CN102229546B - 1,4-pentadiene-3-ketone compound including sulfonic acid ester group, preparation method and use thereof - Google Patents
1,4-pentadiene-3-ketone compound including sulfonic acid ester group, preparation method and use thereof Download PDFInfo
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Abstract
The invention discloses a 1,4-pentadiene-3-ketone compound including a sulfonic acid ester group, a structural general formula (I) of which is as follows: FORMULA, wherein a substitutional sulfonic acid ester base on a benzene ring is in an ortho-position, a meta-position or a para-position; R1 is C1-6 alkyl, phenyl, ortho, meta and para mono-substitutional or multi-substitutional phenyl or heterocyclic ring; and R2 is C1-6 alkyl, phenyl, ortho, meta and para mono-substitutional or multi-substitutional phenyl or heterocyclic ring. The invention further discloses a method for preparing the 1,4-pentadiene-3-ketone compound including the sulfonic acid ester group and use in antitumor inhibitors.
Description
Technical field
The present invention relates to technical field of chemistry, relate in particular to a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, the preparation method of this compound, and purposes in antitumor inhibitor.
Background technology
Curcumine is that a class has extensive bioactive compound, and main pharmacological comprises anti-inflammatory, sterilization, anti-oxidant, anti HIV-1 virus, anticancer etc.The antitumor action of curcumine has been proposed first from India scholar Kuttan in 1985, to nineteen ninety-five Menon find its to melanoma B16-F1 0 cell lung shift inhibited after, existing numerous Chinese scholars have been done large quantity research to curcumine antitumor action and mechanism thereof, have confirmed that curcumine inhibition tumor cell is bred, the definite effect of inducing apoptosis of tumour cell.But beta-diketon structure in curcumine molecule and the existence of active methylene group make it under neutral and alkaline condition, show obvious unstable.In addition, show the shortcomings such as selectivity is low, drug effect is not lasting, body receptivity is poor in clinical study, these deficiencies have had a strong impact on its clinical application.
Isosorbide-5-Nitrae-pentadiene-3-ketone is as Natural Curcumin derivative, has the important biological activitys such as anticancer, anti-oxidant, anti-inflammatory, inhibition HIV-1, also has the advantages such as good stability, toxic side effect be little concurrently.About the molecular designing of this compounds, synthetic and bioactivity research work have caused chemistry and biological study person's concern.As: 2006, Ohori etc. (Mol. Cancer. Ther., 2006,5 (10): 2563-2573) found Isosorbide-5-Nitrae-pentadiene-3-ketone compounds that activity is 0 times of bisdemethoxycurcumin.2007, (the Bioorg. Med. Chem. such as Chandru, 2007,15 (24): 7696-7703) synthesized on serial aromatic ring and had and encircle 1 of the third oxygen replacement, 4-pentadiene-3-ketones derivant, and tested it to suppressing activity and anti-angiogenesis activity in the body of mouse EATC (EAT), research shows: this compounds can significantly suppress the growth of EAT cell, and has inhibition vasculogenesis ability in various degree.2008, (the Bioorg. Med. Chem. such as Um, 2008,16:3608 – 3615) Isosorbide-5-Nitrae-pentadiene-3-ketones derivant of synthetic amide containing is active in to contrast medicine vincristine(VCR) and taxol suitable to the inhibition of human oral KB cell and KBV20C cell.2009, it is active that the synthetic Isosorbide-5-Nitrae-pentadiene-3-ketone compounds of Liang etc. (Bioorg. Med. Chem., 2009,17:2623-2631) has significant inhibition to multiple cancer cells.(the Bioorg. Med. Chem. such as Amolin, 2009,17:360-367) Isosorbide-5-Nitrae-pentadiene-3-ketones derivant of report has significant inhibitions activity to breast cancer cell MCF-7 and SKBB3, part of compounds to breast cancer cell MCF-7 inhibition higher than curcumine.(the Chinese pharmaceutical chemistry magazine such as Liu Yang, 2009,19 (5): 326-329) taking aromatic aldehyde, 4-piperidone as raw material, a series of 3 of reports that have no are synthesized, 5-dibenzylidene piperidines-4 ketone compounds, Bioexperiment result shows that part of compounds can significantly suppress the increment of various human tumour cancer cells, its IC
50value is than the IC of curcumine
50be worth low.2010, (the Bioorg. Med. Chem. such as Hiroyuki, 2010,18:1083-1092) report a series of 1,4 pentadienes-3-ketone compounds, and test the cytotoxicity that it suppresses Human colon cancer HCT-116, result shows: this compounds all has certain inhibition activity to Human colon cancer HCT-116.Therefore taking curcumine as guide, it is carried out to composition optimizes, synthetic more efficient Isosorbide-5-Nitrae-pentadiene-3-ketone compounds has become a study hotspot of pharmaceutical field.
