CN105503978A - Cleistanthin-A derivatives, preparation method and applications thereof - Google Patents
Cleistanthin-A derivatives, preparation method and applications thereof Download PDFInfo
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- CN105503978A CN105503978A CN201410555794.8A CN201410555794A CN105503978A CN 105503978 A CN105503978 A CN 105503978A CN 201410555794 A CN201410555794 A CN 201410555794A CN 105503978 A CN105503978 A CN 105503978A
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- 0 CC(*)CC(C(C(O[C@@]1OC[C@@](*)C(C)C1*)=C1CO2)=CCO)C(c(cc3)cc4c3OCO4)=C1C2=C Chemical compound CC(*)CC(C(C(O[C@@]1OC[C@@](*)C(C)C1*)=C1CO2)=CCO)C(c(cc3)cc4c3OCO4)=C1C2=C 0.000 description 4
Abstract
The invention discloses Cleistanthin-A derivatives represented by the formula (I), geometric isomers and pharmaceutically acceptable salts thereof. The invention also relates to a preparation method of the compounds represented by the formula (I). People find that the derivatives have a strong activity on inhibiting the growth of tumor cells, and thus the derivatives can be used to prepare antitumor drugs.
Description
Technical field
The invention belongs to pharmaceutical chemistry and pharmacological techniques field.Specifically, the present invention relates to the derivative of the Diphylline glucosides Cleistanthin-A shown in formula (I), its geometrical isomer and pharmacy acceptable salt thereof.The invention still further relates to the method for preparation formula (I) compound.These derivatives are found to have stronger growth inhibitory activity to tumor cell, can be used as antineoplastic use.
Background technology
Along with the progress of medical science, general transmissible disease is controlled gradually, and malignant tumour-cancer becomes common and one of principal disease of serious threat human life and quality of life.The antitumor drug of plant origin occupies an important position in clinical treatment.Diphylline wood sugar glucosides Cleistanthin-A and quinoline promise glucosides PatentiflorinA has stronger anti-tumor activity.
We provide Cleistanthin-A derivative in the present invention, the susceptibility of tumor disease and tumour cell is often sent out according to China, we have selected human colon cancer cell (HCT-116), human breast cancer cell (MCF-7), human lung adenocarcinoma cell (A549), human liver cancer cell (HepG2), human cervical carcinoma cell (Hela), human stomach cancer cell line (MKN45), human renal carcinoma cell (Ketr-3), human oral squamous cell carcinoma (KB) is as the index of in vitro cytotoxic effect Pharmacological Evaluation, and the screening of MTT cytotoxicity has been carried out to the compound of synthesis.
Summary of the invention
The object of this invention is to provide a kind of there is growth inhibitory activity to tumor cell there is Diphylline wood sugar glucosides Cleistanthin-A Hete rocyclic derivatives.Specifically, the invention provides the compound that one has formula (1) structure.
Wherein:
N represents the carbonatoms 5-8 of straight-chain alkyl-sub-,
R is for being selected from the heterocycles such as morpholine, N-amino-morpholine, hydroxyethyl piperazine, N methyl piperazine, piperidines, 4-hydroxy piperidine, 3-hydroxy piperidine, 4-piperidinyl piperidine, Pyrrolidine.
Another object of the present invention is to provide the preparation method of formula (1) compound:
Another object of the present invention is to provide the purposes of formula (1) compound for the preparation of control tumor disease medicine.
The invention provides the Cleistanthin-A Hete rocyclic derivatives shown in a kind of formula (1):
Wherein n is 6, R for being compound 2a and 2b shown in formula (2) below when 4-hydroxy piperidine, N methyl piperazine;
Wherein n be that 7, R is morpholine, hydroxyethyl piperazine time be compound 2c and 2d shown in formula (2) below;
Wherein n is 8, R for being compound 2e and 2f shown in formula (2) below when 4-hydroxy piperidine, piperidines:
The preferred formula of the present invention (2) compound comprises:
Compound 2a:2-O-[6 '-(4 "-hydroxy piperidine base)-n-hexyl]-Cleistanthin-A
Compound 2b:2-O-[6 '-(N methyl piperazine base)-n-hexyl]-Cleistanthin-A
Compound 2c:2-O-[7 '-(morpholinyl)-n-heptyl]-Cleistanthin-A
Compound 2d:2-O-[7 '-(4 "-hydroxy piperidine base)-n-heptyl]-Cleistanthin-A
Compound 2e:2-O-[8 '-(4 "-hydroxy piperidine base)-n-octyl]-Cleistanthin-A
Compound 2f:2-O-[8 '-(piperidyl)-n-octyl]-Cleistanthin-A
Another object of the present invention there is provided the preparation method of Cleistanthin-A Hete rocyclic derivatives in formula (1), the feature of this synthesis is to be obtained by reacting bromine alkyl Cleistanthin-A by Cleistanthin-A to sodium hydroxide, two corresponding bromoalkanes in methyl-sulphoxide, then to Anhydrous potassium carbonate, corresponding heterocycle at N, in N '-dimethyl methane amide reaction and obtained.
