CN108904491A - A kind of flavanone compound application in preparation of anti-tumor drugs - Google Patents

A kind of flavanone compound application in preparation of anti-tumor drugs Download PDF

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Publication number
CN108904491A
CN108904491A CN201810749753.0A CN201810749753A CN108904491A CN 108904491 A CN108904491 A CN 108904491A CN 201810749753 A CN201810749753 A CN 201810749753A CN 108904491 A CN108904491 A CN 108904491A
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China
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application
compound
flavanone compound
formula
flavanone
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CN201810749753.0A
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盛琦威
崔冬梅
曾明
张辰
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Zhejiang University of Technology ZJUT
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Zhejiang University of Technology ZJUT
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses one kind flavanone compound application in preparations of anti-tumor drugs as shown in formula (I), flavanone compound provided by the present invention shows preferable anti-gastric cancer cell activity, the certain anti-human placental villi cancer activity of display, it lays a good foundation for new medicament screen and exploitation, there is preferable practical value.

Description

A kind of flavanone compound application in preparation of anti-tumor drugs
(1) technical field
The present invention relates to a kind of flavanone compound application in preparations of anti-tumor drugs.
(2) background technique
Malignant tumour is to seriously threaten the common disease and all one of morbidities of human health, therefore develop novel antineoplastic Object has important practical significance.Flavanone compound is widely present in natural products, and lot of documents reports such chemical combination Object has preferably antimycotic, anti-oxidant etc. bioactivity, further studies flavanone compound and is preparing anti-tumor drug In application have certain social effect.
(3) summary of the invention
The present invention adopts the following technical scheme that：
One kind flavanone compound application in preparation of anti-tumor drugs as shown in formula (I)：
In formula (I), R1、R2、R3、R4It is respectively alone hydrogen, hydroxyl, C1~C10Alkoxy or halogen.
Further, it is preferred that the R1、R2、R3、R4It is respectively alone H, MeO, MeOCH2O or Br.
Further, the flavanone compound is particularly preferred as one of following compound：
Further, the tumour is human placenia cancer cell Bewo or gastric carcinoma cells HGC27.
Further, the tumour be human placenia cancer cell Bewo when, the compound (I-1), (I-6) or (I-7) there is preferable anti-tumor activity, the compound (I-2), (I-3), (I-4) have certain anti-tumor activity；It is described (I-1) antitumous effect it is best.
Further, the tumour be gastric carcinoma cells HGC27 when, compound (I-1), (I-2), (I-4), (I-7), (I-5) there is preferable anti-tumor activity；Compound (I-3), (I-6) have certain anti-tumor activity, and compound (I-2) is antitumor Effect is best.
Flavanone compound preparation method of the present invention mainly according to document by arone shown in formula (II) with Aromatic aldehyde shown in formula (III) at room temperature, is condensed under sodium hydroxide effect and chalcone crude product shown in formula (IV) is made, Later under 80 DEG C of reaction conditions, it is made under pyridine effect by Intramolecular cycloaddition.Flavanone shown in formula (I) Arone compounds shown in formula (II), virtue aldehyde compound shown in formula (III) and sodium hydroxide and pyridine The ratio between the amount of substance of feeding intake is 1：1：9:52,
R in formula (II), formula (III) and formula (IV)1、R2、R3、R4Respectively with R in formula (I)1、R2、R3、R4It is identical.
Flavanone compound provided by the present invention shows preferable anti-gastric cancer cell activity, shows certain anti-human placenta Villioma activity, lays a good foundation for new medicament screen and exploitation, has preferable practical value.
Specific embodiment
Below will by embodiment, the present invention is further illustrated, but the scope of the present invention is not limited thereto.
Embodiment 1：The system of 5,7- dimethoxy -2- (2- methoxyphenyl) 4-chromanone (I-3) compound It is standby
By o-methoxybenzaldehyde (544.7mg, 4.0mmol) and Xanthoxylin (784.8mg, It 4.0mmol) is dissolved in 30mL ethyl alcohol, NaOH aqueous solution (1.44g, 36.0mmol are dissolved in 20mL water) is added dropwise at 0 DEG C, drips It is stirred at room temperature 5 hours after finishing, is 3 with salt acid for adjusting pH, filtering collects solid and obtains 2 '-hydroxyls -4 ', 6 '-dimethoxys - 2- methoxyl group chalcone.Again by 2 '-hydroxyls -4 ', 6 '-dimethoxy -2- methoxyl group chalcones and pyridine (16mL, 206mmol) It is added in 30mL water, in 80 DEG C of reaction 10h, is extracted with ethyl acetate (20mL × 3), merge organic layer, concentration, column chromatography (is washed De- agent is petroleum ether：Ethyl acetate=1：1, v：V), R is collectedf(TLC monitoring, solvent is same to be washed the eluent of value 0.3~0.35 De- agent), vacuum distillation removes solvent, dry target compound (I-3) 250.7mg, yield 20%.1H NMR(500MHz, CDCl3) δ 7.60 (dd, J=7.6,1.5Hz, 1H), 7.40-7.30 (m, 1H), 7.05 (t, J=7.3Hz, 1H), 6.92 (d, J =8.2Hz, 1H), 6.19 (d, J=2.3Hz, 1H), 6.11 (d, J=2.3Hz, 1H), 5.81 (dd, J=9.2,6.8Hz, 1H), 3.92(s,3H),3.84(s,6H),2.92–2.84(m,2H).