Sulphonate is also that a class has extensive bioactive compound, existing multiple kind commercializations.As systemic fungicide ether sulfocarbolate, this medical instrument has that consumption is few, low toxicity, efficient, Powdery Mildew is had to features such as special efficacy; Low toxicity, selecting property of wide spectrum weedicide--ethofumesate, it has good prevention effect to annual wealthy weeds such as lamb's-quarters; Anticarcinogen busulphan, lapatinib ditosylate, sultamicillin etc.In addition, 2004, Yan etc. (J. Med. Chem. 2004,47:1031-1043) reported that the nitrobenzene-sulfonic acid phenylester of purine-containing can be used as adenosine receptor antagonists.5 of Zhou Hongfang in 2007 etc. (fine-chemical intermediate, 2007,37 (2): 28-29) report, 7-dimethyl-1,2,4-triazolo [1,5-a] pyrimidine-2-aromatic sulfonic acid ester cpds has certain fungicidal activity and weeding activity.2009, Peng You (research and development of natural products, 2009,21:796-799) etc. 5 novel soybean aglycon sulfonate derivatives have been synthesized in design, and biological activity test result shows that part of compounds has certain restraining effect to human leukemia cell line HL-60 and human lung carcinoma cell A-549.
Summary of the invention
The object of the invention is to provide a kind of compound stability better, have good anti-tumor activity containing Isosorbide-5-Nitrae-pentadiene-3-ketone compounds of sulfonate ester group.
Another object of the present invention is to provide the preparation method of this Isosorbide-5-Nitrae-pentadiene that contains sulfonate ester group-3-ketone compounds.
Another object of the present invention is to provide the purposes in antitumor inhibitor of this Isosorbide-5-Nitrae-pentadiene that contains sulfonate ester group-3-ketone compounds.
A kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group of the present invention, (I) is as follows for its general structure:
(I)
Wherein: the substituted sulfonic acid ester group on phenyl ring is ortho position, a position, contraposition;
R
1for C
1-6alkyl, phenyl, neighbour,, contraposition monosubstituted or polysubstituted phenyl or heterocycle;
R
2for C
1-6alkyl, phenyl, neighbour,, contraposition monosubstituted or polysubstituted phenyl or heterocycle.
Above-mentioned a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, wherein: R
1, R
2in each group all can be replaced by least one or more halogen atom, itrile group, nitro, hydroxyl substituent.
Above-mentioned a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, wherein: halogen atom is fluorine, chlorine, bromine, iodine atom.
Above-mentioned a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, wherein: heterocycle is to contain 4-12 carbon atom and contain 1-3 heteroatomic monocycle or bicyclic heterocyclic group that is selected from nitrogen, oxygen or sulphur.Preferably pyrazolyl, furyl, tetrahydrofuran base, thienyl, thiazolyl, isothiazolyl, imidazolyl, pyrryl, oxazolyl, isoxazolyl, triazolyl, tetrazyl, thiadiazolyl group, pyridyl, morpholinyl, piperazinyl, triazinyl, piperidyl, pyridazinyl, pyrimidyl.