Synthetic route of the present invention:
The present invention is further illustrated below by embodiment.Embodiment gives the synthesis of representative new compound and dependency structure appraising datum and amount of activated data.Mandatory declaration, following embodiment is for illustration of the present invention instead of limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment
Embodiment 1
By Cleistanthin-A (27mg, 0.05mmol) be dissolved in DMSO (2mL), after stirred at ambient temperature 5min, add NaOH (16mg, 0.4mmol) and 1,6-dibromo-hexane (17mg, 0.07mmol) carries out room temperature reaction.Add after TCL detection reaction terminates with diluted ethyl acetate, wash 3 times, saturated NaHCO
3wash, anhydrous Na
2sO
4drying, pressurization is concentrated, and column chromatography obtains white solid 27mg.This white solid is dissolved in DMF (2mL), after stirred at ambient temperature 5min, adds K
2cO
3(69mg, 0.4mmol) and 4-hydroxy piperidine (10mg, 0.1mmol), room temperature reaction, adds after TCL detection reaction terminates with diluted ethyl acetate, washes 3 times, saturated NaHCO
3wash, anhydrous Na
2sO
4drying, pressurization is concentrated, and column chromatography obtains white solid 2a (25mg, two step overall yields 77%).
m.p.104-106℃；
1HNMR(400Hz,CDCl
3):δ7.77(s,1H,5-ArH-),7.09(s,1H,8-ArH-),6.97(d,J＝7.2Hz,1H,6′-ArH-),6.85-6.79(m,2H,2′,5′-ArH-),6.10(s,1H,7′-CH
2-),6.05(s,1H,7′-CH
2-),5.47-5.46(m,2H,3a-CH
2-),4.84(d,J＝7.6Hz,1H,1″-CH-),4.07(s,3H,6-OMe),4.02-3.98(m,2H,2″,5″-CH-),3.90-3.86(m,1H,5″-CH-),3.81(s,3H,7-OMe),3.67(s,3H,3″-OMe),3.50(s,3H,4″-OMe),3.46-3.35(m,2H,-CH
2-),3.22(t,J＝8.8Hz,1H,4″-CH
2-),3.06(t,J＝10.4Hz,1H,3″-CH-),2.96(s,1H,-CH-),2.49-2.45(m,10H,5×-CH
2-),1.74-1.25(m,8H,4×-CH
2-)；
13CNMR(CDCl
3):δ169.83,151.85,150.21,147.52,144.26,136.20,130.85,130.51,128.35,126.93,123.62,123.56,119.25,110.72,110.67,108.20,106.32,104.60,101.24,100.89,85.43,81.61,79.51,73.64,67.28,63.53,61.00,58.80,58.06,56.28,55.85,50.06,32.94,30.19,29.69,27.29,25.97,25.84；HRMS(ESI-TOF)(m/z)[M+H]
+calcdforC
39H
50NO
12724.3328,found724.3346.
Method according to above embodiment 1 prepares following examples compound
Listing below is the physicochemical data of each compound of 2b-2f:
2b：m.p.120-122℃；[α]
589 27:-47°；
1HNMR(400Hz,CDCl
3):δ7.77(s,1H,5-ArH-),7.09(s,1H,8-ArH-),6.98(d,J＝8.8Hz,1H,6′-ArH-),6.85-6.79(m,2H,2′,5′-ArH-),6.10(s,1H,7′-CH
2-),6.05(s,1H,7′-CH
2-),5.51-5.41(m,2H,3a-CH
2-),4.84(d,J＝7.6Hz,1H,1″-CH-),4.07(s,3H,6-OMe),4.05-3.98(m,2H,2″,5″-CH-),3.90-3.86(m,1H,5″-CH-),3.81(s,3H,7-OMe),3.67(s,3H,3″-OMe),3.49(s,3H,4″-OMe),3.48-3.35(m,2H,-CH
2-),3.24(t,J＝8.8Hz,1H,4″-CH
2-),3.08(t,J＝10.4Hz,1H,3″-CH-),2.450-2.31(m,12H,6×-CH
2-),1.74-1.32(m,8H,4×-CH
2-)；
13CNMR(CDCl
3):δ169.82,151.81,150.15,147.51,144.23,136.20,130.84,130.51,130.46,128.34,126.89,123.62,123.56,119.27,110.73,110.67,108.22,106.26,104.65,101.26,100.81,85.45,81.64,79.50,73.80,67.30,63.53,61.07,58.87,58.55,56.31,55.87,54.85,52.97,45.87,30.27,27.47,26.78,25.99；HRMS(ESI-TOF)(m/z)[M+H]
+calcdforC
39H
51N
2O
12723.3493,found723.3494.
