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine. The organic phase is dried and concentrated to obtain a crude product of the compound (II). And recrystallizing the crude product of the compound (II) by a dichloromethane-methanol mixed solvent to obtain a pure product of the compound (II).
The NMR spectrum data of compound (II) are: 1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，3.28(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，5.42(2H，s)，3.30(3H，s).HR-ESI-MS m/z：found 361.2363，calculated 361.2379[M+H] + 。
example 3
Preparation of Compound (I-1)
18mg of compound (II) (1.0 equivalent) was weighed into a reaction flask, 0.5ml of methylene chloride was added to the reaction flask, and 1.1 equivalent of condensing agent EDCI, 1.1 equivalent of DMAP and 1.1 equivalent of carboxylic acid (RCOOH) were added with stirring at room temperature, and the reaction solution was allowed to continue to react overnight at room temperature. TLC monitored reaction was complete. To the reaction solution, a large amount of methylene chloride was added to dilute the reaction solution, followed by washing the organic phase with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine. The organic phase is dried, filtered and concentrated to obtain crude product. The crude product of the above step was dissolved in 0.5ml of tetrahydrofuran, followed by addition of 1N diluted hydrochloric acid and reaction at room temperature overnight. TLC monitored reaction was complete. To the reaction solution, a large amount of methylene chloride was added, and the organic phase was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine. The organic phase is dried and concentrated to obtain a crude product of the compound (I-1). Recrystallizing the crude product of the compound (I-1) by a dichloromethane-methanol mixed solvent to obtain a pure product of the compound (I-1).
When R is methyl, the compound (I-1) is 3β -oxo- (acetyl) -4 hydroxymethyl-abietyl-8, 11, 13-triene-7-one (I-a)
The NMR data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，4.61(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，2.00(3H，s).HR-ESI-MS m/z：found 359.2231，calculated 359.2222[M+H] + .
when R is tert-butyl, the compound (I-1) is 3β -oxo- (pivaloyl) -4 hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-b)
The NMR data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，4.62(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，1.08(s，9H).HR-ESI-MS m/z：found 401.2699，calculated 401.2692[M+H] + .
when R is isobutyl, the compound (I-1) is 3β -oxo- (isovaleryl) -4 hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-c)
The NMR data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，4.62(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，2.21(2H，d，J＝3.2Hz)，1.24(1H，m)，0.88(d，J＝5.6Hz，6H).HR-ESI-MS m/z：found 401.2689，calculated 401.2692[M+H] + .
when R is vinyl, the compound (I-1) is 3β -oxo- (acryl) -4 hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-d)
The NMR data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，4.62(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，5.83(dd，J＝16.0，16.8Hz)，6.12(dd，J＝16.0，10.0Hz)，6.42(dd，J＝16.8，10.0Hz).HR-ESI-MS m/z：found 371.2217，calculated 371.2222[M+H] + .
when R is phenyl, the compound (I-1) is 3β -oxo- (benzoyl) -4 hydroxymethyl-abietyl-8, 11, 13-triene-7-one (I-e)
The NMR data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，4，63(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，7.69-7.67(2H，m)，7.45-7.43(3H，m).HR-ESI-MS m/z：found 421.2382，calculated 421.2379[M+H] + .
when R is 4-chloro-phenyl, the compound (I-1) is 3β -oxo- (4-chloro-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-f)
The NMR data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，4.63(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，7.91(d，J＝8.6Hz，2H)，7.43(d，J＝8.6Hz，2H).HR-ESI-MS m/z：found 455.1979，calculated 455.1989[M+H] + .
when R is 4-methyl-phenyl, the compound (I-1) is 3β -oxo- (4-methyl-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-g)
The NMR data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，4.63(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，7.57(1H，d，J＝8.0Hz)，7.25(2H，d，J＝8.0Hz)，2.33(3H，s).HR-ESI-MS m/z：found 435.2519，calculated 435.2535[M+H] + .