Above-mentioned a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, wherein: heterocyclic group is replaced by one or more groups that are independently selected from halogen atom, itrile group or nitro.
Above-mentioned a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, wherein: C
1-6alkyl preferable methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, tertiary hexyl, new hexyl.
Above-mentioned a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, wherein preferably synthetic compound is:
(1E, 4E)-1-(2-fluorophenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-phenyl-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2,3-dichlorophenyl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-fluorophenyl)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(the chloro-5-nitrophenyl of 2-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(5-chloro-1,3-dimethyl-1H-pyrazoles-4 base)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-chloro-phenyl-)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2,3-dichlorophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(3-nitrophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2,4 dichloro benzene base)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
Or (1E, 4E)-1-(2-p-methoxy-phenyl)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone.
Of the present invention a kind of containing 1 of sulfonate ester group, the preparation method of 4-pentadiene-3-ketone compounds, be taking monosubstituted hydroxy benzaldehyde, acetone, replacement SULPHURYL CHLORIDE, replace aldehyde, sodium hydroxide, salt of wormwood as raw material, synthetic through three steps taking acetone, dehydrated alcohol, acetonitrile as solvent, synthetic route is as follows:
(1) synthesizing of (E)-4-(monosubstituted hydroxy phenyl)-3-butene-2-one:
10.0 parts of monosubstituted hydroxy aldehydes are joined in the mixing solutions of 150.0 parts, 150.0 parts, acetone and water, be stirred to solid and all dissolve, be added drop-wise in reaction system room temperature reaction 11 ~ 15 h after 12.0 parts, sodium hydroxide being formulated as to 10% the aqueous solution.After reaction finishes, rotary evaporation is removed acetone, in raffinate, adds hot water to solid all to dissolve, and passes into carbonic acid gas to no longer variable color of reaction solution, has solid to produce, and suction filtration, washing, oven dry, separate to obtain product with silica gel column chromatography.
This step is applicable to the synthetic of all above-mentioned (E)-4-(monosubstituted hydroxy phenyl)-3-butene-2-one.
(2) synthesizing of (E)-4-(substituted sulfonic acid ester group phenyl)-3-butene-2-one:
Taking acetonitrile as solvent, add successively 20.0 parts, salt of wormwood, (E)-4-(monosubstituted hydroxy phenyl)-10.0 parts of 3-butene-2-one, after dissolution of solid, slowly drip and replace room temperature reaction 1-3 h after 10.0 parts of SULPHURYL CHLORIDE.After reaction finishes, decompression is sloughed solvent after washing, suction filtration, is dried to obtain solid, separates to obtain product with silica gel column chromatography.
This step is applicable to the synthetic of all above-mentioned (E)-4-(substituted sulfonic acid ester group phenyl)-3-butene-2-one.
(3) target compound is synthetic:
By (E)-4-(substituted sulfonic acid ester group phenyl)-1.0 parts of 3-butene-2-one, replace in the mixing solutions that 1.0 parts, aldehyde joins second alcohol and water (V (ethanol): V (water)=2:1), after NaOH1.2 part being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system room temperature reaction 1-10h.Reaction finishes rear suction filtration, washing, oven dry gained solid, and dehydrated alcohol/DMF recrystallization obtains target compound.
The present invention compared with prior art, there is obvious beneficial effect, as can be known from the above technical solutions: the present invention will have extensive bioactive curcumin derivate 1, the sulfonate ester group of 4-pentadiene-3-ketone and active structure splices, synthesize Isosorbide-5-Nitrae-pentadiene-3-ketone compounds of a class formation novelty.The synthetic route of this compounds is simple, reaction conditions gentleness, and reaction at room temperature just can be carried out; Isosorbide-5-Nitrae-pentadiene-3-ketone compounds stability of synthesized is better, has good anti-tumor activity.
Further illustrate beneficial effect of the present invention by embodiment below.