2c：m.p.68-70℃；
1HNMR(400Hz,CDCl
3):δ7.77(s,1H,5-ArH-),7.09(s,1H,8-ArH-),6.97(d,J＝8.4Hz,1H,6′-ArH-),6.85-6.81(m,2H,2′,5′-ArH-),6.10(s,1H,7′-CH
2-),6.05(s,1H,7′-CH
2-),5.47-5.46(m,2H,3a-CH
2-),4.84(d,J＝7.6Hz,1H,1″-CH-),4.07(s,3H,6-OMe),4.02-3.98(m,2H,2″,5″-CH-),3.90-3.81(m,1H,5″-CH-),3.81(s,3H,7-OMe),3.67(s,3H,3″-OMe),3.50(s,3H,4″-OMe),3.49-3.46(m,2H,-CH
2-),3.24(t,J＝8.8Hz,1H,4″-CH
2-),3.09(t,J＝11.6Hz,1H,3″-CH-),2.96(s,1H,-CH-),2.87(s,2H,-CH
2-),2.49-2.04(m,8H,4×-CH
2-),1.74-1.26(m,8H,4×-CH
2-)；
13CNMR(CDCl
3):δ169.78,151.84,150.20,147.52,144.26,136.22,130.86,130.43,128.36,126.92,123.63,123.56,119.30,110.73,110.68,108.21,106.32,104.67,101.23,100.87,85.50,81.70,79.53,73.85,67.27,66.67,63.55,61.02,58.95,58.82,56.28,55.85,53.51,30.27,29.69,29.42,27.48,25.97；HRMS(ESI-TOF)(m/z)[M+H]
+calcdforC
39H
50NO
12724.3328,found724.3307
2d：m.p.84-86℃；
1HNMR(400Hz,CDCl
3):δ7.78(s,1H,5-ArH-),7.09(s,1H,8-ArH-),6.97(d,J＝7.6Hz,1H,6′-ArH-),6.85-6.79(m,2H,2′,5′-ArH-),6.10(s,1H,7′-CH
2-),6.05(s,1H,7′-CH
2-),5.51-5.41(m,2H,3a-CH
2-),4.84(d,J＝7.6Hz,1H,1″-CH-),4.07(s,3H,6-OMe),4.02-3.98(m,2H,2″,5″-CH-),3.88-3.86(m,1H,5″-CH-),3.81(s,3H,7-OMe),3.68(s,3H,3″-OMe),1.66-1.63(m,2H,-CH
2-),3.50(s,3H,4″-OMe),3.49-3.46(m,1H,-CH
2-),3.39-3.24(m,1H,-CH
2-),3.24(t,J＝8.8Hz,1H,4″-CH
2-),3.08(t,J＝10.0Hz,1H,3″-CH-),2.96(s,1H,-CH-),2.89(s,2H,-CH
2-),2.61-2.55(m,6H,3×-CH
2-),2.38-2.34(m,2H,-CH
2-),2.00(s,1H,-OH-),1.73-1.68(m,2H,-CH
2-),1.39-1.32(m,8H,4×-CH
2-),
13CNMR(CDCl
3):δ169.78,151.83,150.19,147.52,144.26,136.20,130.85,130.41,130.39,128.36,126.92,123.62,123.56,119.28,110.73,110.67,108.20,106.30,104.66,101.24,100.88,85.49,81.68,79.52,73.84,67.27,63.54,61.00,59.26,58.82,58.42,57.64,56.28,55.83,52.73,52.51,30.27,29.40,27.51,26.50,25.96；HRMS(ESI-TOF)(m/z)[M+H]
+calcdforC
41H
55N
2O
12767.3750,found767.3751.