Embodiment 2：(I-1) preparation
Operation with embodiment 1, only by o-methoxybenzaldehyde change into 2,3- 4-dihydroxy benzaldehyde (552.5mg, 4.0mmol), target compound (I-1) 303.9mg, yield 24% is made.1H NMR(500MHz,DMSO-d6)δ9.51(s, 1H), 8.69 (s, 1H), 6.89 (dd, J=7.8,1.3Hz, 1H), 6.79 (dd, J=7.8,1.3Hz, 1H), 6.69 (t, J= 7.8Hz, 1H), 6.22 (d, J=2.3Hz, 1H), 6.20 (d, J=2.3Hz, 1H), 5.67 (dd, J=12.7,2.8Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 2.95 (dd, J=16.3,12.7Hz, 1H), 2.59 (dd, J=16.3,2.8Hz, 1H)
Embodiment 3：(I-2) preparation
Operation only changes o-methoxybenzaldehyde into salicylaldhyde (488.5mg, 4.0mmol) with embodiment 1, Target compound (I-2) 168.2mg, yield 14% is made.1H NMR(500MHz,CDCl3)δ7.53(s,1H),7.48–7.39 (m, 1H), 7.25-7.16 (m, 1H), 6.98-6.95 (m, 2H), 6.20 (d, J=2.2Hz, 1H), 6.11 (d, J=2.2Hz, 1H), 5.77 (dd, J=12.4,3.6Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.06-2.94 (m, 2H)
Embodiment 4：(I-4) preparation
Operation with embodiment 1, only by o-methoxybenzaldehyde change into 2,3- dimethoxy methoxybenzaldehyde (904.8mg, 4.0mmol), target compound (I-4) 630.9mg, yield 39% is made.1H NMR(500MHz,CDCl3)δ7.29–7.72(m, 1H), 7.21-7.11 (m, 2H), 6.16 (d, J=2.2Hz, 1H), 6.11 (d, J=2.2Hz, 1H), 5.87 (dd, J=13.1, 3.2Hz,1H),5.22(s,2H),5.15(s,2H),3.91(s,3H),3.83(s,3H),3.514(s,3H),3.511(s,3H) 2.98–2.86(m,2H).
Embodiment 5：(I-5) preparation
Operation with embodiment 1, only by o-methoxybenzaldehyde change into 2,3- dimethoxy benzaldehyde (664.8mg, 4.0mmol), target compound (I-5) 468.3mg, yield 34% is made.1H NMR(500MHz,CDCl3)δ7.17–7.13(m, 2H), 6.95 (d, J=7.0Hz, 1H), 6.15 (s, 1H), 6.11 (s, 1H), 5.88-5.66 (m, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 2.99 (dd, J=16.3,13.7Hz, 1H), 2.78 (dd, J=16.6, 2.1Hz,1H).
Embodiment 6：(I-6) preparation
Operation only changes o-methoxybenzaldehyde into p-bromobenzaldehyde (740mg, 4.0mmol) with embodiment 1, is made Target compound (I-6) 53.3mg, yield 4%.1H NMR(500MHz,CDCl3) δ 7.55 (d, J=8.5Hz, 2H), 7.34 (d, J=8.5Hz, 2H), 6.16 (d, J=2.3Hz, 1H), 6.11 (d, J=2.3Hz, 1H), 5.38 (dd, J=12.9,3.0Hz, 1H), 3.90 (s, 3H), 3.84 (d, J=6.3Hz, 3H), 2.97 (dd, J=16.5,12.9Hz, 1H), 2.79 (dd, J= 16.5,3.0Hz,1H).
Embodiment 7：(I-7) preparation
Operation with embodiment 1, only by o-methoxybenzaldehyde change into adjacent methoxy methoxy benzaldehyde (664.7mg, 4.0mmol), target compound (I-7) 192.8mg, yield 14% is made.1H NMR(500MHz,CDCl3)δ7.68–7.52(m, 1H), 7.33-7.27 (m, 1H), 7.16-7.13 (m, 1H), 7.12-7.08 (m, 1H), 6.18 (d, J=2.2Hz, 1H), 6.11 (d, J=2.2Hz, 1H), 5.82 (dd, J=11.0,5.1Hz, 1H), 5.21 (s, 2H), 3.91 (s, 3H), 3.83 (s, 3H), 3.46(s,3H),2.95–2.83(m,2H).
Embodiment 8：Anti-human placental villi cancer cell Bewo biological activity test
External anti-human placental villi cancer cell Bewo activity test method：Mtt assay
Experimental procedure：
1) preparation of sample：For solvable sample, every 1mg is dissolved with 20 μ L DMSO, takes 2uL dilute with 1000 μ L culture solutions It releases, makes 100 μ g/mL of concentration, then with culture solution serial dilution to using concentration.
2) culture of cell
2.1) preparation of culture medium:Contain 800,000 units of Penicillin, 1.0g streptomysin, 10% inactivation in every 1000mL culture medium Fetal calf serum.
2.2) culture of cell：By tumor cell inoculation in culture medium, 37 DEG C are set, 5% CO2It is cultivated in incubator, 3 ~5d passage.
3) inhibiting effect of the measurement sample to growth of tumour cell
Cell EDTA- pancreatin digestive juice is digested, and is diluted to 1 × 10 with culture medium5/ mL is added to the training of 96 hole cells It supports in plate, every hole 100uL sets 37 DEG C, 5% CO2It is cultivated in incubator.After inoculation for 24 hours, it is added and uses the diluted sample of culture medium, Every 100 μ L of hole, each concentration add 3 holes, set 37 DEG C, 5% CO2It cultivates in incubator, is added in cell culture well after 72h The MTT of 5mg/mL, every 10 μ L of hole set 37 DEG C of incubation 4h, and DMSO is added, and every 150 μ L of hole is vibrated, Shi Jia Za is complete with oscillator Dissolution, with microplate reader under 570nm wavelength colorimetric.It is used with similarity condition and is free of sample, the culture medium training containing same concentration DMSO Feeding cell calculates sample to tumour cell IC as control50, the results are shown in Table 1.
Using human placenia cancer cell Bewo as model, flavanone compound (I-1)~sample of (I-7) 7 is determined In vitro to the inhibiting effect of osteosarcoma cell growth (see Table 1 for details for result).
IC of each compound of table 1 to human placenia cancer cell Bewo50(μg/mL)
Compound IC50(%)
(I-1) 27.78
(I-2) 40.94
(I-3) 41.64
(I-4) 46.24
(I-5) >100
(I-6) 33.07
(I-7) 38.09
Embodiment 9：Resisting human gastric cancer cell HGC27 biological activity test
Human placenia cancer cell Bewo is changed to gastric carcinoma cells HGC27, other operations are the same as embodiment 1.
Using gastric carcinoma cells HGC27 as model, it is right in vitro to determine flavanone compound (I-1)~sample of (I-7) 7 The inhibiting effect of osteosarcoma cell growth (see Table 2 for details for result).
IC of each compound of table 2 to stomach cancer cell HGC2750(μg/mL)