when R is 4-trifluoromethyl-phenylCompound (I-1) is 3β -oxy- (4-trifluoromethyl-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-h)
The NMR data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，4.63(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，8.03(2H，d，J＝8.4Hz)，7.29-7.25(2H，m).HR-ESI-MS m/z：found 489.2244，calculated 489.2253[M+H] + .
when R is 4-hydroxy-phenyl, the compound (I-1) is 3β -oxo- (4-hydroxy-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-I)
The NMR data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，4.63(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，7.52(2H，d，J＝8.6Hz)，6.81(2H，d，J＝8.6Hz)，9.35(1H，s).HR-ESI-MS m/z：found 437.2319，calculated 437.2328[M+H] + .
when R is 4-cyano-phenyl, the compound (I-1) is 3β -oxo- (4-cyano-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-j)
The NMR data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，4.63(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，8.08(d，J＝8.5Hz，2H)，7.76(d，J＝8.5Hz，2H).HR-ESI-MS m/z：found 446.2324，calculated 446.2331[M+H] + .
when R is 4-cyano-phenyl, the compound (I-1) is 3β -oxo- (4-nitro-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-k)
The NMR spectrum data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，4.63(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，8.04(2H，d，J＝8.4Hz)，7.95(2H，d，J＝8.4Hz).HR-ESI-MS m/z：found 446.2226，calculated 446.2230[M+H] + .
when R is 4-methoxy-phenyl, the compound (I-1) is 3β -oxo- (4-methoxy-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-1)
The NMR spectrum data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，4.63(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，7.63(2H，d，J＝8.8Hz)，6.98(2H，d，J＝8.8Hz)，3.42(3H，s).HR-ESI-MS m/z：found 451.2484，calculated 451.2477[M+H] + .
example 6
Preparation of Compound (I-2)
18mg of compound (II) (1.0 equivalent) was weighed into a reaction flask, 0.5ml of anhydrous DMF was added to the reaction flask, 1.1 equivalent of NaH and 1.1 equivalent of iodoalkane (R' I) were added with stirring at room temperature, and the reaction mixture was allowed to continue to react overnight at room temperature. TLC monitored reaction was complete. To the reaction solution, a large amount of methylene chloride was added to dilute the reaction solution, followed by washing the organic phase with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine. The organic phase is dried, filtered and concentrated to obtain crude product. The crude product of the above step was dissolved in 0.5ml of tetrahydrofuran, followed by addition of 1N diluted hydrochloric acid and reaction at room temperature overnight. TLC monitored reaction was complete. To the reaction solution, a large amount of methylene chloride was added, and the organic phase was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine. The organic phase is dried and concentrated to obtain a crude product of the compound 7. Recrystallizing the crude product of the compound 7 by a dichloromethane-methanol mixed solvent to obtain a pure product of the compound (I-2).
When R' is methyl, the compound (I-2) is 3β -methoxy-4 hydroxymethyl-abietyl-8, 11, 13-triene-7-one (I-m)
Its NMR data were
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，3.31(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，3.26(3H，s).HR-ESI-MS m/z：found 331.2271，calculated 331.2273[M+H] + .
When R' is ethyl, the compound (I-2) is 3 beta-ethoxy-4-hydroxymethyl-abietyl-8, 11, 13-triene-7-ketone,
the NMR data are:
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，3.29(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(1H，d，J＝2.0Hz)，7.48(1H，dd，J＝8.0，10.0Hz)，7.38(1H，d，J＝8.0Hz)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，3.31(2H，q，J＝6.9Hz)，1.24(3H，t，J＝6.9Hz).HR-ESI-MS m/z：found 345.2424，calculated 345.2430[M+H] + .