2e：m.p.106-107℃；
1HNMR(400Hz,CDCl
3):δ7.78(s,1H,5-ArH-),7.09(s,1H,8-ArH-),6.97(d,J＝6.0Hz,1H,6′-ArH-),6.84-6.79(m,2H,2′,5′-ArH-),6.09(s,1H,7′-CH
2-),6.06(s,1H,7′-CH
2-),5.51-5.42(m,2H,3a-CH
2-),4.85(d,J＝7.6Hz,1H,1″-CH-),4.07(s,3H,6-OMe),4.02-3.99(m,2H,2″,5″-CH-),3.89-3.85(m,1H,5″-CH-),3.81(s,3H,7-OMe),3.67(s,3H,3″-OMe),3.49(s,3H,4″-OMe),3.41-3.36(m,2H,-CH
2-),3.24(t,J＝8.8Hz,1H,4″-CH
2-),3.06(t,J＝11.2Hz,1H,3″-CH-),2.81(d,J＝7.6Hz,1H,-CH-),2.30(s,2H,-CH
2-),1.93-1.69(m,8H,4×-CH
2-),1.48-1.26(m,12H,6×-CH
2-)；
13CNMR(CDCl
3):δ169.95,151.86,150.22,147.51,144.34,136.17,130.83,130.22,128.36,127.01,123.63,123.56,119.19,110.73,110.66,108.20,106.28,104.63,101.25,100.97,85.40,81.60,79.47,73.75,67.31,63.53,60.99,58.80,57.37,56.29,53.83,48.47,30.47,30.24,29.28,29.26,29.08,26.88,25.90,24.02；HRMS(ESI-TOF)(m/z)[M+H]
+calcdforC
41H
54NO
12752.3641,found752.3648.
2f：m.p.122-123℃；
1HNMR(400Hz,CDCl
3):δ7.78(s,1H,5-ArH-),7.09(s,1H,8-ArH-),6.95(d,J＝7.6Hz,1H,6′-ArH-),6.85-6.79(m,2H,2′,5′-ArH-),6.10(s,1H,7′-CH
2-),6.05(s,1H,7′-CH
2-),5.51-5.42(m,2H,3a-CH
2-),4.85(d,J＝7.2Hz,1H,1″-CH-),4.07(s,3H,6-OMe),4.03-3.99(m,2H,2″,5″-CH-),3.89-3.86(m,1H,5″-CH-),3.81(s,3H,7-OMe),3.67(s,3H,3″-OMe),3.49(s,3H,4″-OMe),3.41-3.36(m,2H,-CH
2-),3.23(t,J＝8.4Hz,1H,4″-CH
2-),3.07(t,J＝11.2Hz,1H,3″-CH-),2.96(s,2H,-CH
2-),2.89-2.85(m,4H,2×-CH
2-),1.87-1.69(m,6H,3×-CH
2-),1.94-1.39(m,12H,6×-CH
2-)；
13CNMR(CDCl
3):δ169.77,151.83,150.20,147.49,144.33,136.12,130.81,130.18,128.36,126.97,123.61,123.54,119.20,110.71,110.65,108.17,106.27,104.59,101.22,100.95,85.36,81.58,79.45,73.72,67.23,63.51,60.97,58.78,57.43,56.28,55.84,53.06,31.43,30.21,29.23,29.01,26.82,25.89,23.51,22.56,22.17；HRMS(ESI-TOF)(m/z)[M+H]
+calcdforC
41H
54NO
11736.3691,found736.3673.
Formula (1) compound has important biological activity, external to human colon cancer cell (HCT-116), human breast cancer cell (MCF-7), human lung adenocarcinoma cell (A549), human liver cancer cell (HepG2), human cervical carcinoma cell (Hela), human stomach cancer cell line (MKN45), human renal carcinoma cell (Ketr-3), the cytotoxic activity test of human oral squamous cell carcinoma (KB) totally eight kinds of tumour cells shows: the derivative of the Cleistanthin-A of structure shown in this type of formula (1) is inhibited to growth of tumour cell, new control tumour medicine can be developed into.
