CN1850828A - Podophyllotoxin derivatives and their preparing method - Google Patents
Podophyllotoxin derivatives and their preparing method Download PDFInfo
- Publication number
- CN1850828A CN1850828A CN 200610026904 CN200610026904A CN1850828A CN 1850828 A CN1850828 A CN 1850828A CN 200610026904 CN200610026904 CN 200610026904 CN 200610026904 A CN200610026904 A CN 200610026904A CN 1850828 A CN1850828 A CN 1850828A
- Authority
- CN
- China
- Prior art keywords
- preparation
- deoxidation
- nitrophenyl
- amino
- artesunate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
This invention relates to podophyllotoxin derivative and its preparation method. The derivative constitutional formula is shown as formula (I). It is made by 4 beta-(amphi nitryl phenyl group)-amino group-4-deoxygenation-4'-go methyl bill podophyllotoxin and artesunate through esterifying reaction. Two compound of different anti cancer fuction mechanism are combined as one new comound, so the designed and synthesized compound anti cancer effect is improved, and its toxity is reduced.
Description
Technical field
The present invention relates to a kind of podophyllotoxin (podophyllotoxin) derivative and preparation method thereof.
Background technology
Podophyllotoxin (podophyllotoxin), its structure are the natural compoundss that extracts from Berberidaceae plant Chinese podophyllum root (Sinopodophyllum Ying) suc as formula shown in (a).The derivative of some podophyllotoxins has been proved has antitumour activity, as etoposide (VP16), Vumon (VM26) and 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin (GL331) etc. He Kejinshi, Fei Hekejinshi, leukemia, brain tumor, cancer of the stomach, cervical cancer and lung cancer is all had suitable curative effect.Wherein GL331 (its structure is suc as formula shown in (b)) is in clinical 2 stages phase at present, and its cancer therapy effect to anti-etoposide, Vumon is remarkable.GL331 antitumous effect mechanism is that it is special effect inhibitor (the Bioorganic ﹠amp of required topoisomerase II in the cancer cells dna replication dna process; Medicinal Chemistry Letters 14 (2004) 1581-1584).
Artemisinin (Artemisinin) is the antimalarial effective constituent of Chinese medicine sweet wormwood (feverfew Herba Artemisiae annuae Artemisiaannua L.).Artesunate Artesunate, its structure is a kind of derivative of Artemisinin suc as formula shown in (C).Discover that Artemisinin and derivative Artesunate thereof have anti-tumor activity.Artemisinin and derivative Artesunate antitumous effect mechanism thereof are that " o-o-" structure in its molecular structure can generate living radical with the iron ion action in the cell, thus alkylation epicyte protein and cause necrocytosis.Because iron ion content will be higher than the normal cell iron ion content far away in the cancer cells, thereby Artemisinin and derivative thereof have very high selecting cell toxicity (Free Radical Biology ﹠amp to cancer cells; Medicine, Vol.37, No.7, pp.998-1009,2004).
Summary of the invention
One of the object of the invention is, two compounds with different antitumous effect mechanism are combined into a new compound, and expectation realizes improving the anticancer effect of designed compound and reducing its toxicity by many target spots mechanism of action.In brief, provide a kind of antitumour activity the strong and high podophyllotoxin derivative of bioavailability;
Two of the object of the invention is, a kind of method for preparing above-mentioned podophyllotoxin derivative is provided.
The said podophyllotoxin derivative of the present invention, it has structure shown in the formula (1):
A kind of method for preparing the said podophyllotoxin derivative of the present invention, its key step is: with 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin [GL331 or abbreviation compound (b)] and Artesunate (Artesunate, structure is as the formula (2)) be raw material, obtain target compound [compound (1)] through esterification.
The present invention is combined into a new compound with two compounds with different antitumous effect mechanism, has realized improving the anticancer effect of designed and synthetic compound and has reduced its toxic purpose.
Description of drawings
Fig. 1 for the said podophyllotoxin derivative of the present invention and comparison to human liver cancer cell (Bel 7402) growth-inhibiting graphic representation.