Embodiment
embodiment 1:synthesizing of compound (1E, 4E)-1-(2-fluorophenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
In 100 mL there-necked flasks, add successively 4-hydroxy benzaldehyde (10.0 mmol), 11 mL acetone and 11 mL water, being stirred to solid all dissolves, after sodium hydroxide (12.0 mmol) being formulated as to 10% the aqueous solution, be added drop-wise in reaction system, after room temperature reaction 11.0 h, stop reaction.Rotary evaporation is removed acetone, in raffinate, add 50 mL hot water to red solid all to dissolve, pass into carbonic acid gas to no longer variable color of reaction solution, there is faint yellow solid to produce, suction filtration, washing, oven dry, separate [V (ethyl acetate): V (sherwood oil)=2:1] with silica gel column chromatography and obtain faint yellow solid, yield: 74.3%, fusing point: 101-103 ° C.
(2) synthesizing of (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one:
In 50mL there-necked flask, add (E)-4-(4-hydroxy phenyl)-3-butene-2-one (10.0 mmol), salt of wormwood (20.0 mmol), 15mL acetonitrile, under stirring at room temperature, drip the Tosyl chloride (10.0 mmol) that is dissolved in acetonitrile, after 2h, stop reaction.Be spin-dried for solvent after washing, the yellow solid of oven dry, separates [V (ethyl acetate): V (sherwood oil)=3:1] with silica gel thin-layer chromatography and obtains faint yellow solid, fusing point: 58-60 С.
(3) synthesizing of (1E, 4E)-1-(2-fluorophenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2-fluorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 8h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol/DMF recrystallization.
embodiment 2:synthesizing of (1E, 4E)-1-phenyl-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one:
With embodiment 1 (2) step;
(3) synthesizing of (1E, 4E)-1-phenyl-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), phenyl aldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 10h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol/DMF recrystallization.
embodiment 3:synthesizing of (1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one:
With embodiment 1 (2) step;
(3) synthesizing of (1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2-nitro-4-chlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 1h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol/DMF recrystallization.
embodiment 4:synthesizing of (1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one:
With embodiment 1 (2) step;
(3) synthesizing of (1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 4-tolyl aldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 5h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol/DMF recrystallization.
embodiment 5:synthesizing of (1E, 4E)-1-(4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one:
With embodiment 1 (2) step;
(3) synthesizing of (1E, 4E)-1-(4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 4-chlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 8h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 6:synthesizing of (1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one:
With embodiment 1 (2) step;
(3) synthesizing of (1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), the chloro-3-methyl isophthalic acid-phenyl-1H-of 5-pyrazoles formaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 5h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 7:synthesizing of (1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
In 50mL there-necked flask, add (E)-4-(4-hydroxy phenyl)-3-butene-2-one (10.0 mmol), salt of wormwood (20.0 mmol), 15mL acetonitrile, under stirring at room temperature, drip the methylsulfonyl chloride (10.0 mmol) that is dissolved in acetonitrile, after 1h, stop reaction.Be spin-dried for solvent after washing, dry to obtain yellow solid, separate [V (ethyl acetate): V (sherwood oil)=3:1] with silica gel thin-layer chromatography and obtain faint yellow solid, fusing point: 136-138 С.
(3) synthesizing of (1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), the chloro-3-methyl isophthalic acid-phenyl-1H-of 5-pyrazoles formaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 7h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 8:synthesizing of (1E, 4E)-1-(2,3-dichlorophenyl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 7 (2) step;
(3) synthesizing of (1E, 4E)-1-(2,3-dichlorophenyl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2,3-dichlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 5h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 9:synthesizing of (1E, 4E)-1-(4-fluorophenyl)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
In 100 mL there-necked flasks, add successively salicylic aldehyde (10.0 mmol), 11 mL acetone and 11 mL water, being stirred to solid all dissolves, after sodium hydroxide (12 mmol) being formulated as to 10% the aqueous solution, be added drop-wise in reaction system, after room temperature reaction 15 h, stop reaction.Rotary evaporation is removed acetone, in raffinate, add 75 mL hot water to red solid all to dissolve, pass into carbonic acid gas to no longer variable color of reaction solution, there is faint yellow solid to produce, suction filtration, washing, oven dry, separate [V (ethyl acetate): V (sherwood oil)=2:1] with silica gel column chromatography and obtain faint yellow solid, yield: 78.8%, fusing point: 139-141 ° C.
