CN108997149A - A kind of dehydroabietylamine derivatives and its preparation method and application that aryl replaces - Google Patents
A kind of dehydroabietylamine derivatives and its preparation method and application that aryl replaces Download PDFInfo
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- CN108997149A CN108997149A CN201811042850.2A CN201811042850A CN108997149A CN 108997149 A CN108997149 A CN 108997149A CN 201811042850 A CN201811042850 A CN 201811042850A CN 108997149 A CN108997149 A CN 108997149A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes
Abstract
This application involves the dehydroabietylamine derivatives that a kind of aryl replaces, have through structure shown in the following general formula (I):In logical formula (I), group R1, R2, R3, R4 and R5 are each independently selected from hydrogen atom, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy.The application further relates to a kind of method for preparing the dehydroabietylamine derivatives that aryl as described above replaces.The application further relates to the dehydroabietylamine derivatives that aryl as described above replaces and is preparing the application in anticancer drug.The beneficial effects of the present application are as follows the natural prodcuts that have drawn from, raw materials used to have no toxic side effect to patient, and raw material is easy to get, is cheap, and compound synthesis method is simple, and synthesis gained compound anticancer effect is good.
Description
Technical field
This application involves dehydroabietylamine compound synthesis technical fields.Specifically, this application involves a kind of aryl to take
The dehydroabietylamine that the dehydroabietylamine derivatives in generation, the preparation method for the dehydroabietylamine derivatives which replaces and the aryl replace
Derivative is preparing the application in anticancer drug.
Background technique
Dehydroabietylamine (also known as dehydroabietylamine) is a kind of rosin derivative more more stable than rosin, and structural formula is as follows
It is shown:
Natural products is the usually change with pharmacology or biological activity by those of living organism generation in nature
Substance is learned, the medicament research and development and drug that can be used for pharmaceutically design.The rosin annual output in China accounts for about the four of Gross World Product
/ mono-, it is the international main supply country in rosin market.Schiff base compound has the characteristics such as sterilization, antibacterial, anticancer, antiviral
And it is widely used in the research fields such as medicine, drug [Arjmand F, Sayeed F, Muddassir M.Synthesis of
new chiral heterocyclic Schiff base modulated Cu(II)/Zn(II)complexes:their
comparative binding studies with CT-DNA,mononucleotides and cleavage
activity.Journal of Photochemistry and Photobiology Biology,2011,103(2):166-
179.].It has been reported that and shows that pyridine aldehydes react synthesis Schiff and its complex with amido and have antibacterial, anti-tumor activity [week
The synthesis of strong pyridine aldehydes transition metal schiff bases complex, crystal structure and Spectroscopic Characterization Guangxi Normal University, 2004.].
Dehydroabietylamine is one of main component of rosin, and itself has certain sterilizing and antibacterial activity.There is a small amount of research
Show that dehydroabietylamine schiff base compound has the bioactivity [conjunctions for small flat rosin resin acid derivative of 1. having mercy on such as antibacterial, anticancer
It 2. haves mercy on small flat, Song Zhanqian at, characterization and bioactivity research China Forestry Science Research Institute, 2007., the high macro fluorine-containing dehydrogenation fir of
The synthesis of amine Schiff and bacteriostatic activity chemistry of forest product and industry, 2007,27 (2): 97-99. 3. Rao X P, Song Z
Q,Yao X J,et al.Syntheses,Crystal Structure and Properties of
Dehydroabietylamine 5-Nitro-sacyldiene Schiff Base and Its Metal
Complexes.Chemistry&Industry of Forest Products,2007,27(1):1-7.]。
Prostate cancer is the distinctive disease of the mankind, is the most common malignant tumour of male reproductive system, disease incidence and dead
It dies rate and is only second to lung cancer in American-European countries, occupy the 2nd [[Siegel RL, Miller KD, Jemal of male cancer deaths
A.Cancer statistics,2015.CA Cancer J Clin,2015,65(1):5-29.].China, Japan, India etc.
Asian countries's prostate-cancer incidence has growth trend far below America and Europe.[leaf determines the epidemiology of big prostate cancer in
The incidence trend China surgical magazine of state, 2006,44 (6): 362-364.].
