CN104844680B - O-(benzimidazolyl) ethyl derivative of Cleistanone, preparation method and its usage - Google Patents
O-(benzimidazolyl) ethyl derivative of Cleistanone, preparation method and its usage Download PDFInfo
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Abstract
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Cleistanone Cleistanone derivant, preparation method and in the purposes preparing on antitumor drug.The present invention has synthesized a new Cleistanone Cleistanone derivant, and discloses its preparation method.Pharmacological experiment shows, the Cleistanone Cleistanone derivant of the present invention has antineoplastic action, has the value of developing anti-tumor medicaments.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Cleistanone Cleistanone and spread out
Biological, preparation method and its usage.
Background technology
Cancer is one of disease maximum to human life's health hazard, has substantial amounts of people to die from cancer every year.
The focus of the research and development of cancer therapy drug always study of pharmacy.Antitumor drug has 74% be natural product or its spread out
Biology, if paclitaxel and derivant thereof are exactly the antitumor drug that application effectiveness comparison is good the most clinically.Therefore,
From natural product, find compound or lead compound and carry out structural modification and obtain its derivant, thus obtaining
The potential drug of high-efficiency low-toxicity most has important value.
The compound Cleistanone Cleistanone that the present invention relates to is one and within 2011, delivers (Van Trinh Thi
Thanh et al.,2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis with
a New Carbon Skeleton.Volume 2011,Issue 22,Pages 4,108 4111, August 2011)
Compound, we have carried out structural modification to compound Cleistanone Cleistanone, it is thus achieved that one new
Cleistanone Cleistanone derivant, and its anti-tumor activity is evaluated, it has antitumor and lives
Property.
Summary of the invention
The invention discloses a Cleistanone Cleistanone derivant, its structure is:
Cleistanone Cleistanone derivant (III) of the present invention can be prepared by following method:
(1) Cleistanone Cleistanone (I) reacts with glycol dibromide and obtains Cleistanone Cleistanone
O-bromoethyl derivant (II)；
(2) O-bromoethyl derivant (II) of Cleistanone Cleistanone and benzimidazole occur to replace instead
Cleistanone Cleistanone derivant (III) should be prepared.
Further the preparation method of Cleistanone Cleistanone derivant (III) is:
(1) 440mg compound Cleistanone Cleistanone (I) is dissolved in 10mL benzene, adds in solution
The tetrabutyl ammonium bromide of 0.04g, the glycol dibromide of 3.760g and 50% sodium hydroxide solution of 6mL；
Mixture stirs 24h at 25 degrees Celsius；After 24h, reactant liquor is poured in frozen water, use dichloromethane immediately
It is extracted twice, merges organic phase solution；Then to organic phase solution successively with water and saturated aqueous common salt washing 3
Secondary, then be dried with anhydrous sodium sulfate, last concentrating under reduced pressure is removed solvent and is obtained product crude product；Product crude product silicon
Gel column chromatography eluting, flowing is mutually: petroleum ether/acetone=100:1, v/v, collects yellow and concentrates elution band and get final product
Yellow solid to O-bromoethyl derivant (II) of Cleistanone Cleistanone.
(2) the O-bromoethyl derivant of the Cleistanone Cleistanone of 273mg is dissolved in 15mL acetonitrile work as
In, it is added thereto to the Anhydrous potassium carbonate of 345mg, the potassium iodide of 84mg and the benzimidazole of 1180mg,
Mixture is heated to reflux 5h；Reactant liquor is poured in frozen water after terminating by reaction, extracts three with equivalent dichloromethane
Secondary, merge organic facies；Organic facies after merging with water and saturated aqueous common salt washing successively, then use anhydrous slufuric acid
Sodium is dried, and concentrating under reduced pressure is removed solvent and obtained product crude product；Product crude product silica gel column chromatography is purified, and flow phase
For: petroleum ether/acetone=100:1.5, v/v, collects brown and concentrates elution band i.e. to obtain Cleistanone Cleistanone
The brown solid of derivant (III).
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, Cleistanone Cleistanone derivant (III) of the present invention has preferably
Antitumor action.The pharmaceutically acceptable salt of the present invention have with its compound as drug effect.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not had
Any restriction of body embodiment, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Cleistanone Cleistanone
The preparation method of compound Cleistanone Cleistanone (I) is with reference to Crinis Carbonisatus such as Van Trinh Thi Thanh
Document (Van Trinh Thi Thanh et al., the 2011.Cleistanone:A Triterpenoid from of table
Cleistanthus indochinensis with a New Carbon Skeleton.Volume 2011,Issue 22,
Pages 4,108 4111, August 2011) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2 Cleistanone Cleistanone
Compound I (440mg, 1.00mmol) is dissolved in 10mL benzene, in solution, adds tetrabutyl phosphonium bromide
Ammonium (TBAB) (0.04g), glycol dibromide (3.760g, 20.00mmol) and 50% hydrogen of 6mL
Sodium hydroxide solution.Mixture stirs 24h at 25 degrees Celsius.After 24h, reactant liquor is poured in frozen water, vertical
I.e. it is extracted twice with dichloromethane, merges organic phase solution.Then to organic phase solution successively with water and saturated food
Saline washs 3 times, then is dried with anhydrous sodium sulfate, and last concentrating under reduced pressure is removed solvent and obtained product crude product.Produce
Thing crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1, v/v), collects yellow and concentrates
Elution band i.e. obtains the yellow solid (344mg, 63%) of compound II.