Embodiment
A kind of method for preparing the said podophyllotoxin derivative of the present invention, its key step is: is 1 with 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin (GL331) in molar ratio with Artesunate (Artesunate): (1～2) is dissolved in the exsiccant methylene dichloride, then at 0 ℃ or be lower than under 0 ℃ of condition, with N, N '-dicyclohexyl carbimide (DCC) and 4-dimethylamino pyridine (DMAP) add in the said methylene dichloride that is dissolved with GL331 and Artesunate, stirred 1～2 hour, be warming up to 20～30 ℃ and continue to stir 8～10 hours, the gained reaction solution after filtration, concentrate and column chromatographic isolation and purification after target compound [i.e. 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin Artesunate (GA) or abbreviation compound (1)].
The invention will be further described below in conjunction with embodiment,
Embodiment 1
Synthesizing of 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin Artesunate (GA):
104mg (0.2mmol) 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin (GL331) and 152mg (0.4mmol) Artesunate (Artesunate) are dissolved in the 20ml exsiccant methylene dichloride, 0 ℃ adds 50mg (0.24mmol) N down, N '-dicyclohexyl carbimide (DCC) and 30mg (0.16mmol) 4-dimethylamino pyridine (DMAP) stirring reaction are after 1～2 hour, be warming up to 20～30 ℃ of stirring reactions finished in 10 hours, filtering reacting liquid, filtrate decompression is concentrated into dried back silicagel column (200～300 orders, column chromatography silica gel, Haiyang Chemical Plant, Qingdao produces) the chromatographic separation purifying, eluent is a methylene dichloride: acetone=95: 5 (V/V), obtain the yellow powdery solid of 73mg (0.08mmol) at last and be 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin Artesunate (GA), mp 165-167 ℃, [α]
D 20+ 16 ° of (C=0.5, CHCl
3), C
46H
50O
16N
2, yield is 70%.
1H NMR (CDCl
3) δ: 8.15 (d, J=8.77Hz, 2H, 3 " H and 5 "-H of A parts), 6.76 (s, 1H, 5-H of A part), 6.5 (d, 3-H, 8-H, 2 " H and 6 "-H of A parts), 6.32 (s, 2H, 2 ＇-H and 6 ＇-H of A part), 6.0 (s, 1H, OCH
2O), 5.98 (s, 1H, OCH
2O), 5.8 (d.J=9.82,1H, 12-H of B parts), 5.45 ((s, 1H, 5-H of B part), 4.83 (m, 2H, NH and 1-H), 4.62 (d, J=3.96,1H, 4-H), 4.40 (t, 1H, 11-H), 3.90 (t, 1H, 11-H), 3.72 (s, 6H ,-OCH
3), 3.12～3.04 (m, 2H, 2-H and 3-H of A parts), 2.95 (t, 2H, 18-CH
2), 2.8 (t, 2H, 17-CH
2), 2.55 (m, 1H, 11-H of B parts), 2.36 (m, 1H, 10-H of B parts), 2.03 (m, 1H, 3-CH
2Of B part), 1.90 (m, 1H, 3-CH
2Of B part), 1.80～1.60 (m, 4H, 8,9-CH
2), 1.55～1.42 (m, 1H, 7-CH of B parts), 1.39～1.35 (m, 1H, 1-CH of B parts), 1.31 (m, 2H, 2-CH
2Of B part) 0.86 (d, J=6.95,3H, 14-CH
3), 1.00 (d, J=5.68,3H, 13-CH
3), 1.41 (s, 3H, 15-CH
3).
13C NMR δ: 174.60 (12-C=O of A parts), (171.47 16-C=O of B part), (170.66 19-C=O of B part), (152.82 3 ＇-C and 5 ＇-C of A part), 152.31 (1 " C ofA part); 149.40 (6-C of A parts); 148.62 (7-C of A parts), 139.86 (1 ＇-C of A part), 138.14 (4 " C of A part), (132.51 1-C of A part), (129.61 9-C of A part), 128.73 (4 ＇-C of A part), 127.30 (3 " CH and 5 "-CH of A parts), (111.79 2 " CH and 6 "-CH of A part), (110.91 8-CH of A part), 109.80 (5-CH of A parts), 108.44 (2 ＇-CH and 6 ＇-CH of A part), (105.15 4-C of B part), 102.47 (OCH
2O-), 92.93 (12-CH of B parts), 92.13 (5-CH of B parts), 80.81 (6-C of B parts), 68.92 (8-CH
2O-of A part), 52.86 (OCH
3), 52.26 (OCH
3), 45.94 (4-CH of A parts), 44.29 (3-CH of A parts), 42.50 (7-CH of B parts), 38.97 (2-CH of A parts), 37.96 (1-CH of B parts), 36.92,34.78 (17-CH
2And 18-CH
2Of B part), 32.47 (2-CH of B parts), 26.60 (10-CH of B parts), 30.09,29.23,25.26,22.68 (2,3,8,9-CH
2Of B part), 20.87 (14,15-CH
3), 12.71 (13-CH
3).