It include clinically at present operative treatment, radiotherapy, endocrine therapy, Chemo-Therapy to the treatment method of prostate cancer
Treatment and immunization therapy etc., wherein endocrine therapy is the main means of therapy approaches of advanced prostate cancer.Prostate cancer has height different
Matter and hormone-sensitive.For Late-stage Prostate Cancer, Androgen deprivation therapy (androgen deprive therapy)
It is its essential therapeutic arsenals, but gradually development is castration-resistant forefront to Most patients after treatment in 14~30 months
Gland cancer (castration-resistant prostate cancer, CRPC), median survival interval less than 20 months [Han Bo,
Qi Mei, Tan Weiwei, the occurrence and development mechanism and Advancement in drug therapy of the easy castration-resistant prostate cancer of poplar, Shandong University
Journal (medicine), 2015,53 (9): 1-7.].In recent years, the clinical treatment status of CRPC there has been very big change, Ke Yiming
The drug for really improving patient's prognosis also continues to bring out.But while therapeutic scheme is more and more, also occur more choosing
War and problem.For example, what is the most suitable patient population of every kind of novel drugs? the biological markers that whether can choose specificity come
Will the CRPC patient that benefit from a certain particular treatment be screened? most suitable treatment method how is selected for each individual, such as
How what balance curative effect and adverse reaction, overcome the problems, such as that the drug resistance of drug is all to solve in a hurry.
For this purpose, aryl substitution without side-effects when there is an urgent need in the art to develop a kind of low cost and before the treatment column gland cancer
Dehydroabietylamine derivatives and preparation method thereof.
Summary of the invention
What a kind of aryl without side-effects when being designed to provide low cost and before the treatment column gland cancer of the application replaced
Dehydroabietylamine derivatives, thus solve it is above-mentioned in the prior art the technical issues of.The application passes through using containing benzaldehyde structure
Aromatic compound is modified dehydroabietylamine, obtains the dehydroabietylamine derivatives of aromatic radical substitution.Specifically, the application will take off
Hydrogen abietyl amine basic framework introduces aromatic ring structure and has synthesized 3 dehydroabietylamine reduction schiff base compounds, obtains with anticancer activity
Dehydroabietylamine derivatives.Inventor is surprisingly, it was found that the dehydroabietylamine derivatives of this specific structure can be killed effectively
Prostate gland cancer cell, such as Human Prostate Cancer PC-3 Cell Line.
In addition, inventor's discovery is according to the dehydroabietylamine derivatives of the application to Escherichia coli, staphylococcus aureus etc.
With good bactericidal effect.
3 kinds of dehydroabietylamine schiff base compounds that the application specifically synthesizes have expanded dehydroabietylamine schiff base compounds kind
Class, the relationship between research dehydroabietylamine schiff base compounds structure and performance create conditions.Meanwhile the series dehydrogenation fir
Amine schiff base compounds show good anticancer activity, provide foundation for the exploitation of antiprostate cancer.
To achieve the goals above, the application provides following technical proposals.
In the first aspect, the application provides a kind of dehydroabietylamine derivatives that aryl replaces, and has by following logical
Structure shown in formula (I):
In logical formula (I), group R1, R2, R3, R4 and R5 be each independently selected from hydrogen atom, hydroxyl, C1-C3 alkyl or
C1-C3 alkoxy.
In a kind of embodiment of first aspect, group R1 or R2 are hydroxyl.
In a kind of embodiment of first aspect, group R3 is selected from hydroxyl, methoxyl group, ethyoxyl, propoxyl group or isopropyl
Oxygroup.
In a kind of embodiment of first aspect, group R2 or R4 are hydrogen atom, methyl, ethyl, propyl or isopropyl.
In a kind of embodiment of first aspect, the dehydroabietylamine derivatives that the aryl replaces include having following knots
Any compound in structure formula (1)-(3):
Or
In second aspect, it is derivative that the application provides a kind of dehydroabietylamine that the aryl prepared as described in relation to the first aspect replaces
The method of object, the method includes the following steps:
S1: making dehydroabietylamine and aromatic compound react the first predetermined amount of time in the first organic solvent, obtains
One reaction mixture；
S2: so that the first mixture and excessive reducing agent is reacted second time period under condition of ice bath, obtain the second reaction
Mixture；And
S3: being added water in the second reaction mixture, then extracts organic phase, the dry organic phase with the second organic solvent
And the dehydroabietylamine derivatives that the aryl replaces are obtained after removing solvent；
Wherein the aromatic compound has the structure as shown in the following general formula (II):
In logical formula (II), wherein group R1, R2, R3, R4 and R5 are each independently selected from hydrogen atom, hydroxyl, C1-C3
Alkyl or C1-C3 alkoxy.
In a kind of embodiment of second aspect, the aromatic compound includes salicylide, parahydroxyben-zaldehyde, right
Methoxybenzaldehyde, p-ethoxybenzaldehyde, to propoxybenzaldehyde or to isopropoxide benzaldehyde.
In a kind of embodiment of second aspect, the first organic solvent includes methanol.
In a kind of embodiment of second aspect, second organic solvent includes methylene chloride or ethyl acetate.
In a kind of embodiment of second aspect, the reducing agent includes sodium borohydride or potassium borohydride.
In a kind of embodiment of second aspect, first predetermined amount of time is 5-10 hours.
In a kind of embodiment of second aspect, second predetermined amount of time is 2-12 hours.
