CN102516347A - Camptothecin 20-site cholic acid derivative and preparation method thereof - Google Patents
Camptothecin 20-site cholic acid derivative and preparation method thereof Download PDFInfo
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- CN102516347A CN102516347A CN2011104183474A CN201110418347A CN102516347A CN 102516347 A CN102516347 A CN 102516347A CN 2011104183474 A CN2011104183474 A CN 2011104183474A CN 201110418347 A CN201110418347 A CN 201110418347A CN 102516347 A CN102516347 A CN 102516347A
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- camptothecin derivative
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- glycocoll
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- VRPJIFMKZZEXLR-UHFFFAOYSA-N CC(C)(C)OC(NCC(O)=O)=O Chemical compound CC(C)(C)OC(NCC(O)=O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- MQWNVPKBDCYGRS-QHCPKHFHSA-N CCc1c(CN(C2=CC([C@@]34OC(CN)=[O]C3)=C3COC4=O)C3=O)c2nc2c1cccc2 Chemical compound CCc1c(CN(C2=CC([C@@]34OC(CN)=[O]C3)=C3COC4=O)C3=O)c2nc2c1cccc2 MQWNVPKBDCYGRS-QHCPKHFHSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a camptothecin derivative shown in formula (I) and a medicine of the camptothecin derivative, and relates to a method for preparing the compound as well as application of the compound as a medicine, especially in treating tumor. In the formula (I), R1 is hydrogen or ethyl; R2 is hydrogen or nitro group; and R3 and R4 are hydrogen or hydroxyl group.
Description
Technical field
The present invention relates to the preparation method of Cmptothecine derivative and the application in antineoplaston.
Background technology
1966; NSC 94600 has been studied since people such as the U.S. scientist MonroeE.Wall discovery of natural product with its notable antitumor activity; In the time in 38 years, Pharmaceutical Chemists have been made extensive work on the structural modification of NSC 94600 in the past, and countries such as the U.S., Japan, Britain, Canada all actively put in the research and development of camptothecin derivative; And obtained great achievement; A large amount of camptothecin derivatives is designed synthetic, successively has two camptothecin derivative Topotecan, Irinotecan to be approved for antitumor drug and to have gone on the market in all parts of the world, and other tens camptothecin derivatives are in the different steps of development of clinical studies.Camptothecin derivative demonstrates remarkable anti-tumor activity, is being of great use as cancer therapy drug, but because its spinoff receives strict control in clinical application.As everyone knows, NSC 94600,9-nitrocamptothecin and 7-SN 22 etc. have anti-tumor activity, clinically are used to treat cancer of the stomach, intestinal cancer, bladder cancer, lung cancer and white blood disease, but can cause spinoffs such as marrow resistance, vomiting, diarrhoea and severe haemorrhage.As: Iinothecan [CPT-11] puts goods on the market, and in clinical application, shows potential anti-tumor activity, but the same with other antitumor drug, demonstrates violent toxicity, causes the therapeutic action of CPT-11 to be restricted.[referring to the 709th page of " cancer and chemotherapy " 21 volume].
The NSC 94600 indissoluble, photo-thermal is unstable, and spinoff is big.Water insoluble and numerous organic solvents such as NSC 94600,9-nitrocamptothecin and 7-SN 22.In order to improve the camptothecin analogues anti-tumor activity, increase its stability and water-soluble simultaneously, increase bioavailability; Reduce its toxic side effect as much as possible; NSC 94600 and 9-nitrocamptothecin, 7-SN 22 to having serious side effects are modified research, seek good water solubility, and be stable; Toxic side effect is little, and the camptothecine with aequum is delivered to target tissue effectively.
Cholic acid is present unique oral hepatic targeting drug carrier, and it has special movement system in vivo.Cholic acid can be absorbed by liver specifically, and this absorption is to realize through Na+ dependency movement system (NTCP) on the liver plasma membrane and Na+ dependent/non-dependent movement system (OTAP).Cholic acid is the specific natural aglucon of endogenic liver cell, has the organ specificity of height.Cholic acid in liver cell by the SUV biosynthesizing; Combine with glycocoll or taurine then; With bile row people small intestine; Be absorbed into liver again, constantly carry out liver sausage and circulate in the human body liver sausage circulation and repeat to participate in round-robin cholic acid total amount 6-15 time every day and reach 17-40g, so have higher turn-over capacity.Cholic acid is that the approach through active transport is absorbed; Be that targeting vector can improve bioavailability of medicament and has good bio-compatibility as endogenic natural aglucon cholic acid with the cholic acid; Being suitable for the carrier as targeted drug, is targeting vector with the cholic acid, not only can realize the liver target of medicine; Reduce toxic side effect, and can improve the bioavailability in vivo of medicine.
