WO2000063212A1 - Derives de triptolide ainsi que leurs preparation et utilisations - Google Patents

Derives de triptolide ainsi que leurs preparation et utilisations Download PDF

Info

Publication number
WO2000063212A1
WO2000063212A1 PCT/CN1999/000123 CN9900123W WO0063212A1 WO 2000063212 A1 WO2000063212 A1 WO 2000063212A1 CN 9900123 W CN9900123 W CN 9900123W WO 0063212 A1 WO0063212 A1 WO 0063212A1
Authority
WO
WIPO (PCT)
Prior art keywords
triptolide
cells
compound
cancers
bcl
Prior art date
Application number
PCT/CN1999/000123
Other languages
English (en)
Inventor
Dayuan Wang
Xiaoping Gao
Wenwu Li
Bogang Li
Original Assignee
Chengdu Diao Pharmaceutical Group Company Limited
W & K International, Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Chengdu Diao Pharmaceutical Group Company Limited, W & K International, Inc filed Critical Chengdu Diao Pharmaceutical Group Company Limited
Priority to AU53686/99A priority Critical patent/AU5368699A/en
Publication of WO2000063212A1 publication Critical patent/WO2000063212A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to derivatives of triptolide, the method for producing the same and their uses in treatment of cancer diseases.
  • the present invention also relates to the pharmaceutical compositions containing the derivatives of the invention.
  • Lei Gong Teng (Tripterygium wilfordii Hook F) is an herb with a variety of bioactivities, which can be used in traditional Chinese medicine.
  • Several laboratories have demonstrated its anti-cancer activity.
  • Kopachan et al. Kerathan, SM, William AC, Richard GD et al., J. Am. Chem. Soc, 1972:94(2): 7194
  • Lei Gong Ten a diterpine containing epoxy (Triptolide) and demonstrated that 0.2 and 0.25 mg/kg of triptolide (intrapertoneal injection) can prolong the life time of L 615 leukemia mice.
  • triptolide 1 ng/ml can inhibit in vitro proliferation of KB cell of nasopharyngeal carcinoma (Zhang Qinmu et al, Zhong Guo Yao Li Xue Bao. 1981 ; 2:128).
  • Triptolide inhibit colony formation of breast or stomach cancer cells to a similar extend as that of human leukemia HL-60 cells, and the IC 50 is 0.504 -1.22 ⁇ g/L.
  • the experiment on effect of triptolide on cytokinetic of Hela cells indicates that triptolide has cytocidal effects on phase-synchronized cells, and cells at the S phase are most sensitive to triptolide.
  • triptolide inhibits synthesis of RNA and protein, selectively inactivates_sulfhydryl of phosphofructokinase, inhibits synthesis of liver glycogen, interferes with DNA replication (Xu Jianhua et al, Zhong Guo Yao Li Xue Bao. 1989; 10:550). Owing to epoxy diterpine isolated from Lei Gong Teng have multiple bioactivities, it has drawn great attention among scientists. The chemical synthesis, structure modification and bioactivities of it have been extensively investigated (Berchtold GA et al, J. Am. Chem. Soc. 1980; 102:1200). Synthesized triptolide was achieved in the early 1980s, but it involves numerous reaction steps and strict reaction conditions.
  • Yu Dequan et al (Yu Dequan et al, Yao Xue Xue Bao. 1992; 27:11) made structure modification of triptolide and obtained a number of valuable analogs. Because the effective bioactive dosage of triptolide is closed to its LD 50 , it can not be applied to clinical practice. Due to unique immunomodulation mechanism of triptolide compared with other natural agents, currently most of researches are focused on its immunosuppressing effects, and few of them relate to its anti-cancer effects. The advancement in the field of molecular oncology allows the use of oncogene as a novel target to which an anticancer drug directs. Bcl-2 is an oncogenic protein that inhibits programmed cell death. It involves the physiologic and pathological processes in organisms. Bcl-2 was also found to suppress the activation of caspases and became an important target for the therapy of tumors.
  • the present invention provides a new anticancer agent that is an analog of the compound triptolide.
  • the compound shows excellent cytocidal activity against cancer cells of renal, ovarian, melanoma, breast or colon origin, especially the cells overexpressing bcl-2 oncogene.
  • the present invention also provides a method of producing the compound, and a new anti-tumor therapeutic strategy based on the use of the compound in combination with an antisense oligonucleotide that is an effective inhibitor of human cancer cell growth in vitro and in vivo. It is an object of the present invention to provide a triptolide derivative with low toxicity and useful in clinical application.