In a kind of embodiment of second aspect, in step sl, the dehydroabietylamine and the aromatic compound
Charged molar ratio be 1:1.
In a third aspect, prepared by the dehydroabietylamine derivatives that the application provides that aryl as described in relation to the first aspect replaces
Application in anticancer drug.
In a kind of embodiment of the third aspect, the anticancer drug includes the drug of anti-prostate cancer.
Compared with prior art, the beneficial effects of the present application are as follows the natural prodcuts that have drawn from, raw materials used nontoxic to patient
Side effect, and raw material is easy to get, is cheap, compound synthesis method is simple, and synthesis gained compound anticancer effect is good.
Detailed description of the invention
Fig. 1 shows the nuclear magnetic resonance H spectrum of the dehydroabietylamine derivatives with structural formula (1).
Fig. 2 shows the nuclear magnetic resonance C spectrum of the dehydroabietylamine derivatives with structural formula (1).
Fig. 3 shows the nuclear magnetic resonance H spectrum of the dehydroabietylamine derivatives with structural formula (2).
Fig. 4 shows the nuclear magnetic resonance C spectrum of the dehydroabietylamine derivatives with structural formula (2).
Fig. 5 shows the nuclear magnetic resonance H spectrum of the dehydroabietylamine derivatives with structural formula (3).
Fig. 6 shows the nuclear magnetic resonance C spectrum of the dehydroabietylamine derivatives with structural formula (3).
Fig. 7 shows the dehydroabietylamine derivatives with structural formula (1) to the inhibiting effect of Human Prostate Cancer PC-3 Cell Line.
Fig. 8 shows the dehydroabietylamine derivatives with structural formula (1) to the inhibiting effect of LNCaP clone FGC cell.
Fig. 9 shows the dehydroabietylamine derivatives with structural formula (2) to the inhibiting effect of Human Prostate Cancer PC-3 Cell Line.
Figure 10 shows the dehydroabietylamine derivatives with structural formula (2) to the inhibiting effect of LNCaP clone FGC cell.
Figure 11 shows the dehydroabietylamine derivatives with structural formula (3) to the inhibiting effect of Human Prostate Cancer PC-3 Cell Line.
Figure 12 shows the dehydroabietylamine derivatives with structural formula (3) to the inhibiting effect of LNCaP clone FGC cell.
Specific embodiment
Term "comprising", " comprising ", " having " and their derivative are not excluded for any other component, step or mistake
The presence of journey, and whether disclose in this application with these other components, step or process unrelated.To eliminate any query,
Unless expressly stated, otherwise in the application it is all use term "comprising"s, " comprising ", or " having " composition may include appoint
What additional additive, auxiliary material or compound.On the contrary, in addition to necessary to operating characteristics those, term " substantially by ...
Composition " excludes any other component, step or process except the hereinafter described range of any term.Term " by ...
Composition " does not include any component, step or the process for not specifically describing or listing.Unless expressly stated, otherwise term "or" refers to
Separate member listed or any combination thereof.
Embodiment
Below in conjunction with the embodiment of the present invention, clear and complete description is carried out to technical solution of the present invention.Such as nothing
It illustrates, reagent used and raw material can all be bought by commercial sources.
One, preparation has the embodiment of the method for the dehydroabietylamine derivatives of structural formula (1) as follows:
Embodiment 1: dehydroabietylamine (1.425g, 5mmol) and salicylide (610mg, 5mmol) is added to the round bottom of 250mL
In flask, methanol is then added and makes it dissolve, has apparent yellow solid to be precipitated after being stirred at room temperature 6 hours, then weigh excessive
Sodium borohydride (580mg, 15mmol) is slowly added in reaction flask under ice bath, under ice bath react 2h after continue at room temperature it is stirred
Night.Solvent is drained after reaction, a small amount of water is added and shakes up, is extracted with dichloromethane and collects the organic phase of extract liquor, is used
It is saturated common salt water washing 3 times, dry.It is filtered to remove solid sodium sulfate, filtrate decompression is collected and solvent is distilled off, pass through ethyl alcohol weight
Crystallize to obtain the dehydroabietylamine derivatives white solid with structural formula (1).
Embodiment 2: dehydroabietylamine (712.5mg, 2.5mmol) and salicylide (305mg, 2.5mmol) is added 250mL's
In round-bottomed flask, methanol is then added and makes it dissolve, has apparent yellow solid to be precipitated after being stirred at room temperature 6 hours, then weighed
The sodium borohydride (290mg, 7.5mmol) of amount is slowly added in reaction flask under ice bath, is continued at room temperature after reacting 2h under ice bath
It is stirred overnight.Solvent is drained after reaction, a small amount of water is added and shakes up, and is extracted with dichloromethane and is collected the organic of extract liquor
Phase, it is dry with saturated common salt water washing 3 times.It is filtered to remove solid sodium sulfate, filtrate decompression is collected and solvent is distilled off, pass through
Ethyl alcohol recrystallization must have the dehydroabietylamine derivatives white solid of structural formula (1).