Claims (9)

1. a kind of flavanone compound application in preparation of anti-tumor drugs as shown in formula (I)：
In formula (I), R1、R2、R3、R4It is respectively alone hydrogen, hydroxyl, C1~C10Alkoxy or halogen.
2. application as described in claim 1, it is characterised in that：The R1、R2、R3、R4It is respectively alone H, MeO, MeOCH2O or Br。
3. application as described in claim 1, it is characterised in that：Flavanone compound shown in the formula (I) be it is following it One compound：
4. application as described in claim 1, it is characterised in that：The tumour is human placenia cancer cell Bewo.
5. application as described in claim 1, it is characterised in that：The tumour is gastric carcinoma cells HGC27.
6. application as claimed in claim 4, it is characterised in that：The flavanone compound is (I-1), (I-6) or (I- 7)。
7. application as claimed in claim 6, it is characterised in that：The flavanone compound is (I-1).
8. application as claimed in claim 5, it is characterised in that：The flavanone compound is (I-1), (I-2), (I- 4), (I-5) or (I-7).
9. application as claimed in claim 8, it is characterised in that：The flavanone compound is (I-2).
CN201810749753.0A 2018-07-10 2018-07-10 A kind of flavanone compound application in preparation of anti-tumor drugs Pending CN108904491A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113045527A (en) * 2021-03-22 2021-06-29 广东省科学院动物研究所 Dihydrothromone derivative and synthesis method and application thereof

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KR20090090472A (en) * 2008-02-21 2009-08-26 덕성여자대학교 산학협력단 Composition against cancer comprising flavanone derivatives
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113045527A (en) * 2021-03-22 2021-06-29 广东省科学院动物研究所 Dihydrothromone derivative and synthesis method and application thereof
CN113045527B (en) * 2021-03-22 2022-11-08 广东省科学院动物研究所 Dihydrothromone derivative and synthesis method and application thereof

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Application publication date: 20181130