(2) synthesizing of (E)-4-(2-(tosic acid ester group) phenyl)-3-butene-2-one
In 50mL there-necked flask, add (E)-4-(2-hydroxy phenyl)-3-butene-2-one (10.0 mmol), salt of wormwood (20.0 mmol), 15mL acetonitrile, under stirring at room temperature, drip the Tosyl chloride (10.0 mmol) that is dissolved in acetonitrile, after 3h, stop reaction.Be spin-dried for solvent after washing, suction filtration, dry to obtain faint yellow solid, separate [V (ethyl acetate): V (sherwood oil)=3:1] with silica gel thin-layer chromatography and obtain product, fusing point: 77-79 С.
(3) synthesizing of (1E, 4E)-1-(4-fluorophenyl)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone
In 50mL there-necked flask, add (E)-4-(2-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 4-fluorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 10:synthesizing of (1E, 4E)-1-(the chloro-5-nitrophenyl of 2-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 9 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 9 (2) step;
(3) synthesizing of (1E, 4E)-1-(the chloro-5-nitrophenyl of 2-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), the chloro-5-nitrobenzaldehyde of 2-(1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 1h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 11:synthesizing of (1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 9 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 9 (2) step;
(3) synthesizing of (1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2-nitro-4-chlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 1h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 12:(1E, 4E)-1-(5-chloro-1,3-dimethyl-1H-pyrazoles-4 base)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone synthetic, comprises the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 9 (1) step;
(2) synthesizing of (E)-4-(2-(tosic acid ester group) phenyl)-3-butene-2-one:
With embodiment 9 (2) step;
(3) (1E, 4E)-1-(5-chloro-1,3-dimethyl-1H-pyrazoles-4 base)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone synthetic:
In 50mL there-necked flask, add (E)-4-(2-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 5-chloro-1,3-dimethyl-1H-pyrazoles formaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 1h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 13:synthesizing of compound (1E, 4E)-1-(2-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
In 50mL there-necked flask, add (E)-4-(2-hydroxy phenyl)-3-butene-2-one (10.0 mmol), salt of wormwood (20.0 mmol), 15mL acetonitrile, drips methylsulfonyl chloride (10.0 mmol) under stirring at room temperature, stop reaction after 1h.Be spin-dried for solvent after washing, suction filtration, oven dry gained solid, silica gel thin-layer chromatography separates [V (ethyl acetate): V (sherwood oil)=3:1] and obtains light yellow crystal, fusing point: 100-103 С.
(3) synthesizing of (1E, 4E)-1-(2-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), Benzaldehyde,2-methoxy (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellowish brown solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 14:synthesizing of (1E, 4E)-1-(4-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 13 (2) step;
(3) synthesizing of (1E, 4E)-1-(2-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), Benzaldehyde,2-methoxy (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellowish brown solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 15:synthesizing of (1E, 4E)-1-(4-chloro-phenyl-)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 13 (2) step;
(3) synthesizing of (1E, 4E)-1-(4-chloro-phenyl-)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone
In 50mL there-necked flask, add (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 4-chlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 16:synthesizing of (1E, 4E)-1-(2,3-dichlorophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 13 (2) step;
(3) synthesizing of (1E, 4E)-1-(2,3-dichlorophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2,3-dichlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 17:synthesizing of compound (1E, 4E)-1-(3-nitrophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 13 (2) step;
(3) synthesizing of (1E, 4E)-1-(3-nitrophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 3-nitrobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellowish brown solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 18:synthesizing of (1E, 4E)-1-(2,4 dichloro benzene base)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 13 (2) step;
(3) synthesizing of (1E, 4E)-1-(2,4 dichloro benzene base)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2,4-dichlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 19:synthesizing of (1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(Phenylsulfonic acid ester group) phenyl)-3-butene-2-one:
In 50mL there-necked flask, add (E)-4-(4-hydroxy phenyl)-3-butene-2-one (10.0 mmol), salt of wormwood (20.0 mmol), 15mL acetonitrile, drips benzene sulfonyl chloride (10.0 mmol) under stirring at room temperature, stop reaction after 2h.Be spin-dried for solvent after washing, suction filtration, oven dry gained solid, silica gel thin-layer chromatography separates [V (ethyl acetate): V (sherwood oil)=3:1] and obtains yellow crystals, fusing point: 58-61 С.