Embodiment 3: dehydroabietylamine (356.25mg, 1.25mmol) and salicylide (152.5mg, 1.25mmol) is added
In the round-bottomed flask of 250mL, methanol is then added and makes it dissolve, has apparent yellow solid to be precipitated after being stirred at room temperature 6 hours, then
It weighs excessive sodium borohydride (145mg, 3.75mmol) to be slowly added in reaction flask under ice bath, room temperature after 2h is reacted under ice bath
Under continue to be stirred overnight.Solvent is drained after reaction, and a small amount of water is added and shakes up, is extracted with dichloromethane and collects extract liquor
Organic phase, it is dry with saturated common salt water washing 3 times.It is filtered to remove solid sodium sulfate, collection filtrate decompression is distilled off molten
Agent must have the dehydroabietylamine derivatives white solid of structural formula (1) by ethyl alcohol recrystallization.
The dehydroabietylamine derivatives with structural formula (1) that embodiment 1 is prepared are the compound as white solid of 1.52g,
Yield is 78%.
Dehydroabietylamine derivatives with structural formula (1) nuclear magnetic resonance H spectrum result as shown in Figure 1, and be analyzed as follows:1H
NMR(400MHz,CDCl3): δ 7.18 (t, J=6.6Hz, 2H), 7.01 (d, J=7.6Hz, 2H), 6.92 (s, 1H), 6.86 (d,
J=8.1Hz, 1H), 6.80 (t, J=7.4Hz, 1H), 3.96 (s, 2H), 2.94 (t, J=6.8Hz, 2H), 2.85 (dt, J=
13.7,6.9Hz, 1H), 2.63 (d, J=11.7Hz, 1H), 2.47 (d, J=11.6Hz, 1H), 2.32 (d, J=12.9Hz,
1H), 1.86-1.66 (m, 4H), 1.54 (dd, J=19.5,12.5Hz, 2H), 1.41 (d, J=12.7Hz, 2H), 1.25 (d, J
=6.8Hz, 9H), 1.00 (s, 3H).
Dehydroabietylamine derivatives with structural formula (1) nuclear magnetic resonance C spectrum result as shown in Fig. 2, and be analyzed as follows:13C
NMR(101MHz,CDCl3):δ158.26,147.18,145.67,134.65,128.87,128.32,126.94,124.28,
123.96,122.90,119.05,116.40,61.32,53.73,45.91,38.46,37.57,36.80,36.52,33.55,
(30.09,25.51,24.11 d, J=1.5Hz), 19.39,18.89 (d, J=10.6Hz).
The above results prove that compound manufactured in the present embodiment is the dehydroabietylamine derivatives with structural formula (1) really.
Two, preparation has the embodiment of the method for the dehydroabietylamine derivatives of structural formula (2) as follows:
Embodiment 4: it is anhydrous that dehydroabietylamine (855mg, 3mmol) and parahydroxyben-zaldehyde (367mg, 3mmol) are dissolved in 45mL
Methanol is then added in the round-bottomed flask of 250mL, after being stirred at room temperature 10 hours, then weigh excessive sodium borohydride (380mg,
It 10mmol) is slowly added in reaction flask under ice bath, continues to stir 10h, remove solvent after reaction, a small amount of water is added, use
EA extraction, collected organic layer are dry.Solvent is removed after filtering, and there is structure by the way that column chromatography (PE:EA=1:1) is isolated
The dehydroabietylamine derivatives oily liquids of formula (2).
Embodiment 5: dehydroabietylamine (427.5mg, 1.5mmol) and parahydroxyben-zaldehyde (183.5mg, 1.5mmol) are dissolved in
45mL anhydrous methanol is then added in the round-bottomed flask of 250mL, after being stirred at room temperature 10 hours, then weighs excessive sodium borohydride
(190mg, 5mmol) is slowly added in reaction flask under ice bath, is continued to stir 10h, is removed solvent after reaction, is added a small amount of
Water is extracted with EA, collected organic layer, dry.Solvent is removed after filtering, is had by the way that column chromatography (PE:EA=1:1) is isolated
The dehydroabietylamine derivatives oily liquids of structural formula (2).
Embodiment 6: it is anhydrous that dehydroabietylamine (1.71g, 6mmol) and parahydroxyben-zaldehyde (734mg, 6mmol) are dissolved in 45mL
Methanol is then added in the round-bottomed flask of 250mL, after being stirred at room temperature 10 hours, then weigh excessive sodium borohydride (760mg,
It 20mmol) is slowly added in reaction flask under ice bath, continues to stir 10h, remove solvent after reaction, a small amount of water is added, use
EA extraction, collected organic layer are dry.Solvent is removed after filtering, and there is structure by the way that column chromatography (PE:EA=1:1) is isolated
The dehydroabietylamine derivatives oily liquids of formula (2).