when R' is benzyl, the compound (I-2) is 3β -benzyloxy-4 hydroxymethyl-abietyl-8, 11, 13-triene-7-one (I-o)
1 H NMR(500MHz，DMSO-d 6 )：δ1.54(1H，m)，2.36(1H，m)，1.75(1H，m)，1.83(1H，m)，3.33(1H，m)，1.80(1H，m)，2.89(1H，m)，2.61(1H，dd，J＝3.0，18.5Hz)，7.68(3H，m)，7.48(3H，m)，7.38(2H，m)，2.91(1H，m)，1.18(3H，d，J＝7.0Hz)，1.19(3H，d，J＝7.0Hz)，3.62(1H，d，J＝11.0Hz)，3.87(1H，d，J＝11.0Hz)，1.10(3H，s)，1.21(3H，s)，4.84(2H，s)，.HR-ESI-MS m/z：found 407.2577，calculated 407.2586[M+H] + .
example 7
In vitro antitumor activity of begonia ketone 3 hydroxy derivative detected by MTT method
Principle of MTT colorimetric assay: the assay is based on the reduction of 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT), a common method for detecting cell viability and growth. MTT is a common cell stain, succinic dehydrogenase related to NADP exists in mitochondria of living cells, and exogenous yellow MTT can be reduced into insoluble blue-violet crystal formazan (formazan) and deposited in the cells, dead cells disappear, and MTT is not reduced. And (3) detecting the change of the optical density at the wavelength of 550nm by using an enzyme-labeled instrument after the formazan is dissolved by DMSO to measure the growth inhibition effect of the test drug on cells, thereby evaluating cytotoxicity.
The experimental steps are as follows: digesting the cultured cells with 0.25% pancreatin, sucking out pancreatin, stopping digestion with 10% FBS-containing culture solution, mixing cell suspension, and counting to adjust density to 1×10 4 Adding the prepared cell suspension into 96-well plate, 180ul each, placing at 37deg.C, 5% CO 2 Is cultured in a incubator for 24 hours, is added with medicine after 24 hours, has 5 compound holes at each concentration, and is continuously placed at 37 ℃ after being added with medicine, and is 5 percent CO 2 After 48 hours of incubation in incubator, 5mg/ml MTT20ul was added to each well and the incubation was continued at 37℃with 5% CO 2 After 4 hours, 96 plates were removed, the supernatant was aspirated, 100ul of DMSO was added to each well, and absorbance was measured at 570nm using an microplate reader. Inhibition = (1-dosing/blank OD) x100%
TABLE 1 preferred half-effective concentration of IC for inhibiting proliferation of different normal and tumor cells 50 (μM)
Experimental results: (1) Compound (I-d), compound (I-j), compound (I-k) against normal cells and tumors of the lung, breast, colorectalThe cells have stronger inhibition effect, which indicates that the three compounds have stronger toxicity and can be related to toxic groups in the structure of the compounds; (2) Compound (I-a), compound (I-f), compound (I-I), compound (I-o) have weak inhibition effect on normal lung cells, and have strong inhibition effect on lung cancer cells, and IC 50 2.3-4.1uM; (3) Compound (I-f), compound (I-o) has weak inhibition effect on normal cells of mammary gland, and has strong inhibition effect on breast cancer cells, and IC 50 2.4-3.0uM; (4) The compounds (I-a), (I-I) have weak inhibition on colorectal normal cells, and have strong inhibition on colorectal cancer cells, and IC 50 2.7-2.8uM; (5) In addition to the outstanding antitumor effect of the above compounds on the above tumor cells, other compounds have some degree of antitumor effect on the test tumor cells, as shown in Table 1.
Example 8 detection of the autophagic death Capacity of Malone 3 hydroxy derivatives to induce tumor cells A549-GFP-LC3
Experimental principle: autophagy is an intracellular metabolic pathway that evolutionarily highly conserved lysosomes engulf degrading its own components, and excessive autophagy in the cell leads to programmed death of the cell, a new way of cell death in addition to apoptosis and necrosis. The autophagy level of a cell can be assessed by detecting the number of autophagosomes within the cell; LC3 protein is typically measured. LC3 is a currently accepted autophagy marker, which is cleaved at its carboxy terminus by Atg4 after synthesis to expose glycine residues, yielding cytoplasmic localized LC3-I; during autophagy, LC3-I will be modified by ubiquitin-like systems like Atg7 and Atg3, yielding PE covalently bound LC3-II and localized on the autophagosome membrane.