In recent years, people are to being that the research of the hepatic targeting drug of carrier deepens continuously with the cholic acid, bibliographical information polypeptide, lipid lowerers, antiviral drug, antitumour drug, antidiabetic drug and nitrate esters medicine etc. and cholic acid bonded hepatic targeting drug arranged.Show that through cell and animal experiment study after medicine and the cholic acid coupling, the liver that has increased medicine to some extent absorbs, and has reduced the toxic side effect of medicine.Some medicine such as cholic acid and nitric acid vinegar conjugates one have advanced people's clinical study stage.Kramer etc. utilize TV as model drug and cholic acid coupling, have investigated the liver target and the anti-tumor activity of conjugates.TV is connected to 3 hydroxyls of cholic acid, obtains cholic acid-TV conjugates.The result shows that former medicine has only faint effect to liver cholic acid transporter, and corresponding cholic acid conjugates strongly inhibited the liver of tca absorb, explaining has stronger interaction between conjugates and cholic acid transporter, medium effective concentration is IC
50=3-5 μ mol/L; Former medicine>100 μ mol/L are visible, and conjugates has the transport features of cholic acid, and the liver that can increase medicine absorbs, and reaches the target purpose.
People such as Monte form glycine cholic acid-cis-platinum inner complex with glycine cholic acid and cis-platinum coupling, in vivo tests show this inner complex can by tumour cell absorb and absorbed dose apparently higher than former medicine.As natural cholic acid, can advance the circulation of people's liver sausage, increase the little intestinal absorption and the choleresis of former medicine,, have only a small amount of through the urine eliminating.Simultaneously, also can effectively suppress the growth of external and interior tumor cell, have certain anti-tumor activity.Referring to [2006 15 the 3rd phases of volume of Chinese Journal of New Drugs].
Summary of the invention
The object of the present invention is to provide the antineoplastic pharmacologically active of a kind of abundant maintenance NSC 94600, solve its poor solubility, light, thermally labile, the camptothecin derivative of problem such as target property is poor, and bioavailability is low, and toxic side effect is big.Improved the target property of medicine.
Another object of the present invention provides the preparation method of such camptothecin derivative.
In order to accomplish the object of the invention, the contriver has carried out a large amount of creationary researchs, is filling under the antineoplastic pharmacologically active prerequisite of maintenance NSC 94600; Solve its poor solubility; Light, thermally labile, target property is poor, and bioavailability is low; Problems such as toxic side effect is big have finally been found and can have been generated the camptothecin derivative with liver target through 20 hydroxyls of camptothecin derivative and chlolic acid derivatives reaction.
The new camptothecin derivative of the present invention is represented with formula (I):
Wherein
R
1Be hydrogen, ethyl;
R
2Be hydrogen, nitro;
R
3Be hydrogen, hydroxyl;
R
4Be hydrogen, hydroxyl.
The preparation method 1 of the camptothecin derivative that the present invention is new:
It is characterized in that the camptothecin derivative shown in the formula (II)
Wherein
R
1And R
2Definition with claim 2;
With the glycine reactant shown in the formula (III)
With the camptothecin derivative shown in the production (IV)
Wherein
R
1And R
2Definition with claim 2;
Camptothecin derivative shown in (IV) formula is taken off the protection base to generate (V) in the methanol solution of hydrochloric acid
With chlolic acid derivatives shown in (VI) formula
(VI)
Wherein
R
3And R
4Definition is with claim 3;
Generate chlolic acid derivatives Acibenzolar (VII) with N-maloyl imine reaction.
R
3And R
4Definition is with claim 3;
With camptothecin derivative shown in (V) formula and the reaction of (VII) Acibenzolar of chlolic acid derivatives shown in the formula to generate the described camptothecin derivative of claim 1
The present invention also comprise described in claim 1 to 4 compound preparation in the antitumor drug purposes and contain antitumor drug just like compound described in the claim 1 to 4.
Advantage of the present invention: camptothecin derivative of the present invention has not only kept the stability of reactive site lactonic ring; And good water solubility; Greatly reduce the toxicity that camptothecine compounds brings because of the water surrounding that is insoluble to body fluid; Increase bioavailability of medicament, fully kept the antineoplastic pharmacologically active of NSC 94600.There is the activity of the inhibition topoisomerase I of part of compounds to be superior to NSC 94600 in the camptothecin derivative involved in the present invention, the selection activity of topoisomerase I is superior to NSC 94600.