The dehydroabietylamine derivatives with structural formula (2) that embodiment 5 is prepared are the grease of 1.12g, and yield is
95%.
Dehydroabietylamine derivatives with structural formula (2) nuclear magnetic resonance H spectrum result as shown in figure 3, and be analyzed as follows:1HNMR (400MHz, DMSO): δ 9.21-9.06 (m, 1H), 7.13 (d, J=8.1Hz, 1H), 7.09 (d, J=8.0Hz, 2H),
6.93 (d, J=7.7Hz, 1H), 6.83 (s, 1H), 6.69 (d, J=8.1Hz, 2H), 3.56 (q, J=13.3Hz, 2H), 2.75
(dd, J=13.2,6.3Hz, 3H), 2.42 (d, J=11.8Hz, 1H), 2.23 (d, J=12.4Hz, 1H), 2.09 (d, J=
11.8Hz, 1H), 1.74-1.44 (m, 7H), 1.24 (d, J=12.5Hz, 2H), 1.15 (d, J=6.8Hz, 6H), 1.11 (s,
3H),0.81(s,3H).
Dehydroabietylamine derivatives with structural formula (2) nuclear magnetic resonance C spectrum result as shown in figure 4, and be analyzed as follows:13CNMR(101MHz,DMSO)δ:156.37,147.69,145.15,134.88,131.88,129.28,126.77,124.45,
(123.87,115.20,60.32,54.01,44.73,38.66,37.23 d, J=18.6Hz), 36.11,33.31,30.11,
25.62,24.35 (d, J=3.7Hz), 19.84,18.94,18.61.
The above results prove that compound manufactured in the present embodiment is the dehydroabietylamine derivatives with structural formula (2) really.
Three, preparation has the embodiment of the method for the dehydroabietylamine derivatives of structural formula (3) as follows:
Embodiment 7: dehydroabietylamine (427.5mg, 1.5mmol) and P-methoxybenzal-dehyde (204.5mg, 1.5mmol) are molten
In the round-bottomed flask that 25mL anhydrous methanol is then added to 250mL, after being stirred at room temperature 8 hours, then excessive sodium borohydride is weighed
(190mg, 5mmol) is slowly added in reaction flask under ice bath, continues to be stirred overnight.Solvent is removed after reaction, is added
30mL distilled water, is extracted with dichloromethane, collected organic layer, dry.Solvent is removed after filtering, passes through column chromatography (PE:EA=
10:1) the isolated dehydroabietylamine derivatives white solid with structural formula (3).
Embodiment 8: dehydroabietylamine (855mg, 3mmol) and P-methoxybenzal-dehyde (409mg, 3mmol) be dissolved in 45mL without
Water methanol is then added in the round-bottomed flask of 250mL, after being stirred at room temperature 8 hours, then weigh excessive sodium borohydride (380mg,
It 10mmol) is slowly added in reaction flask under ice bath, continues to be stirred overnight.Solvent is removed after reaction, and 30mL distillation is added
Water is extracted with dichloromethane, collected organic layer, dry.Solvent is removed after filtering, is separated by column chromatography (PE:EA=10:1)
Obtain the dehydroabietylamine derivatives white solid with structural formula (3).
Embodiment 9: dehydroabietylamine (1.71g, 6mmol) and P-methoxybenzal-dehyde (818mg, 6mmol) be dissolved in 90mL without
Water methanol is then added in the round-bottomed flask of 250mL, after being stirred at room temperature 8 hours, then weigh excessive sodium borohydride (760mg,
It 20mmol) is slowly added in reaction flask under ice bath, continues to be stirred overnight.Solvent is removed after reaction, and 60mL distillation is added
Water is extracted with dichloromethane, collected organic layer, dry.Solvent is removed after filtering, is separated by column chromatography (PE:EA=10:1)
Obtain the dehydroabietylamine derivatives white solid with structural formula (3).
The dehydroabietylamine derivatives with structural formula (3) that embodiment 8 is prepared are the compound as white solid of 1.05g,
Yield is 86%.
Dehydroabietylamine derivatives with structural formula (3) nuclear magnetic resonance H spectrum result as shown in figure 5, and be analyzed as follows:1HNMR(400MHz,CDCl3): δ 7.35 (d, J=8.5Hz, 2H), 7.30 (d, J=8.2Hz, 1H), 7.11 (d, J=7.7Hz,
1H), 7.01 (s, 1H), 6.97 (d, J=8.6Hz, 2H), 3.89 (s, 3H), 3.81 (t, J=10.8Hz, 2H), 2.95 (dd, J
=17.1,10.3Hz, 3H), 2.65 (d, J=11.8Hz, 1H), 2.40 (dd, J=12.0,7.0Hz, 2H), 1.96-1.72 (m,
5H), 1.57 (ddd, J=29.1,19.3,8.2Hz, 3H), 1.37 (s, 3H), 1.34 (d, J=5.8Hz, 6H), 1.04 (s,
3H).