  • the present invention provides a triptolide derivative with the following formula:
  • R 2 is -SCN and R, is H.
  • Yu et al. opened the epoxide at C 12 and C 13 by using different agents and obtained a series of triptolide derivatives including tripchlororide and tripbromide.
  • the halogen at C 12 position may be removed in vivo under enzymatic catalysis, and the oxygen ring at C 12 and C 13 may be formed again and toxicity of triptolide may be recovered.
  • the present invention uses ammonium thiocyanide to react with triptolide under mild condition to open epoxide at C 12 and C 13 , and obtains a compound, 12- -thiocyano- 13- -hydroxy triptolide (hereinafter referred to as T12) with high anti-cancer activity and low toxicity.
  • T12 12- -thiocyano- 13- -hydroxy triptolide
  • R can be added with knowtimethod.
  • the present invention also provides a method for producing the triptolide derivatives, comprising the step of reacting triptolide represented by the following formula with ammonium thiocyanide under heating conditions.
  • the reaction is performed in an organic solvent at a temperature of 65-
  • the organic solvent is t-butyl alcohol.
  • the present invention also provides the uses of the compound of the present invention in the preparation of pharmaceutical compositions for treatment of cancers.
  • the cancers to be treated may be cancers of breast, lung, renal, melanoma, colon or ovarian origin.
  • the cancers are of melanoma, renal, colon, ovarian and breast origin.
  • the present invention further provides a pharmaceutical composition comprising an effective amount of the derivatives of the invention for treatment of cancers, and pharmaceutical acceptable carriers or vehicles.
  • the cancers to be treated in the composition may be of breast, lung, renal, melanoma, colon or ovarian origin.
  • the cancers are of melanoma, renal, ovarian, colon and breast origin.
  • the present invention still provides a composition comprising the derivatives of the present invention and bcl-2 antisense oligonucleotides in a synergistic effective amount for treatment of cancers, and pharmaceutically acceptable carriers or vehicles.
  • Figure 1 shows DNA degradation of T12-induced cell apoptosis
  • Figure 2 shows T12-induced Bcl-2 cleavage in HL-60 cells
  • Figure 3 shows comparison of Bcl-2 cleavage induced by T12 and other 3 compounds
  • Figure 4 shows synergistic effect of T12 and bcl-2 antisense oligonucleotides on Col- 06 cells.
  • Triptolide (3.6g, 0.01 mole) was added to 400ml t-butyl alcohol under stirring at
  • the 12- -thiocyano-13- -hydroxy triptolide was the major product on TLC with traces of triptolide and other by-products. 10g 70-140 ⁇ silica gel was added to the acetone solution with stirring, and then the acetone was evaporated. Triptolide was first removed by silica gel (40-70 ⁇ ) with CHCI 3 , and then eluted with CHCI 3/ CH 3 OH solution (95:5). Fractions of T12 were collected under TLC-monitoring. Combine the T12 fractions, and the solvent was evaporated under vacuum.
  • the assay involves plating the cells, preincubating for 24 hours, followed by a 48 hours continuous drug exposure at appropriate concentration against 6 cell lines originated from 6 tumors (breast, colon, lung, melanoma, ovarian and renal). The cytotoxicity was assessed with the sulforhodamine B (SRB) protein assay. An evaluation parameter was used: The drug concentration which inhibits growth by 50% (Gl 50 ).
  • T12 The growth inhibitory activity of the present invention (T12) was examined and compared with two other compound: Triptolide (T, leading compound of T12) and T8 (a derivative of T, see Jung, M. J., 1/1999 PCT/US98/08562).
  • a known chemotherapeutic agent, taxol was also tested in the experiment, so as to compare the anticancer activity of known compounds and that of the compound in the present invention.
  • T, T8 and T12 were tested for their effect on cell growth.
  • Cells were harvested from exponential-phase maintenance culture, counted by trypan blue exclusion method, and dispensed on 96-well culture plates in 100 ⁇ l volumes. Following a 24 hr incubation at 37°C, 5% CO 2 , 100% relative humidity, 100 ⁇ l of culture medium, the culture medium containing drug or the culture medium containing drug vehicle was dispensed within appropriated wells. Plates were then incubated for 48 hours.