FT-IR (KBr, cm
-1): 3470 (NH), 2920 (aliphatic C-H), 1775 (lactones), 1115,881,831 (O-C-O-), 1660,1520,1490 (aromatic C=O), 1330,1310 (NO
2).
Mass：(ESI+Na，m/z)，909.1
Embodiment 2
Mtt assay is measured the inhibition of 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin Artesunate (GA) to human liver cancer cell Bel 7402 growths:
Bel 7402 cells (Institute Of Biochemistry And Cell Biology, Shanghai Institutes For Biological Sciences, Chinese Academy Of Sciences provides) 10 with logarithmic phase
4Individual/ml is inoculated in 96 well culture plates, be divided into blank group, with concentration homotactic 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin Artesunate (GA, self-control, purity is 98%) group, 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin (GL331, purity is 98%) group, Artesunate (Artesunate, purity is 98%) group and etoposide (VP16) (available from PVG modern pharmaceutical company limited, purity is 98%), do control group, every hole 0.15ml, with the RPMI1640 nutrient solution that contains 10% calf serum at 37 ℃, 5%CO
2And cultivate when covering with under the saturated humidity, discard nutrient solution, add respectively and contain 75 μ mmol/L, 37.5 μ mmol/L, 18.75 μ mmol/L, 9.375 μ mmol/L, 4.6875 μ mmol/L 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin Artesunate (GA), 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin (GL331), the RPMI1640 nutrient solution 0.15ml of Artesunate (Artesunate) and etoposide (VP16) and 10% calf serum continues to cultivate 48 hours, measure the cell extent of growth with mtt assay, with blank group numerical value is 100%, and intracellular growth inhibition figure (as shown in Figure 1) runs business into particular one.
As shown in Figure 1,4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin Artesunate (GA) has the obvious growth restraining effect to this cell strain, and with under the concentration conditions, its to this cell strain growth inhibiting rate all than 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin (GL331), Artesunate (Artesunate) and etoposide (VP16) to this cell strain growth inhibiting rate height.
Claims (4)
1, a kind of podophyllotoxin derivative, it has structure shown in the formula (1):
2, a kind of preparation is as the method for the said podophyllotoxin derivative of claim 1, it is characterized in that, said preparation method's key step is: with compound shown in 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin and the formula (2) is raw material, obtain target compound through esterification
3, preparation method as claimed in claim 2, it is characterized in that, its key step of said preparation method is: with compound shown in 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin and the formula (2) is 1 in molar ratio: (1～2) is dissolved in the exsiccant methylene dichloride, then at 0 ℃ or be lower than under 0 ℃ of condition, with N, N '-dicyclohexyl carbimide and 4-dimethylamino pyridine add in the said methylene dichloride that is dissolved with compound shown in 4 β-(p-nitrophenyl)-amino-4-deoxidation-4 '-demethyl epipodophyllotoxin and the formula (2), stirred 1～2 hour, be warming up to 20～30 ℃ and continue to stir 8～10 hours, the gained reaction solution after filtration, concentrate and column chromatographic isolation and purification after target compound.