1H NMR(500MHz,DMSO-d6) δ 5.04 (s, 1H), 4.82 (s, 1H), 3.94 (d, J=26.5Hz,
1H), 3.87 (d, J=26.5Hz, 2H), 3.57 (s, 2H), 2.40 (d, J=14.0Hz, 1H), 2.39 (d, J=
14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H),1.82(s,1H),1.62(s,2H),1.57
(d, J=3.3Hz, 1H), 1.54 (d, J=3.3Hz, 1H), 1.50 (d, J=1.2Hz, 1H), 1.47 (d, J=1.2
Hz, 1H), 1.39 (d, J=15.3Hz, 2H), 1.34 (d, J=15.3Hz, 1H), 1.26 (dd, J=32.6,13.7
Hz, 4H), 1.13 (d, J=18.0Hz, 2H), 1.05 (s, 6H), 0.98 (s, 1H), 0.88 (s, 12H), 0.78 (s,
3H),0.74(s,1H)。
13C NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.63(s),
69.85(s),59.71(s),52.55(s),51.21(s),47.92(s),44.10(s),42.25(s),41.73(s),
40.64 (s), 40.16 (s), 38.88 (s), 38.65 (s), 37.21 (s), 36.23 (s), 33.34 (d, J=1.1Hz),
32.96(s),29.91(s),27.18(s),26.03(s),24.23(s),23.96(s),20.77(s),18.48(s),
17.98(s),16.93(s)。
HRMS(ESI)m/z[M+H]+calcd for C32H52BrO2:547.3151；found 547.3159.
The conjunction of O-(benzimidazolyl) ethyl derivative (III) of embodiment 3 Cleistanone Cleistanone
Become
Compound II (273mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and benzimidazole (1180mg,
10mmol), mixture is heated to reflux 5h.Reactant liquor is poured in frozen water after terminating by reaction, uses equivalent dichloro
Methane extracts three times, merges organic facies.Organic facies after merging with water and saturated aqueous common salt washing successively, then
Being dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product silica gel column chromatography is pure
Change (flowing is mutually: petroleum ether/acetone=100:1.5, v/v), collect brown and concentrate elution band, concentrate and i.e. obtain
The brown solid (105.2mg, 36%) of compound III.
1H NMR (500MHz, DMSO-d6) δ 8.27 (s, 1H), 7.68 (d, J=25.0Hz, 2H), 7.31 (s,
1H), 7.21 (s, 1H), 4.65 (s, 1H), 4.56 (s, 1H), 4.14 (d, J=7.9Hz, 2H), 4.05 (s, 1H),
3.93 (s, 2H), 2.51 (d, J=127.9Hz, 1H), 2.37 (s, 1H), 2.28 (d, J=15.8Hz, 2H), 2.22
(s, 1H), 1.90 (s, 2H), 1.83 (s, 1H), 1.66 (s, 2H), 1.62 1.49 (m, 4H), 1.29 (t, J=17.7
Hz, 3H), 1.19 (d, J=14.3Hz, 2H), 1.11 (d, J=7.6Hz, 7H), 1.02 (dd, J=42.5,9.8Hz,
13H),0.88(s,3H),0.80(s,1H),0.63(s,1H).
13C NMR(125MHz,DMSO-d6)δ216.57(s),154.46(s),146.57(s),139.24(s),
134.35(s),124.01(s),123.47(s),118.67(s),110.97(s),105.19(s),74.62(s),67.84
(s),59.73(s),52.52(s),51.17(s),47.88(s),45.48(s),44.08(s),42.26(s),41.75(s),
40.61(s),40.13(s),38.83(s),38.62(s),37.22(s),36.24(s),33.30(s),32.92(s),
29.86(s),27.16(s),26.04(s),24.24(s),23.92(s),20.75(s),18.43(s),17.97(s),
16.93(s).
HRMS(ESI):m/z[M+H]+calcd for C39H57N2O2:585.4420；found:585.4416.
Embodiment 4 anti tumor activity in vitro screens
Screening cell strain is HepG2 (human liver cancer cell), PANC-1 (human pancreas cancer), MCF-7 (people
Breast cancer cell), SW620 (human colon cancer cell), A549 (human lung carcinoma cell), HGC-27 (people's gastric cancer
Cell).
Experimental technique:
The cell that trophophase of taking the logarithm is in good condition, trypsinization, make 5 × 104The suspension of cell/mL.
Cell suspension is moved into 96 well culture plates, every hole 100 μ L, puts 37 DEG C, 5%CO2Under the conditions of cultivate 24h.