(3) synthesizing of (1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(Phenylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2-tolyl aldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 8h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 20:synthesizing of compound (1E, 4E)-1-(2-p-methoxy-phenyl)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(4-(Phenylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 19 (2) step;
(3) (1E, 4E)-1-(5-chloro-1,3-dimethyl-1H-pyrazoles-4 base)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone synthetic:
In 50mL there-necked flask, add (E)-4-(4-(Phenylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), Benzaldehyde,2-methoxy (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 8h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
qualitative data is as follows:
Proton nmr spectra (1H NMR) data to above-described embodiment 1-20 gained compound are as shown in table 1, physico-chemical property and ultimate analysis data are as shown in table 2, infrared spectra (IR) data are as shown in table 3, and carbon-13 nmr spectra (13C NMR) data are as shown in table 4.
The proton nmr spectra data of table 1 compound
The physico-chemical property of table 2 compound and ultimate analysis
The IR data of table 3 compound
| Embodiment | IR, ν max(cm -1) |
| 1 | IR (KBr): n max:3037, 1670, 1575, 1502, 1458, 1415, 1375, 1199 |
| 2 | IR (KBr): n max:3053, 1653, 1591, 1573, 1500, 1448, 1375, 1176 |
| 3 | IR (KBr): n max:3068, 1653, 1595, 1527, 1498, 1473, 1369, 1172, |
| 4 | IR (KBr): n max:3099, 1649, 1595, 1568, 1456, 1369, 1155 |
| 5 | IR (KBr): n max:3051, 1653, 1558, 1521, 1456, 1375, 1195 |
| 6 | IR (KBr): n max:3062, 1651, 1591, 1500, 1456, 1373, 1197 |
| 7 | IR (KBr): n max:3005, 1666, 1593, 1579, 1527, 1473, 1359, 1176 |
| 8 | IR (KBr): n max:3066, 1668, 1587, 1577, 1554, 1454, 1569, 1195 |
| 9 | IR (KBr): n max:2999, 1685, 1624, 1593, 1500, 1473, 1365, 1193 |
| 10 | IR (KBr): n max:3101, 1672, 1618, 1589, 1519, 1452, 1373, 1182 |
| 11 | IR (KBr): n max:3072, 1680, 1625, 1595, 1529, 1479, 1375, 1193 |
| 12 | IR (KBr): n max:3062, 1670, 1616, 1595, 1523, 1481, 1369, 1192 |
| 13 | IR (KBr): n max:3020, 1649, 1616, 1581, 1489, 1438, 1342, 1182 |
| 14 | IR (KBr): n max:3022, 1668, 1622, 1583, 1508, 1452, 1363, 1182 |
| 15 | IR (KBr): n max:3018, 1668, 1622, 1587, 1489, 1355, 1186 |
| 16 | IR (KBr): n max:3020, 1649, 1612, 1587, 1477, 1342, 1197 |
| 17 | IR (KBr): n max:3034, 1676, 1625, 1595, 1525, 1481, 1350, 1186 |
| 18 | IR (KBr): n max:3022, 1651, 1616, 1585, 1471, 1340, 1182 |
| 19 | IR (KBr): n max:3024, 1649, 1624, 1581, 1500, 1448, 1330, 1170 |
| 20 | IR (KBr): n max:3010, 1668, 1616, 1575, 1504, 1448, 1338, 1195 |
Table 4 compound
13c NMR data
biological activity test test is as follows:
test example 1:to PC 3 cell 72 h vitro inhibition screening active ingredients tests
The Anticancer Activity in vitro of target compound is tested using DMSO as object of reference, adopt MTT colorimetry through three replications the inhibiting rate of compound to Human Prostate Cancer Cells PC3.