4, preparation method as claimed in claim 3 is characterized in that, wherein used eluent is made up of methylene dichloride and acetone in the column chromatography, and the volume ratio of methylene dichloride and acetone is 95: 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100269047A CN100349898C (en) | 2006-05-26 | 2006-05-26 | Podophyllotoxin derivatives and their preparing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100269047A CN100349898C (en) | 2006-05-26 | 2006-05-26 | Podophyllotoxin derivatives and their preparing method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1850828A true CN1850828A (en) | 2006-10-25 |
| CN100349898C CN100349898C (en) | 2007-11-21 |
Family
ID=37132330
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100269047A Expired - Fee Related CN100349898C (en) | 2006-05-26 | 2006-05-26 | Podophyllotoxin derivatives and their preparing method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100349898C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104163823A (en) * | 2014-04-30 | 2014-11-26 | 浙江工业大学 | Camptothecin and artesunate conjugate, preparation method and application thereof |
| CN104926841A (en) * | 2015-06-30 | 2015-09-23 | 遵义医学院 | Application of artesunate and podophyllotoxin conjugates in anti-leukemia drugs and preparation method |
| CN107964014A (en) * | 2017-10-28 | 2018-04-27 | 兰州大学 | A kind of adjacent nitro aroylation derivatives quasi-compound, preparation method and applications |
-
2006
- 2006-05-26 CN CNB2006100269047A patent/CN100349898C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104163823A (en) * | 2014-04-30 | 2014-11-26 | 浙江工业大学 | Camptothecin and artesunate conjugate, preparation method and application thereof |
| CN104926841A (en) * | 2015-06-30 | 2015-09-23 | 遵义医学院 | Application of artesunate and podophyllotoxin conjugates in anti-leukemia drugs and preparation method |
| CN107964014A (en) * | 2017-10-28 | 2018-04-27 | 兰州大学 | A kind of adjacent nitro aroylation derivatives quasi-compound, preparation method and applications |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100349898C (en) | 2007-11-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20100228014A1 (en) | Novel ent-kaurene diterpene compound and its derivatives, their preparation and their use | |
| Ishibashi et al. | NOVEL ANTIBIOTICS, FURAQUINOCINS C, D, E, F, G AND H | |
| ITMI950533A1 (en) | DERIVATIVES OF 10-DEACETYLBACCATIN III AND OF 10-DEACETYL-14B- HYDROXYBACCATIN III THEIR METHOD OF PREPARATION AND FORMULATIONS | |
| CN100349898C (en) | Podophyllotoxin derivatives and their preparing method | |
| Kletskov et al. | Synthesis and biological activity of novel comenic acid derivatives containing isoxazole and isothiazole moieties | |
| HU206221B (en) | Process for producing acylated derivatives of etoposide and pharmaceutical compositions comprising such compounds as active ingredient | |
| CN113173857B (en) | Cannabidiol derivative and preparation method and application thereof | |
| US5132322A (en) | Etoposide analogues | |
| CN112300104B (en) | Lignanoid compound in purslane and extraction and separation method and application thereof | |
| EP0461141B1 (en) | Etoposide analogues | |
| WO2004073375A2 (en) | Podophyllotoxin derivatives as antitumor agents | |
| CN115073406B (en) | Eucalyptus type sesquiterpene lactone TBA derivative and application thereof | |
| US5079377A (en) | Novel androst-4-ene-3,17-dione derivatives and method for preparing same | |
| AU2020103289A4 (en) | Preparation and Application of Alkaloid Derivatives for Reversing Human Tumor Drug Resistance and Anti-canine Breast Cancer | |
| CN115252624A (en) | Betulinic acid derivative and preparation method and application thereof | |
| KR101478758B1 (en) | Halogenated dideoxy saccharide derivatives, preparation method and use thereof | |
| CN108125962B (en) | Application of benzo [ d ] aza-quinazoline compound in preparation of drugs for treating lung cancer | |
| CN113788809B (en) | 3-site mosaic nitrogen mustard derivative of chromone and application | |
| CN112062743B (en) | Resveratrol derivative and application thereof | |
| CN114702506B (en) | 11-carbonyl-20-ethoxy source oridonin and 14-OH esterified serial derivatives and application thereof | |
| CN111635395B (en) | Spirolactone type diterpene derivative, preparation method and anti-tumor application thereof | |
| CN111018885B (en) | 1, 2-dioxycyclohexene [3,4-f ] nitrogen oxo cyclononane derivative and synthetic method and application thereof | |
| CN114685420B (en) | Compound with anti-tumor activity and preparation method and application thereof | |
| HU208019B (en) | Process for producing alkoxy-methyliden-epi-podofillotoxin-glucosides and pharmaceutical compositions containing them | |
| CN109879873B (en) | Tetrahydrodibenzonaphthyridine compound and synthesis method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20071121 Termination date: 20100526 |