  • the growth inhibitory activity of T, T8, T12 were evaluated with SRB assay (Skehan P., 1990).
  • Col-06 (colon) 0.03 0.02 0.1 0.007
  • Example 3 Inhibitory effect of T12 on colony formation of renal cancer cell line
  • Clonogenic assays have the advantage of selecting tumor cells in a mixed population, since only the latter have the capacity to grow at low density.
  • the assay has been widely used to assess the effects of tumor chemotherapy.
  • Re-01 cells were harvested from exponential-phase maintenance culture, counted by trypan blue exclusion, and dispensed in 6-well culture plates (50 cells/ well) in 0.5 ml volumes. Following a 24 hours incubation at 37°C, 5% CO 2 , 100% relative humidity, 0.5 ml of culture medium, the culture medium containing drug or the culture medium containing drug vehicle was dispensed within appropriated plates. Culture plates were then incubated for 14 days. Cell colonies were fixed in site followed by Giemsa staining and counted under microscopy. After using a colony forming assay with renal cancer cells and continuous drug exposure for 21 days, T12 showed significant inhibition effects (50% of growth inhibition) in renal cancer cell lines at 0.005 ⁇ g/ml of drug concentration.
  • T12 was evaluated in nude mice against human melanoma xenografts.
  • Female Bab/c nude mice, 6-8 weeks old, were obtained from Shanghai Institute of Pharmaceutical Industry, and randomly assigned to experimental groups of n 6 nude mice.
  • the tumor cells Mel-08 used were implanted subcutaneously into the auxiliary region ( 1X10 7 cells/0.2 mi/mouse).
  • T12 treatment was initiated 24 hours after the implantation of the tumor cells.
  • T12 (formulated in 0.5% of CMC-Na solution) were injected intraperitoneally for 14 days (4mg/kg body weight/day), and the tumor were removed at the indicated times.
  • dacarbazine (DTIC, 20 mg/kg/day) and 0.5% of CMC-Na solution (0.5 ml/mouse) were injected intraperitoneally as positive and negative control, respectively.
  • Tumor inhibition (%) were calculated as follows:
  • C and T represent the mean tumor weight for control and treated groups, respectively.
  • DTIC and the compound of the present invention showed potent inhibitory effects (54.92% and 50.17%) on the growth of melanoma in nude mice, whereas no effects on tumor growth were observed for control group.
  • Apoptotic cell death involves the activation of a preprogrammed cascade of molecular events that culminate in DNA degradation, nuclear disintegration and packaging of the cell's remnants into membrane-enclosed "apoptosis bodies" which are subsequently removed by phagocytosis.
  • agents who directly or indirectly cause DNA damage induce apoptosis.
  • the formation of distinct DNA fragments of oligonucleosomal size (180-200 bp lengths) is a biochemical hallmark of apoptosis in many cells.
  • the DNA is cleaved between the nucleosomes resulting in a "ladder" of DNA fragments of multiples of 180-200 bp.
  • 3 x 10 6 HL-60 cells were washed in PBS, and then lysed in 100 ⁇ l lysis solution (50mM Tris, pH 8.0; 10 mM EDTA and 0.25% NP-40) containing 3 ⁇ l proteinase K (1 mg/ml). The lysates were incubated at 37 °C for 30 minutes. Supernatants (20 ⁇ l) were collected as described for agarose gel electrophoresis (Frank T, 1993).
  • FIG 1 shows that an exposure to 1 ⁇ g/ml T12 for 4, 12 and 24 hours (lanes 3-5) causes intemucleosomal DNA fragmentation of the genomic DNA of HL-60 cells, and no intemucleosomal DNA fragmentation of the genomic DNA for the control and 2 hours with T12 (lanes 1 and 2).
  • Re-01 cell lines with or without T12 were incubated at 37 C for 4-72 hours (2, 4, 8 and 24 hours for HL-60 cell lines; 12, 24, 48 and 72 hours for Re-01 cell lines). After centrifugation (700 g at room temperature for 5 minutes), the pellets were washed for two times and then resuspended in 50 ⁇ l of PBS. Aliquots containing 10 6 cells/ 50 ⁇ l were fixed in 70% ethanol at -20 ° C overnight. Cells were washed and resuspended in PBS (0.5 ml) containing 0.25 mg/ml RNase and 0.1 mg/ml PI. Samples were kept in dark for 30 minutes.