Dehydroabietylamine derivatives with structural formula (2) nuclear magnetic resonance C spectrum result as shown in fig. 6, and be analyzed as follows:13CNMR(101MHz,CDCl3):δ158.58,147.67,145.40,134.89,133.31,129.12,126.83,124.35,
123.82,113.71,60.95,55.25,54.25,45.34,38.67,37.51,37.14,36.37,33.54,30.43,
25.47,24.10 (d, J=1.6Hz), 19.49,18.94 (d, J=15.0Hz).
The above results prove that compound manufactured in the present embodiment is the dehydroabietylamine derivatives with structural formula (3) really.
Four, detection of the application to the toxicity of two kinds of prostate gland cancer cells proves by the following technical programs:
When the dehydroabietylamine derivatives of the application are used to treat prostate gland cancer cell, concrete operation step are as follows: with completely
Culture medium prepares the dehydroabietylamine derivatives of various concentration, after incubated cell 24 hours, is deposited with CCK8 method detection cancer cell is opposite
Motility rate.
Cancer cell used in embodiment hereof is Human Prostate Cancer PC-3 Cell Line and LNCaP clone FGC cell.
The dehydroabietylamine derivatives of the application are configured to dehydroabietylamine derivatives mass concentration with pure DMSO is analyzed first
For the DMSO solution of 50mmol/L, it is then diluted to the low concentration solution of different gradients with complete medium, in final solution
DMSO content is no more than 1%.
For complete medium used in DMSO solution of the diluted compounds mass concentration for 50mmol/L are as follows: LNCaP
Clone FGC cell use 1640 culture mediums, PC-3 cell use F-12 culture medium, with corresponding culture medium be diluted to 5 μm of ol/L,
10μmol/L,25μmol/L,50μmol/L.Control group is culture medium plus the DMSO agent contained by 50 μm of ol/L of maximum concentration
Amount.
It is 450nm that the CCK8 method, which detects selected absorbing wavelength when cancer cell relative survival rate,.
With structural formula (1), (2), (3) dehydroabietylamine derivatives to the toxotest tests concrete steps of 2 kinds of cancer cells
It is as follows, wherein every kind of derivative tests at least more than three times the toxotest of every kind of cancer cell, and in experimental data, every kind is spread out
Biological effect is average value in the survival rate of every kind of cancer cell:
(1), the dehydroabietylamine derivatives with structural formula (1) test the toxotest of 2 kinds of prostate gland cancer cells:
1, the dehydroabietylamine derivatives stock solution with structural formula (1) is prepared
It weighs 4.89mg and is dissolved in 250 μ L DMSO solvents with the dehydroabietylamine derivatives of structural formula (1), be configured to containing tool
The DMSO solution that the dehydroabietylamine derivatives for having structural formula (1) are 50mmol/L.
2, CCK8 surveys IC50 experiment
The dehydroabietylamine derivatives stock solution in above-mentioned 1 with structural formula (1) is diluted to substance with complete medium
The solution that amount concentration is followed successively by 0,5,25,50,100,200 μm of ol/L (tests cancer cell LNCaP clone FGC using 1640 trainings
Base is supported, PC-3 cell uses F-12 culture medium), the cell to be tested of logarithmic growth phase is configured to 105A/mL's is unicellular
Suspension is inoculated on 96 well culture plates, every empty 100 μ L, in volume fraction be 5% carbon dioxide, saturated humidity, 37 DEG C culture
It is cultivated one day in case, the sample to be tested of 100 μ L various concentrations is added on culture plate, multiple multiple holes are set, continue culture for 24 hours
Afterwards, every hole adds the CCK8 solution of 10 μ L, continues to cultivate 2h in the incubator, measures OD (extinction at 450nm wavelength in microplate reader
Degree) value, sample is calculated by the following formula to prostate gland cancer cell PC-3 and LNCaP clone FGC cell viability:
The OD of the OD/ control sample of m=sample, m indicates cell viability in formula.
With reference to Fig. 7 and Fig. 8, the inhibiting effect to PC-3 and LNCaP clone FGC cell is the results show that have structural formula
(1) IC50 of dehydroabietylamine derivatives is respectively 58.67 μm of ol/L and 208.2 μm of ol/L, illustrates there is structural formula (1)
Dehydroabietylamine derivatives have good anticancer activity to PC-3 cancer cell, and to LNCaP clone FGC cell without effect.