Embodiment:
Embodiment 1: cholic acid-20-O-glycocoll-NSC 94600 is synthetic:
(1) 20-O-glycocoll NSC 94600 is synthetic:
In the 25ml there-necked flask, add NSC 94600 174mg (0.5mmol); N-tertbutyloxycarbonyl-glycocoll 175mg (1mmol); 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol), 4-Dimethylamino pyridine (DMAP) 18mg (0.17mmol), anhydrous methylene chloride 10ml; Stirred 3.5 hours under the room temperature, follow the tracks of reaction by TLC.In reaction solution, add chloroform 20ml after reacting completely, use 50ml water, the saturated NaHCO of 50ml successively
3Solution washing 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure adds the methanol hydrochloride solution dissolving, and stirring at room 3 hours is followed the tracks of reaction by TLC, and reflection is the back concentrating under reduced pressure fully.Get yellow solid, yield 90%; Molecular weight 405;
Structural formula is following:
(2) the cholic acid Acibenzolar is synthetic:
In the 25ml there-necked flask, add cholic acid 204 (0.5mmol); N-maloyl imines 172.5mg (1.5mmol); 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol); Anhydrous methylene chloride 10ml stirred 3 hours under the room temperature, followed the tracks of reaction by TLC.In reaction solution, add chloroform 20ml after reacting completely, use 50ml water, the saturated NaHCO of 50ml successively
3Solution washing 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure gets white solid, yield 74%; Molecular weight 505.5; Structural formula is following:
(3) cholic acid-20-O-glycocoll NSC 94600 is synthetic:
In the 25mL round-bottomed flask, add compound 20-O-glycocoll NSC 94600 42.3mg (0.1mmol), 1mL DMSO and excess of bile acids Acibenzolar add the 0.1ml triethylamine; Stir 4h, follow the tracks of reaction by TLC, back zero(ppm) water in reaction solution reacts completely; Separate out white solid product; Filter oven dry, silica gel column chromatography separating purification.Get compound cholic acid-20-O-glycocoll NSC 94600 (A1), pale yellow powder, 34.0mg, molecular weight are 795.96, yield 80%.Structural formula is following:
Embodiment 2: Septochol-20-O-glycocoll-NSC 94600 is synthetic:
(1) 20-O-glycocoll NSC 94600 is synthetic:
Method is identical with instance 1 (1)
(2) the Septochol Acibenzolar is synthetic:
In the 25ml there-necked flask, add Septochol 196 (0.5mmol); N-maloyl imines 172.5mg (1.5mmol); 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol); Anhydrous methylene chloride 10ml stirred 3 hours under the room temperature, followed the tracks of reaction by TLC.In reaction solution, add chloroform 20ml after reacting completely, use 50ml water, the saturated NaHCO of 50ml successively
3Solution washing 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure gets white solid 153mg, yield 64.9%; Molecular weight 489; Structural formula is following:
(3) Septochol-20-O-glycocoll NSC 94600 is synthetic:
In the 25mL round-bottomed flask, add compound 20-O-glycocoll NSC 94600 42.3mg (0.1mmol), 1mLDMSO and excessive Septochol Acibenzolar add the 0.1ml triethylamine; Stir 4h, follow the tracks of reaction by TLC, back zero(ppm) water in reaction solution reacts completely; Separate out white solid product; Filter oven dry, silica gel column chromatography separating purification.Get compound Septochol-20-O-glycocoll NSC 94600 (A2), pale yellow powder; Molecular weight 779.9; Yield 81%.Structural formula is following:
Embodiment 3: Ursodeoxycholic Acid (UDCA)-20-O-glycocoll-NSC 94600 is synthetic:
(1) 20-O-glycocoll NSC 94600 is synthetic:
Method is identical with instance 1 (1)
(2) the Ursodeoxycholic Acid (UDCA) Acibenzolar is synthetic:
In the 25ml there-necked flask, add Septochol 196 (0.5mmol); N-maloyl imines 172.5mg (1.5mmol); 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol); Anhydrous methylene chloride 10ml stirred 3 hours under the room temperature, followed the tracks of reaction by TLC.In reaction solution, add chloroform 20ml after reacting completely, use 50ml water, the saturated NaHCO of 50ml successively
3Solution washing 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure gets white solid, yield 77%; Molecular weight 489; Structural formula is following:
(3) Ursodeoxycholic Acid (UDCA)-20-O-glycocoll NSC 94600 is synthetic:
In the 25mL round-bottomed flask, add compound 20-O-glycocoll NSC 94600 42.3mg (0.1mmol), 1mLDMSO and excessive Ursodeoxycholic Acid (UDCA) Acibenzolar add the 0.1ml triethylamine; Stir 4h, follow the tracks of reaction by TLC, back zero(ppm) water in reaction solution reacts completely; Separate out the white solid thing; Filter oven dry, silica gel column chromatography separating purification.Get compound Ursodeoxycholic Acid (UDCA)-20-O-glycocoll NSC 94600 (A3), pale yellow powder, molecular weight are 779.9, yield 79%.Structural formula is following:
Embodiment 4: gallodesoxycholic acid-20-O-glycocoll-NSC 94600 is synthetic:
(1) 20-O-glycocoll NSC 94600 is synthetic:
Method is identical with instance 1 (1)
(2) the gallodesoxycholic acid Acibenzolar is synthetic:
In the 25ml there-necked flask, add gallodesoxycholic acid 196 (0.5mmol); N-maloyl imines 172.5mg (1.5mmol); 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol); Anhydrous methylene chloride 10ml stirred 3 hours under the room temperature, followed the tracks of reaction by TLC.In reaction solution, add chloroform 20ml after reacting completely, use 50ml water, the saturated NaHCO of 50ml successively
3Solution washing 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure gets white solid, m.p; Yield 74%; Molecular weight 489; Structural formula is following:
(3) gallodesoxycholic acid-20-O-glycocoll NSC 94600 is synthetic:
In the 25mL round-bottomed flask, add compound 20-O-glycocoll NSC 94600 42.3mg (0.1mmol), 1mLDMSO and excessive gallodesoxycholic acid Acibenzolar add the 0.1ml triethylamine; Stir 4h, follow the tracks of reaction by TLC, back zero(ppm) water in reaction solution reacts completely; Separate out white solid product; Filter oven dry, silica gel column chromatography separating purification.Get compound gallodesoxycholic acid-20-O-glycocoll NSC 94600 (A4), pale yellow powder, molecular weight are 779.9, yield 84%.Structural formula is following:
Embodiment 5: cholic acid-20-O-glycocoll-7-ethyl-NSC 94600 is synthetic:
(1) 20-O-glycocoll-7-SN 22 is synthetic:
In the 25ml there-necked flask, add 7-SN 22 188mg (0.5mmol); N-tertbutyloxycarbonyl-glycocoll 175mg (1mmol); 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol), 4-Dimethylamino pyridine (DMAP) 18mg (0.17mmol), anhydrous methylene chloride 10ml; Stirred 3.5 hours under the room temperature, follow the tracks of reaction by TLC.In reaction solution, add chloroform 20ml after reacting completely, use 50ml water, the saturated NaHCO of 50ml successively
3Solution washing 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure adds the methanol hydrochloride solution dissolving, and stirring at room 3 hours is followed the tracks of reaction by TLC, and the back concentrating under reduced pressure that reacts completely is used the chloroform methanol recrystallization.Get yellow solid, yield 87%; Molecular weight 433; Structural formula is following:
(2) the cholic acid Acibenzolar is synthetic:
Method is identical with instance 1 (2)
(3) cholic acid-20-O-glycocoll-7-SN 22 is synthetic:
In the 25mL round-bottomed flask, add compound 20-O-glycocoll-7-SN 22 100mg (0.2mmol), 2mL DMSO and excess of bile acids Acibenzolar add the 0.1ml triethylamine; Stir 4h, follow the tracks of reaction by TLC, back zero(ppm) water in reaction solution reacts completely; Separate out white solid product; Filter oven dry, silica gel column chromatography separating purification.Get compound cholic acid-20-O-glycocoll-7-SN 22 (A5), pale yellow powder, molecular weight are 824, yield 75%.Structural formula is following:
Embodiment 6: cholic acid-20-O-glycocoll-9-nitrocamptothecin is synthetic:
(1) 20-O-glycocoll-9-nitrocamptothecin is synthetic:
In the 25ml there-necked flask, add 9-nitrocamptothecin 196mg (0.5mmol); N-tertbutyloxycarbonyl-glycocoll 175mg (1mmol); 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol), 4-Dimethylamino pyridine (DMAP) 18mg (0.17mmol), anhydrous methylene chloride 10ml; Stirred 3.5 hours under the room temperature, follow the tracks of reaction by TLC.In reaction solution, add chloroform 20ml after reacting completely, use 50ml water, the saturated NaHCO of 50ml successively
3Solution washing 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure adds the methanol hydrochloride solution dissolving, and stirring at room 3 hours is followed the tracks of reaction by TLC, and the back concentrating under reduced pressure that reacts completely is used the chloroform methanol recrystallization.Get yellow solid, yield 76%; Molecular weight 450; Structural formula is following:
(2) the cholic acid Acibenzolar is synthetic:
Method is identical with instance 1 (2)
(3) cholic acid-20-O-glycocoll-9-nitrocamptothecin is synthetic:
In the 25mL round-bottomed flask, add compound 20-O-glycocoll-9 nitrocamptothecin 14.2mg (0.2mmol), 2mL DMSO and excess of bile acids Acibenzolar add the 0.1ml triethylamine; Stir 4h, follow the tracks of reaction by TLC, back zero(ppm) water in reaction solution reacts completely; Separate out white solid product; Filter oven dry, silica gel column chromatography separating purification.Get compound cholic acid-20-O-glycocoll-9-nitrocamptothecin (A6), pale yellow powder, molecular weight are 840.9, yield 80%.Structural formula is following:
Claims (6)
2. camptothecin derivative according to claim 1, wherein R
1Be hydrogen, ethyl; R
2Be hydrogen, nitro.