  • Table 4 and 5 show the distribution of HL-60 and Re-01 cells in various phases of the cell cycle after treatment with T12. Exponentially growing cells were treated with and without 1 ⁇ g/ml T12 for 4 hours. T12 increases the proportion of cells in the G0/G1 phases with 1 ⁇ g/ml for 2 hours and 4 hours, and decreases the population of cells in S/G2/M phases, indicating that apoptosis is selective to S phase cells.
  • Apoptosis has become a basic tool in developing and establishing new strategies of cancer therapy.
  • the molecular mechanism of T12-induced apoptosis is not well understood.
  • the Bcl-2 protein plays an essential role in preventing cell death and is one of the major factors causing tumor formation.
  • T12 can induce the cleavage and inactivation of Bcl-2 in a caspase-dependent manner. Both biochemical and genetic evidence indicates that Bcl-2 can regulate cell death induced by caspases.
  • caspase-3 which can cleave poly(ADP-ribose) polymerase (PARP) and play an important role in triptolide- induced T lymphocyte apoptosis (Yang Yili et. al. Immunopharmacology 40: 139- 149,1998).
  • Three cell lines (human leukemia HL-60 line, human breast cancer Bre-01 line and lymphoma Ly-01 line) were cultured at 1 x 10 6 /ml and treated with 1 ⁇ g/ml T12 for 24, 48 and 72 hours. Untreated cell lines were taken as control. Cells were washed and resuspended in lysis buffer containing 20 mM Tris.HCI (pH 8.0), 4% sodium dodecyl sulfate (SDS). Cell lysates were migrated on 12% SDS-polyacrylamide gel and transferred onto PVDF membrane.
  • Tris.HCI pH 8.0
  • SDS sodium dodecyl sulfate
  • Membrane was blocked overnight with PBS containing 5% nonfat milk powder and incubated for 2 hours with anti-human Bcl-2 monoclonal antibody (Santa Cruz), followed by peroxidase-conjugated anti-lg antibody. Detection was carried out with ECL solution.
  • bcl-2 antisense oligonucleotides are effective inhibitors of human tumor cell growth in vitro and in vivo. This antitumor activity was associated with an early down-regulation of bcl-2 expression (mRNA), followed by inhibition of cell growth and induction of apoptosis. It has been demonstrated that the combination of certain chemotherapeutic agents and bcl-2 antisense oligonucleotides shows a synergistic inhibitory effect on melanoma cells in vitro and in vivo (Campbell M J et al, British Journal of Cancer. 1998; 77:739-744). However, no studies have been reported on the efficacy of the combination of bcl-2 antisense and T12 that are directed to the same molecular target (protein of bcl-2).
  • Colon cancer Col-06 cells (10 6 /mL) overexpressing bcl-2 cultured in RPMI-1640 medium supplemented with bovine serum, L-glutamine, and penicillin-streptomycin (100 ⁇ g/mL each) were treated with bcl-2 antisense (5 ⁇ M). After 24 hours, T12 were added. The cytotoxicity of the antisense oligonucleotide or the antisense oligonucleotide + T12 in colon cancer cells was determined by SRB assay.
  • FIG 4 illustrates the combination of T12 and bcl-2 antisense oligonucleotide exerts significantly greater antitumor effects than either agent used alone on human colon and melanoma cell lines in vitro.
  • Kunming strain mouse (6 weeks old) was chosen for evaluating the acute toxicity of the compound of the present invention.
  • Groups of mice (ten of each sex) were injected intraperitoneally with T12 at doses of 40.96, 51.2, 64, 80, and 100mg/kg in 0.5% of CMC-Na solution. The mice were observed for two weeks for lethality.
  • the LD JO dose required to produce 50% lethality
  • the LD 50 of triptolide was reported to be 0.85mg/kg (Folkman J, Nature med 1995, 1 :27). The result shows that the toxicity of T12 is significantly lower than that of T.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de formule (I) dans laquelle R1 désigne H, un alkyle contenant entre 1 et 4 atomes de carbone, -Ac, -C(=O)(CH2)nCO2 ou un acide aminé, où n désigne un entier compris entre 1 et 4; R2 désigne -SCN, -NCS. Les composés inhibent considérablement la croissance des cellules tumorales à la fois in vitro et in vivo.
PCT/CN1999/000123 1999-04-16 1999-08-20 Derives de triptolide ainsi que leurs preparation et utilisations WO2000063212A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53686/99A AU5368699A (en) 1999-04-16 1999-08-20 Derivatives of triptolide, and preparation and uses thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN99105796.1 1999-04-16
CN99105796 1999-04-16