(2), the dehydroabietylamine derivatives with structural formula (2) test the toxotest of 2 kinds of prostate gland cancer cells:
1, the dehydroabietylamine derivatives stock solution with structural formula (2) is prepared
It weighs 4.89mg and is dissolved in 250 μ L DMSO solvents with the dehydroabietylamine derivatives of structural formula (2), be configured to containing tool
The DMSO solution that the dehydroabietylamine derivatives for having structural formula (2) are 50mmol/L.
2, CCK8 surveys IC50 experiment
The dehydroabietylamine derivatives stock solution in above-mentioned 1 with structural formula (2) is diluted to substance with complete medium
The solution that amount concentration is followed successively by 0,1,5,10,25,50 μm of ol/L (tests cancer cell LNCaP clone FGC using 1640 cultures
Base, PC-3 cell use F-12 culture medium), the cell to be tested of logarithmic growth phase is configured to the unicellular outstanding of 105/mL
Liquid is inoculated on 96 well culture plates, every empty 100 μ L, in volume fraction be 5% carbon dioxide, saturated humidity, 37 DEG C of incubators
Middle culture one day, the sample to be tested of 100 μ L various concentrations is added on culture plate, multiple multiple holes are arranged, and continues culture for 24 hours
Afterwards, every hole adds the CCK8 solution of 10 μ L, continues to cultivate 2h in the incubator, measures OD value at 450nm wavelength in microplate reader, leads to
It crosses following formula and calculates sample to prostate gland cancer cell PC-3 and LNCaP clone FGC cell viability:
The OD of the OD/ control sample of m=sample, in formula, m is cell viability.
With reference to Fig. 9 and Figure 10, the inhibiting effect to PC-3 and LNCaP clone FGC cell is the results show that have structure
The IC50 of the dehydroabietylamine derivatives of formula (2) is respectively 18.71 μm of ol/L and 59.63 μm of ol/L, is illustrated with structural formula (2)
Dehydroabietylamine derivatives good anticancer activity is all had to PC-3 and LNCaP clone FGC cancer cell.
(3), the dehydroabietylamine derivatives with structural formula (3) test the toxotest of 2 kinds of prostate gland cancer cells:
1, the dehydroabietylamine derivatives stock solution with structural formula (3) is prepared
It weighs 5.07mg and is dissolved in 250 μ L DMSO solvents with the dehydroabietylamine derivatives of structural formula (3), be configured to containing tool
The DMSO solution that the dehydroabietylamine derivatives for having structural formula (3) are 50mmol/L.
2, CCK8 surveys IC50 experiment
The dehydroabietylamine derivatives stock solution in above-mentioned 1 with structural formula (3) is diluted to substance with complete medium
The solution that amount concentration is followed successively by 0,1,5,10,25,50 μm of ol/L (tests cancer cell LNCaP clone FGC using 1640 cultures
Base, PC-3 cell use F-12 culture medium), the cell to be tested of logarithmic growth phase is configured to the unicellular outstanding of 105/mL
Liquid is inoculated on 96 well culture plates, every empty 100 μ L, in volume fraction be 5% carbon dioxide, saturated humidity, 37 DEG C of incubators
Middle culture one day, the sample to be tested of 100 μ L various concentrations is added on culture plate, multiple multiple holes are arranged, and continues culture for 24 hours
Afterwards, every hole adds the CCK8 solution of 10 μ L, continues to cultivate 2h in the incubator, measures OD value at 450nm wavelength in microplate reader, leads to
It crosses following formula and calculates sample to prostate gland cancer cell PC-3 and LNCaP clone FGC cell viability:
The OD of the OD/ control sample of m=sample, in formula, m is cell viability.
With reference to Figure 11 and Figure 12, the inhibiting effect to PC-3 and LNCaP clone FGC cell is the results show that have structure
The dehydroabietylamine derivatives of formula (3) are 47.05 μm of ol/L to the IC50 of PC-3, illustrate the dehydroabietylamine with structural formula (3)
Derivative has good anticancer activity to PC-3 cancer cell, and to LNCaP clone FGC cell without effect.
Anti-prostate cancer activity research (the IC of 1 dehydroabietylamine derivatives of table50,μM)
The above-mentioned description to embodiment is that this Shen can be understood and applied for the ease of those skilled in the art
Please.Person skilled in the art obviously easily can make various modifications to these embodiments, and described herein
General Principle is applied in other embodiments without paying creative labor.Therefore, the application is not limited to implementation here
Example, those skilled in the art make according to herein disclosed content in the case where not departing from the application scope and spirit
It improves and modifies within all scope of the present application.
Claims (10)
1. the dehydroabietylamine derivatives that a kind of aryl replaces have through structure shown in the following general formula (I):
In logical formula (I), group R1, R2, R3, R4 and R5 are each independently selected from hydrogen atom, hydroxyl, C1-C3 alkyl or C1-
C3 alkoxy.