The experimental method comprises the following steps: lung adenocarcinoma a549 cells were transfected with GFP-LC3 lentivirus to construct a stably transfected cell line. Cells were treated with 5uM of the above compound for 24 hours in a unified manner, and the number of fluorescent spots was observed and counted by a fluorescence microscope. Without autophagy, GFP-LC3 fusion protein is dispersed in the cytoplasm; when autophagy is formed, GFP-LC3 fusion protein is translocated to an autophagosome membrane, a plurality of bright green fluorescent spots are formed under a fluorescent microscope, one spot corresponds to one autophagosome, the number of autophagy spots formed in a single cell is more than or equal to 4, the autophagy cells are judged, 100 cells are counted in each group of samples, and the ratio of the number of the autophagy cells to the total number of the cells is calculated, so that the autophagy activity of the tumor cells induced by the compound is judged.
Experimental results: typical results of the experiment are shown in FIG. 1, in which DMSO control group cannot induce cells to produce autophagosome spots, the ratio of the total cell count to the total cell count induced by all tested compounds of 2uM is shown in Table 2, and in the figures, 1, 2 and 3 are the experimental results of compound (I-a), compound (I-g) and compound (I-h), respectively. As can be seen from the results, compound (I-d), compound (I-j) and compound (I-k) have greater toxicity to cause massive cell death, while compound (I-a), compound (I-e), compound (I-f), compound (I-I) and compound (I-o) can significantly induce autophagy.
TABLE 2 preferred ratio of Compound-induced autophagy of lung cancer A549-GFP-LC3 (%)
Example 9 detection of the ability of Malus spectabilis ketone 3 hydroxy derivatives to inhibit tumor (HUVEC cells) neovascularization
Experimental principle: the growth and metastasis of tumor in living body depends on the formation of tumor angiogenesis microvessels, and the process of destroying or inhibiting the tumor angiogenesis can cut off the nutrition and energy of tumor growth, so that various new drugs such as apatinib and the like clinically resist tumors by inhibiting tumor angiogenesis. HUVEC umbilical vein endothelial cells are inoculated on Matrigel, and are cultured under certain conditions to easily form a three-dimensional reticular structure, namely the microvascular formation experiment. The experiment is an effective detection method for measuring in vitro angiogenesis capacity.
The experimental method comprises the following steps: HUVEC cells were cultured with EGM2 medium, treated with DMSO control, 10 μm, 20 μm 3-carbonyl begonia ketone for 24 hours; pancreatin was digested and plated in 24 well plates containing Matrigel 5X 10 per well 4 The cells are cultured for 3 to 5 hours in an incubator at 37 ℃ by using EGM2 culture mediumWhen (1). The supernatant was aspirated, gently washed once with PBS buffer, 250ul of culture medium was added to each well, photographed within 1h, and the proportion of vascularization was counted using IPP software.
Experimental results: typical experimental results are shown in FIG. 2, wherein 1, 2 and 3 are graphs of experimental results of the compound (I-a), the compound (I-b) and the compound (I-c) respectively. HUVEC cells of VEGFA positive control group can well form a tubular structure of microvessels, and after 2uM of HUVEC cells are treated by each test compound, part of the compounds have obvious defect on the ability of HUVEC cells to form microvessels, and the statistical results are shown in the table 3 below. As can be seen from the results, the compounds (I-d), (I-j) and (I-k) have greater toxicity to cause massive cell death, while the compounds (I-a), (I-e), (I-f) and (I-I) inhibit the microvascular formation ability of HUVEC cells.
TABLE 3 ratio of preferred Compounds to induce HUVEC tube formation (%)
EXAMPLE 10 comparison of in vivo antitumor Capacity of Malone 3 hydroxy derivatives
Experimental principle: subcutaneously injecting A549 cells into BALB/c nude mice to construct a lung cancer subcutaneous tumor mouse model; each group of compounds was administered to mice by intragastric administration, and the actual inhibitory effect of the compounds on lung cancer in animals was examined.