In order to understand essence of the present invention better, below respectively with the derivative of the Cleistanthin-A of structure such formula (1) Suo Shi to the inhibiting the pharmacological results of the growth of eight kinds of tumor cell lines, its novelty teabag in antitumor drug research field is described.Pharmacological Examples gives the amount of activated data of representative compound.Mandatory declaration, Pharmacological Examples of the present invention is for illustration of the present invention instead of limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out
Medications Example 1: the human colon cancer cell HCT-116 cytotoxic activity that compound 2a is right
HCT-116 cell RPMI1640 culture medium culturing, containing the foetal calf serum of 10% in substratum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL.Cell is with every hole 5 × 10
3concentration join in 96 orifice plates, at 37 DEG C containing 5%CO
2damp atmosphere incubator in cultivate 24 hours.
The vegetative period cell of taking the logarithm is inoculated in 96 orifice plates, the medicine of different concns is added after 24h is adherent, each concentration establishes 4 parallel holes, add tetramethyl-azo azoles salt (MTT) solution after cultivating 68h, continue to cultivate 4h, discard nutrient solution, add methyl-sulphoxide 150 μ L, vibration 10min, measures 570nm optical density (A) value by microplate reader, calculation of half inhibitory concentration (IC
50).The IC of compound 2a
50be 1.5 × 10
-9m, and positive control Taxol is to the IC of HCT-116 cell
50be 2.1 × 10
-9m.
Shown in this type of formula of experiment conclusion (1), the Cleistanthin-A derivative of structure has stronger cytotoxic activity to HCT-116 cell, likely develops into the new medicine with antitumor action.
Following table is that basis detects the cytotoxic activity of following examples compound with the method for above embodiment 1.
From above Pharmacological Examples, we can find out that these compounds all show stronger cytotoxic activity to these eight kinds of tumour cells, and cytotoxic activity exceedes or suitable with positive control Taxol, can be developed into antitumor drug.
Claims (4)
1. the Cleistanthin-A derivative shown in general formula (I) and medically acceptable salt thereof:
Wherein:
n＝5-8，
R independently can be selected from morpholine, N-amino-morpholine, hydroxyethyl piperazine, N methyl piperazine, piperidines, 4-hydroxy piperidine, 3-hydroxy piperidine, 4-piperidinyl piperidine, Pyrrolidine.
2. the Cleistanthin-A derivative shown in following molecular formula and medically acceptable salt thereof:
3. the preparation method of Cleistanthin-A derivative according to claim 1 and 2, is characterized in that:
A. in methyl-sulphoxide, bromine alkyl Cleistanthin-A is obtained by reacting by Cleistanthin-A to sodium hydroxide, two corresponding bromoalkanes,
B. then to Anhydrous potassium carbonate, corresponding heterocycle at N, in N '-dimethyl methane amide reaction and obtain,
Reaction formula is as follows:
Wherein n=6-8,
R is 4-hydroxy piperidine, N methyl piperazine, hydroxyethyl piperazine, 4-hydroxy piperidine, morpholine, piperidines.
4. the application of Cleistanthin-A derivative according to claim 1 in the medicine of preparation control oral epithelium cancer, cancer of the stomach, kidney, colorectal carcinoma, lung cancer, liver cancer, cervical cancer and mammary cancer.
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| CN111303137A (en) * | 2020-03-05 | 2020-06-19 | 南通大学 | Diphyllin ether derivative and preparation method and application thereof |
| CN114213481A (en) * | 2021-12-31 | 2022-03-22 | 南通大学 | 2, 3, 6-trideoxyglycosyl diphyllin and preparation method thereof |
| CN115057851A (en) * | 2022-06-29 | 2022-09-16 | 南通大学 | Application of diphyllin 5-substituted triazole derivative in preparation of antitumor drugs |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303137A (en) * | 2020-03-05 | 2020-06-19 | 南通大学 | Diphyllin ether derivative and preparation method and application thereof |
| CN114213481A (en) * | 2021-12-31 | 2022-03-22 | 南通大学 | 2, 3, 6-trideoxyglycosyl diphyllin and preparation method thereof |
| CN114213481B (en) * | 2021-12-31 | 2024-01-26 | 南通大学 | 2,3, 6-trideoxy glycosyl mountain nuciferine and preparation method thereof |
| CN115057851A (en) * | 2022-06-29 | 2022-09-16 | 南通大学 | Application of diphyllin 5-substituted triazole derivative in preparation of antitumor drugs |
| CN115057851B (en) * | 2022-06-29 | 2023-10-31 | 南通大学 | Application of mountain lotus leaf element 5-substituted triazole derivative in preparation of antitumor drugs |
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| CN105503978B (en) | 2019-06-21 |
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