MTT test method: by sterilizing intermediate water edge sealing for the uplink and downlink of 96 orifice plates, every hole 200
μl(peripheral hole moisture easily evaporates).The cell in vegetative period of taking the logarithm, with after 0.25% trypsinase rule digestion, is resuspended in containing in RPMI 1640 substratum of 10% FBS, with 2 × 10
4the final concentration of individual/mL is inoculated in 96 well culture plates, every hole 100
μl, the rightmost side one is classified blank group as, adds acellular serum RPMI 1640 substratum that have.Be placed in 37 DEG C, 5% CO
2saturated humidity incubator in cultivate 24 h and make cell attachment.Sop up substratum, add the blood serum medium that has containing different pharmaceutical concentration, every hole 200
μl, notices that in substratum, DMSO final concentration can not exceed 0.1%, and the every hole of blank group adds 200
μl perfect medium.Process respectively the requirement of experiment time, remove supernatant, add 100
μthe MTT of L/well concentration 0.5 mg/mL.After cultivating 4 h, add again 100
μ10% the SDS of L/well.At 37 DEG C, 12 h make crystallisate fully dissolve rear taking-up, and 5 min are swung in microseism, place 30 min under room temperature, survey OD value, and calculate inhibiting rate and P value under A595 wavelength.Compound is as shown in table 5 to PC 3 cell 72 h vitro inhibition activity test results.
Taking drug level or treatment time as transverse axis, OD value or inhibiting rate are the longitudinal axis, curve plotting.Every concentration of specimens repeats six holes, and each experiment in triplicate, is averaged as net result.
Experimental result is carried out variance analysis with SPSS software, when P<0.05, is significant difference, is that difference is extremely remarkable when P<0.01.The inhibiting rate calculation formula of cell proliferation is as follows:
Table 5 embodiment 1-20 compound is to PC3 cell 72 h vitro inhibition activity test results
test example 2:to the 72 h vitro inhibition screening active ingredients tests of Bcap-37 cell
Test method is identical with test example 1 with the calculation formula of inhibiting rate, and acquired results is in table 6.
Table 6: embodiment 1-20 compound is to Bcap-37 cell 72 h vitro inhibition activity test results
The above, it is only preferred embodiment of the present invention, not the present invention is done to any pro forma restriction, any technical solution of the present invention content that do not depart from, any simple modification, equivalent variations and the modification above embodiment done according to technical spirit of the present invention, all still belong in the scope of technical solution of the present invention.
Claims (3)
1. containing Isosorbide-5-Nitrae-pentadiene-3-ketone compounds of sulfonate ester group, (I) is as follows for its general structure:
(I)
Wherein: the substituted sulfonic acid ester group on phenyl ring is ortho position, a position, contraposition;
R
1for C
1-6alkyl, phenyl;
R
2for phenyl or pyrazolyl; R
2in each group all can be replaced by least one or more halogen atom, nitro, hydroxyl substituent; Halogen atom is fluorine, chlorine atom.
2. containing Isosorbide-5-Nitrae-pentadiene-3-ketone compounds of sulfonate ester group, wherein preferably synthetic compound is:
(1E, 4E)-1-(2-fluorophenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-phenyl-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2,3-dichlorophenyl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-fluorophenyl)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(the chloro-5-nitrophenyl of 2-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(5-chloro-1,3-dimethyl-1H-pyrazoles-4 base)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-chloro-phenyl-)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2,3-dichlorophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(3-nitrophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2,4 dichloro benzene base)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
Or (1E, 4E)-1-(2-p-methoxy-phenyl)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone.