3. camptothecin derivative according to claim 1, wherein R
3Be hydrogen, hydroxyl; R
4Be hydrogen, hydroxyl.
4. the preparation method of the described camptothecin derivative of claim 1:
It is characterized in that the camptothecin derivative shown in the formula (II)
Wherein
R
1And R
2Definition with claim 2;
With the glycine reactant shown in the formula (III)
With the camptothecin derivative shown in the production (IV)
Wherein
R
1And R
2Definition with claim 2;
Camptothecin derivative shown in (IV) formula is taken off the protection base to generate (V) in the methanol solution of hydrochloric acid
Wherein
R
1And R
2Definition with claim 2;
With the chlolic acid derivatives shown in (VI) formula
R wherein
3And R
4Definition is with claim 3;
Generate chlolic acid derivatives Acibenzolar (VII) with N-maloyl imine reaction.
R wherein
3And R
4Definition is with claim 3;
Again with camptothecin derivative shown in (V) formula and the reaction of (VII) Acibenzolar of chlolic acid derivatives shown in the formula to generate the described camptothecin derivative of claim 1.
5. the compound of claim 1-4 is as the purposes in the preparation antitumor drug.
6. the compound of claim 1-4 is used to treat the application of activeconstituents of the medicine of tumour as preparation.
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Cited By (7)
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CN110577552A (en) * | 2018-06-08 | 2019-12-17 | 遵义医学院 | Camptothecin-glycine-5, 6-didehydro norcantharidin conjugate and application thereof |
CN110577550A (en) * | 2018-06-08 | 2019-12-17 | 遵义医学院 | Camptothecin-glycine-norcantharidin conjugate and application thereof |
CN110577551A (en) * | 2018-06-08 | 2019-12-17 | 遵义医学院 | Camptothecin-glycine-5, 6-dibromo norcantharidin conjugate and application thereof |
CN110862403A (en) * | 2018-08-27 | 2020-03-06 | 遵义医学院 | Camptothecin-glycolic acid-norcantharidin conjugate and application thereof |
US11826430B2 (en) | 2019-05-14 | 2023-11-28 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
US11834458B2 (en) | 2021-03-23 | 2023-12-05 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
US11952349B2 (en) | 2019-11-13 | 2024-04-09 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110577552A (en) * | 2018-06-08 | 2019-12-17 | 遵义医学院 | Camptothecin-glycine-5, 6-didehydro norcantharidin conjugate and application thereof |
CN110577550A (en) * | 2018-06-08 | 2019-12-17 | 遵义医学院 | Camptothecin-glycine-norcantharidin conjugate and application thereof |
CN110577551A (en) * | 2018-06-08 | 2019-12-17 | 遵义医学院 | Camptothecin-glycine-5, 6-dibromo norcantharidin conjugate and application thereof |
CN110862403A (en) * | 2018-08-27 | 2020-03-06 | 遵义医学院 | Camptothecin-glycolic acid-norcantharidin conjugate and application thereof |
US11826430B2 (en) | 2019-05-14 | 2023-11-28 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
US11952349B2 (en) | 2019-11-13 | 2024-04-09 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
US11834458B2 (en) | 2021-03-23 | 2023-12-05 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
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