The experimental method comprises the following steps: recovering lung cancer A549 cells, and preparing into 1x10 after pancreatin digestion 7 cells/mL cell suspension, each mouse was inoculated with 200 μl cell suspension subcutaneously. After two weeks of feeding, the volume of subcutaneous tumor of the mice is detected by a vernier caliper, and the volume is not less than 100mm 3 Subcutaneous tumor-bearing mice were considered to be successfully constructed. The mice in the experimental group and the control group were taken 5 mice each. Mice in experimental group are administrated by lavage once daily and transformedThe amount of the compound was 10mg/Kg, the administration was continued for two weeks, the mice were sacrificed to take out subcutaneous tumors, the tumor volume was calculated using vernier calipers, and t-test was performed using SPSS22.0 software.
Experimental results: the average tumor volume statistics of the experimental and control mice are shown in table 4. From the results, it can be seen that compound (I-d), compound (I-j) and compound (I-k) have greater toxicity to cause death of mice, while compound (I-a), compound (I-e), compound (I-f), compound (I-I) and compound (I-o) can significantly inhibit growth of lung cancer cells in mice.
Table 4 preferred ratio of Compounds to inhibit lung cancer cells in mice (%)
Example 11
Formulation examples
Compound (I-a), compound (I-f), compound (I-I) and Compound (I-o) were prepared in the same manner as in example 3 and example 6, and then formulated into tablets according to the following methods: each tablet is composed of the following components
100mg of active ingredient, proper amount of starch, proper amount of corn steep liquor and proper amount of magnesium stearate, and the components are prepared into tablets according to a conventional tablet preparation method.
The active ingredients are respectively compounds (I-a), compounds (I-f), compounds (I-I) or compounds (I-o).
Claims (3)
1. The 3-modified derivative of the crab apple ketone is characterized by comprising the following compounds:
3β -oxy- (acetyl) -4 hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-a);
3β -oxy- (benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-e);
3β -oxy- (4-chloro-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-f);
3β -oxy- (4-hydroxy-benzoyl) -4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-I);
3β -benzyloxy-4-hydroxymethyl-abietyl-8, 11, 13-trien-7-one (I-o).
2. The use of the modified derivatives of maltulone 3 as claimed in claim 1 for the preparation of a medicament for the treatment of tumors, such as non-small cell lung cancer, colorectal cancer and breast cancer.
3. The use according to claim 2, wherein the tumour is non-small cell lung cancer.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406670A (en) * | 2010-09-21 | 2012-04-11 | 中国人民解放军第三军医大学 | Extraction method of total alkaloids from tripterygium hypoglaucum and application of extract |
| CN105906610A (en) * | 2016-05-24 | 2016-08-31 | 绍兴文理学院 | 3-(4-phenyl-1H-imidazolyl-5-yl)-1H-indole derivatives, and preparation method and application thereof |
| CN111704535A (en) * | 2020-06-22 | 2020-09-25 | 天津师范大学 | 3-carbonyl malus spectabilis ketone, extraction method and application in preparing antitumor drugs |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406670A (en) * | 2010-09-21 | 2012-04-11 | 中国人民解放军第三军医大学 | Extraction method of total alkaloids from tripterygium hypoglaucum and application of extract |
| CN105906610A (en) * | 2016-05-24 | 2016-08-31 | 绍兴文理学院 | 3-(4-phenyl-1H-imidazolyl-5-yl)-1H-indole derivatives, and preparation method and application thereof |
| CN111704535A (en) * | 2020-06-22 | 2020-09-25 | 天津师范大学 | 3-carbonyl malus spectabilis ketone, extraction method and application in preparing antitumor drugs |
Non-Patent Citations (2)
| Title |
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| Hydroxylation of Some Dehydroabietanes with Corticium sasakii;D. R. BRANNOHN et al.;《The Journal of Organic Chemistry》;19681231;第33卷(第12期);第4462-4466页 * |
| 昆明山海棠根茎的化学成分研究;宋强等;《中草药》;20191103;第50卷(第22期);第5395-5399页 * |
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