3. the preparation method of a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group as claimed in claim 1 or 2, synthetic route is as follows:
(1) synthesizing of (E)-4-(monosubstituted hydroxy phenyl)-3-butene-2-one:
10.0 parts of monosubstituted hydroxy aldehydes are joined in the mixing solutions of 150.0 parts, 150.0 parts, acetone and water, be stirred to solid and all dissolve, be added drop-wise in reaction system room temperature reaction 11 ~ 15 h after 12.0 parts, sodium hydroxide being formulated as to 10% the aqueous solution; After reaction finishes, rotary evaporation is removed acetone, in raffinate, adds hot water to solid all to dissolve, and passes into carbonic acid gas to no longer variable color of reaction solution, has solid to produce, and suction filtration, washing, oven dry, separate to obtain product with silica gel column chromatography;
(2) synthesizing of (E)-4-(substituted sulfonic acid ester group phenyl)-3-butene-2-one:
Taking acetonitrile as solvent, add successively 20.0 parts, salt of wormwood, (E)-4-(monosubstituted hydroxy phenyl)-10.0 parts of 3-butene-2-one, after dissolution of solid, slowly drip and replace room temperature reaction 1-3 h after 10.0 parts of SULPHURYL CHLORIDE; After reaction finishes, decompression is sloughed solvent after washing, suction filtration, is dried to obtain solid, separates to obtain product with silica gel column chromatography;
(3) target compound is synthetic:
By (E)-4-(substituted sulfonic acid ester group phenyl)-1.0 parts of 3-butene-2-one, replace in the mixing solutions that 1.0 parts, aldehyde joins second alcohol and water, ethanol: the volume ratio of water is 2:1, after NaOH1.2 part being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system room temperature reaction 1-10h; Reaction finishes rear suction filtration, washing, oven dry gained solid, and dehydrated alcohol/DMF recrystallization obtains target compound.
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| CN103275008B (en) * | 2013-06-06 | 2015-03-25 | 浙江大学 | 3,4, 5-trisubstituted pyrazole compound and preparation method thereof |
| CN108069906A (en) * | 2016-11-11 | 2018-05-25 | 武汉科技大学 | （1E, 4E）-1-（Pyrazoles -4- bases）- 5- phenyl-Isosorbide-5-Nitrae pentadiene -3- ketone derivatives and preparation method thereof and medical usage |
| CN106928176B (en) * | 2017-03-08 | 2020-02-18 | 贵州大学 | Coumarin-containing 1, 4-pentadiene-3-ketone derivative and preparation method and application thereof |
| CN109970704B (en) * | 2019-04-22 | 2022-01-28 | 贵州大学 | Chalcone derivative containing thiophene sulfonate, and preparation method and application thereof |
| CN109942540B (en) * | 2019-04-22 | 2021-06-18 | 贵州大学 | 1, 4-pentadiene-3-ketone derivative containing thiophene sulfonate, preparation method and application thereof |
| CN112679458B (en) * | 2020-12-15 | 2023-01-17 | 贵州大学 | Sulfonic ester-containing myricetin derivative and preparation method and application thereof |
| CN114634465B (en) * | 2022-03-09 | 2023-05-30 | 贵州大学 | Pentadienone derivative containing sulfonyl piperazine as well as preparation method and application thereof |
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| WO2010045395A2 (en) * | 2008-10-14 | 2010-04-22 | Danyang Chen | Curcumin analog compositions and related methods |
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| James R.Fuchs等.Structure-activity relationship studies of curcumin analogues.《Bioorg.Med.Chem.Lett》.2009,第19卷(第7期),第2065-2066页, 图3, 化合物20-22. |
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