Publications (1)

Publication Number Publication Date
WO2000063212A1 true WO2000063212A1 (fr) 2000-10-26

Family

ID=5272134

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN1999/000123 WO2000063212A1 (fr) 1999-04-16 1999-08-20 Derives de triptolide ainsi que leurs preparation et utilisations

Country Status (2)

Country Link
AU (1) AU5368699A (fr)
WO (1) WO2000063212A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6569893B2 (en) 2001-03-15 2003-05-27 Pharmagenesis, Inc. Amino acid derivatives of triptolide compounds as immune modulators and anticancer agents
WO2004026298A1 (fr) * 2002-09-18 2004-04-01 Farreach Lab. Derives de triptolide presentant un puissant effet immunosuppresseur et une forte solubilite dans l'eau, utilisations de ces derives de triptolide
US7662976B2 (en) 2002-05-31 2010-02-16 Pharmagenesis, Inc. Triptolide derivatives for modulation of apoptosis and immunosuppression
US7820834B2 (en) 2003-12-24 2010-10-26 Pharmagenesis, Inc. Triptolide 5,6-derivatives as immunomodulators and anticancer agents
US7863464B2 (en) 2004-03-02 2011-01-04 Pharmagenesis, Inc. Triptolide lactone ring derivatives as immunomodulators and anticancer agents
US8048914B2 (en) 2004-02-09 2011-11-01 Pharmagenesis, Inc. Methods for isolation of triptolide compounds from Tripterygium wilfordii
US8507552B2 (en) 2009-05-07 2013-08-13 Regents Of The University Of Minnesota Triptolide prodrugs
US8617906B2 (en) 2004-10-13 2013-12-31 Pharmagenesis, Inc. Identification and screening of triptolide target molecules
US9150600B2 (en) 2009-05-07 2015-10-06 Regents Of The University Of Minnesota Triptolide prodrugs
CN116606803A (zh) * 2023-06-26 2023-08-18 北京原生元生物科技有限公司 雷公藤单体在抑制间充质干细胞的促瘤性中的相关应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4005108A (en) * 1973-04-03 1977-01-25 Research Corporation Novel anti-leukemic diterpenoid triepoxides
CN1052859A (zh) * 1989-12-22 1991-07-10 中国医学科学院皮肤病研究所 17-羟基雷藤内酯醇及类似物的结构与制备方法
CN1052861A (zh) * 1989-12-22 1991-07-10 中国医学科学院皮肤病研究所 雷醇内酯的制备方法及抗生育用途
CN1052860A (zh) * 1989-12-22 1991-07-10 中国医学科学院皮肤病研究所 雷藤氯内酯醇的制备方法及抗生育用途
WO1997031921A1 (fr) * 1996-03-01 1997-09-04 Pharmagenesis, Inc. Composes et procedes de traitement immunosupressif

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4005108A (en) * 1973-04-03 1977-01-25 Research Corporation Novel anti-leukemic diterpenoid triepoxides
CN1052859A (zh) * 1989-12-22 1991-07-10 中国医学科学院皮肤病研究所 17-羟基雷藤内酯醇及类似物的结构与制备方法
CN1052861A (zh) * 1989-12-22 1991-07-10 中国医学科学院皮肤病研究所 雷醇内酯的制备方法及抗生育用途
CN1052860A (zh) * 1989-12-22 1991-07-10 中国医学科学院皮肤病研究所 雷藤氯内酯醇的制备方法及抗生育用途
WO1997031921A1 (fr) * 1996-03-01 1997-09-04 Pharmagenesis, Inc. Composes et procedes de traitement immunosupressif
WO1997031920A1 (fr) * 1996-03-01 1997-09-04 Pharmagenesis, Inc. Composes immunodepresseurs et therapie