2. the dehydroabietylamine derivatives that aryl as described in claim 1 replaces, which is characterized in that group R1 or R2 are hydroxyl；
And/or group R3 is selected from hydroxyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy；
And/or group R2 or R4 are hydrogen atom, methyl, ethyl, propyl or isopropyl.
3. the dehydroabietylamine derivatives that aryl as described in claim 1 replaces, which is characterized in that the dehydrogenation that the aryl replaces
Abietyl amine derivative includes with compound any in following structural formula (1)-(3):
4. a kind of method for preparing the dehydroabietylamine derivatives that aryl as described in claim 1 replaces, the method includes under
State step:
S1: making dehydroabietylamine and aromatic compound react the first predetermined amount of time in the first organic solvent, and it is anti-to obtain first
Answer mixture；
S2: making the first mixture and excessive reducing agent react second time period under condition of ice bath, obtains the second reaction mixing
Object；And
S3: being added water in the second reaction mixture, then extracts organic phase with the second organic solvent, and the dry organic phase is simultaneously removed
The dehydroabietylamine derivatives that the aryl replaces are obtained after removing solvent；
Wherein the aromatic compound has the structure as shown in the following general formula (II):
In logical formula (II), wherein group R1, R2, R3, R4 and R5 be each independently selected from hydrogen atom, hydroxyl, C1-C3 alkyl,
Or C1-C3 alkoxy.
5. method as claimed in claim 4, which is characterized in that the aromatic compound includes salicylide, para hydroxybenzene first
Aldehyde, P-methoxybenzal-dehyde, p-ethoxybenzaldehyde, to propoxybenzaldehyde or to isopropoxide benzaldehyde.
6. method as claimed in claim 4, which is characterized in that the first organic solvent includes methanol；
And/or second organic solvent includes methylene chloride or ethyl acetate；
And/or the reducing agent includes sodium borohydride or potassium borohydride.
7. method as claimed in claim 4, which is characterized in that first predetermined amount of time is 5-10 hours；And/or institute
Stating the second predetermined amount of time is 2-12 hours.
8. method as claimed in claim 4, which is characterized in that in step sl, the dehydroabietylamine and the aromatic series
The charged molar ratio for closing object is 1:1.
9. the dehydroabietylamine derivatives as aryl of any of claims 1-4 replaces are preparing answering in anticancer drug
With.
10. application as claimed in claim 9, which is characterized in that the anticancer drug includes the drug of anti-prostate cancer.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101580477A (en) * | 2009-06-18 | 2009-11-18 | 南京林业大学 | Dehydroabietylamine derivatives and application thereof in bactericidal and antineoplastic medicaments |
| WO2012078667A2 (en) * | 2010-12-06 | 2012-06-14 | The Penn State Research Foundation | Compositions and methods relating to proliferative diseases |
| CN107759475A (en) * | 2017-11-09 | 2018-03-06 | 嘉兴学院 | Dehydroabietylamine derivatives and its preparation method and application |
-
2018
- 2018-09-07 CN CN201811042850.2A patent/CN108997149A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101580477A (en) * | 2009-06-18 | 2009-11-18 | 南京林业大学 | Dehydroabietylamine derivatives and application thereof in bactericidal and antineoplastic medicaments |
| WO2012078667A2 (en) * | 2010-12-06 | 2012-06-14 | The Penn State Research Foundation | Compositions and methods relating to proliferative diseases |
| CN107759475A (en) * | 2017-11-09 | 2018-03-06 | 嘉兴学院 | Dehydroabietylamine derivatives and its preparation method and application |
Non-Patent Citations (7)
| Title |
|---|
| ACS: "RN：1045706-15-7", 《STN REGISTRY 数据库》 * |
| ACS: "RN：1212206-21-7", 《STN REGISTRY 数据库》 * |
| ACS: "RN：1212823-30-7", 《STN REGISTRY 数据库》 * |
| ACS: "RN：1212823-35-2", 《STN REGISTRY 数据库》 * |
| ACS: "RN：93622-70-9", 《STN REGISTRY 数据库》 * |
| XINBIN YANG，等: ""Synthesis and antitumor activities of piperazine and cyclen-conjugated dehydroabietylamine derivatives"", 《HETEROCYCL. COMMUN.》 * |
| 黄道战，等: ""N－(邻羟基苯甲基)脱氢枞胺的合成及在盐酸溶液中对碳钢的缓蚀性能"", 《林产化学与工业》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113773288A (en) * | 2021-09-30 | 2021-12-10 | 南京林业大学 | Heterocyclic ring-containing dehydroabietyl formamide compounds and preparation method and application thereof |
| CN113773288B (en) * | 2021-09-30 | 2023-09-29 | 南京林业大学 | Heterocyclic dehydroabietyl formamide compound and preparation method and application thereof |
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