Test-compound III DMSO is configured to certain density mother solution, then uses RPMI1640 culture medium
Derivant mother solution is diluted to the diluent of different activity.Remove old culture medium, add containing of variable concentrations
Medicine culture medium, every hole 100 μ L.Separately set blank group.After medicine effect 48h, inhale and abandon pastille culture medium,
In every hole addition serum-free, without phenol red 1640 culture medium 100 μ L, add MTT solution (5mg/mL)
10 μ L, continue incubation 4h.
Sucking supernatant in each hole, every hole adds DMSO 150 μ L, dark place vibration 10min, makes crystal
Fully dissolving, microplate reader measures the absorbance value (OD value) in each hole at 490nm, and the propagation calculating cell presses down
Rate processed: suppression ratio (%)=(1-medication group mean OD value/blank group mean OD value) × 100%.Should
Carry out data process with SPSS16.0 software and calculate the half-inhibition concentration (IC of cancer cell multiplication50), result
It is shown in Table 1.
The table 1 compound III in-vitro multiplication inhibitory action to 7 kinds of cancerous cell
As shown in table 1 result, synthesized derivant is respectively provided with certain Proliferation Ability to different tumor cells
Effect.Derivant synthesized by explanation shows preferable active anticancer, has the potentiality of exploitation cancer therapy drug.
Embodiment 5 compound involved in the present invention II and the preparation of III tablet
Taking the one in the middle of 20 g of compound III or its pharmaceutically acceptable salt, the normal of tablet is prepared in addition
Rule adjuvant 180 grams, mixing, conventional tablet presses makes 1000.
Embodiment 6 compound involved in the present invention II and the preparation of III capsule
Taking the one in the middle of 20 g of compound III or its pharmaceutically acceptable salt, the normal of capsule is prepared in addition
Rule adjuvant such as starch 180 grams, mixes, encapsulated makes 1000.
Claims (7)
1. a Cleistanone Cleistanone derivant with structure shown in formula III and pharmaceutically acceptable salt thereof:
2. the preparation method of Cleistanone Cleistanone derivant as claimed in claim 1, is characterized by:
(1) Cleistanone Cleistanone (I) reacts with glycol dibromide and obtains Cleistanone Cleistanone
O-bromoethyl derivant (II)；
(2) O-bromoethyl derivant (II) of Cleistanone Cleistanone and benzimidazole occur to replace instead
Cleistanone Cleistanone derivant (III) should be prepared；
3. the preparation method of Cleistanone Cleistanone derivant as claimed in claim 2, is characterized by:
(1) 440mg compound Cleistanone Cleistanone (I) is dissolved in 10mL benzene, adds in solution
The tetrabutyl ammonium bromide of 0.04g, the glycol dibromide of 3.760g and 50% sodium hydroxide solution of 6mL；
Mixture stirs 24h at 25 degrees Celsius；After 24h, reactant liquor is poured in frozen water, use dichloromethane immediately
It is extracted twice, merges organic phase solution；Then to organic phase solution successively with water and saturated aqueous common salt washing 3
Secondary, then be dried with anhydrous sodium sulfate, last concentrating under reduced pressure is removed solvent and is obtained product crude product；Product crude product silicon
Gel column chromatography eluting, flowing is mutually: petroleum ether/acetone=100:1, v/v, collects yellow and concentrates elution band and get final product
Yellow solid to O-bromoethyl derivant (II) of Cleistanone Cleistanone；
(2) the O-bromoethyl derivant of the Cleistanone Cleistanone of 273mg is dissolved in 15mL acetonitrile work as
In, it is added thereto to the Anhydrous potassium carbonate of 345mg, the potassium iodide of 84mg and the benzimidazole of 1180mg,
Mixture is heated to reflux 5h；Reactant liquor is poured in frozen water after terminating by reaction, extracts three with equivalent dichloromethane
Secondary, merge organic facies；Organic facies after merging with water and saturated aqueous common salt washing successively, then use anhydrous slufuric acid
Sodium is dried, and concentrating under reduced pressure is removed solvent and obtained product crude product；Product crude product silica gel column chromatography is purified, and flow phase
For: petroleum ether/acetone=100:1.5, v/v, collects brown and concentrates elution band i.e. to obtain Cleistanone Cleistanone
The brown solid of derivant (III).
4. Cleistanone Cleistanone derivant as claimed in claim 1 and pharmaceutically acceptable salt thereof are in system
Application in standby antitumor drug.
5. Cleistanone Cleistanone derivant as claimed in claim 4 and pharmaceutically acceptable salt thereof are in system
Application in standby antitumor drug, is characterized by: described tumor is digestive system tumor.
6. Cleistanone Cleistanone derivant as claimed in claim 5 and pharmaceutically acceptable salt thereof are in system
Application in standby antitumor drug, is characterized by: described digestive system tumor is hepatocarcinoma, cancer of pancreas, colon cancer
Or gastric cancer.
7. Cleistanone Cleistanone derivant as claimed in claim 4 and pharmaceutically acceptable salt thereof are in system
Application in standby antitumor drug, is characterized by: described tumor is breast carcinoma or pulmonary carcinoma.
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