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6569893B2 (en) 2001-03-15 2003-05-27 Pharmagenesis, Inc. Amino acid derivatives of triptolide compounds as immune modulators and anticancer agents
US7662976B2 (en) 2002-05-31 2010-02-16 Pharmagenesis, Inc. Triptolide derivatives for modulation of apoptosis and immunosuppression
US7847109B2 (en) 2002-05-31 2010-12-07 Pharmagenesis, Inc. Triptolide derivatives for modulation of apoptosis and immunosuppression
WO2004026298A1 (fr) * 2002-09-18 2004-04-01 Farreach Lab. Derives de triptolide presentant un puissant effet immunosuppresseur et une forte solubilite dans l'eau, utilisations de ces derives de triptolide
JP2006503831A (ja) * 2002-09-18 2006-02-02 成都▲達▼▲遠▼▲薬▼物有限公司 高免疫抑制活性の水溶性トリプトリド誘導体及びその応用
US7820834B2 (en) 2003-12-24 2010-10-26 Pharmagenesis, Inc. Triptolide 5,6-derivatives as immunomodulators and anticancer agents
US8048914B2 (en) 2004-02-09 2011-11-01 Pharmagenesis, Inc. Methods for isolation of triptolide compounds from Tripterygium wilfordii
US7863464B2 (en) 2004-03-02 2011-01-04 Pharmagenesis, Inc. Triptolide lactone ring derivatives as immunomodulators and anticancer agents
US8426616B2 (en) 2004-03-02 2013-04-23 Pharmagenesis, Inc. Triptolide lactone ring derivatives as immunomodulators and anticancer agents
US8617906B2 (en) 2004-10-13 2013-12-31 Pharmagenesis, Inc. Identification and screening of triptolide target molecules
US8507552B2 (en) 2009-05-07 2013-08-13 Regents Of The University Of Minnesota Triptolide prodrugs
US9150600B2 (en) 2009-05-07 2015-10-06 Regents Of The University Of Minnesota Triptolide prodrugs
US9623035B2 (en) 2009-05-07 2017-04-18 Regents Of The University Of Minnesota Triptolide prodrugs
US10183033B2 (en) 2009-05-07 2019-01-22 Regents Of The University Of Minnesota Triptolide prodrugs
CN116606803A (zh) * 2023-06-26 2023-08-18 北京原生元生物科技有限公司 雷公藤单体在抑制间充质干细胞的促瘤性中的相关应用

Also Published As

Publication number Publication date
AU5368699A (en) 2000-11-02

Similar Documents

Publication Publication Date Title
US20090291998A1 (en) Eponemycin and epoxomicin analogs and uses thereof
AU2002254400A1 (en) Molecular conjugates for use in treatment of cancer
ZA200502271B (en) Pyrazolopyridines as cyclin dependent kinase inhibitors.
WO2002076448A1 (fr) Conjugues moleculaires destines a etre utilises dans le traitement du cancer
US20140186872A1 (en) Bisacodyl and its analogues as drugs for use in the treatment of cancer
WO2000063212A1 (fr) Derives de triptolide ainsi que leurs preparation et utilisations
JP2000506841A (ja) 新規なオルソ―ナフトキノン誘導体、その新規な合成法、及び新生細胞成長の抑制におけるそれらの使用
KR101971128B1 (ko) Ｅｒ-베타 효능제로서 6-치환된 데메틸-에스트라디올 유도체
AU2005218308A1 (en) Synthesis of epothilones, intermediates thereto, analogues and uses thereof
CN1261602A (zh) 雷公藤内酯醇衍生物及其应用
GB2362648A (en) Triterpenoid derivatives
US20060167097A1 (en) Compositions and uses of Amooranin compounds
US6548536B2 (en) Agent for inducing apoptosis
KR100372911B1 (ko) 파네실 전이효소의 저해 활성, 세포 주기의 조절 활성 및신생혈관유도 저해 활성을 갖는 9-아세틸아테미놀라이드화합물, 이의 분리 방법 및 이를 포함하는 약학 조성물
JP2003503503A (ja) 新規のキサントン化合物、その製造および医薬としての使用
KR20120006543A (ko) 튜불린 중합 저해제로서 치환된 4-아미노-5-벤조일-2-(페닐아미노)티오펜-3-카르보니트릴및 치환된 4-아미노-5-벤조일-2-(페닐아미노)티오펜-3-카르복스아미드
KR102360356B1 (ko) 효소 억제를 위한 에폭시케톤 화합물
EP2086539A1 (fr) Inhibiteurs de glycosidases sélectifs
CN102050867A (zh) 四肽类似物、制备方法及其应用
Popsavin et al. Antitumour tiazofurin analogues embedded with an amide moiety at the C-2′ position
KR101281955B1 (ko) 신규한 화합물, 이의 제조방법 및 이를 포함하는 암의 예방 또는 치료용 약학적 조성물
CN113929614B (zh) 一种藜芦胺类化合物、其制备方法及其应用
CN113929729B (zh) 一种藜芦胺类化合物、其制备方法及其应用
Gunasekera et al. Chemistry and biology of the discodermolides, potent mitotic spindle poisons
AU2005223325B2 (en) Epothilone derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: CA

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase