WO2001012579A2 - New stilbenes with vascular damaging activity - Google Patents
New stilbenes with vascular damaging activity Download PDFInfo
- Publication number
- WO2001012579A2 WO2001012579A2 PCT/GB2000/003067 GB0003067W WO0112579A2 WO 2001012579 A2 WO2001012579 A2 WO 2001012579A2 GB 0003067 W GB0003067 W GB 0003067W WO 0112579 A2 WO0112579 A2 WO 0112579A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compounds
- cis
- stilbene
- formula
- alkyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
Definitions
- Neovascularisation is also a clinical feature of skin lesions in psoriasis, of the invasive pannus in the joints of rheumatoid arthritis patients and of atherosclerotic plaques
- Retinal neovascularisation is pathological in macular degeneration and in diabetic retinopathy In all these diseases reversal of neovascularisation by damaging the newly-formed vascular endothelium is expected to have a beneficial therapeutic effect
- tumour vasculature has several important advantages over a direct attack on the tumour
- the endothelial cells of tumour vasculature are more genetically stable than those of the tumour itself and are therefore less likely to become resistant to the damaging agent
- vascular damaging agents are able to attack a wide range of tumour types
- tubulin-binding agents including the stilbenes combretastatin Al, combretastatin A4 (D J Chaplin et al , British J Cancer 27, S86-S88 (1996))and combretastatin A4 phosphate (D J Chaplin et al , Anticancer Research 19, 189-196, (1999)) are known to selectively damage neovasculature of solid tumours in animal models.
- vascular-damaging stilbenes combretastatin Al, combretastatin A4 and combretastatin A4 phosphate have a 4-methoxy group in the "B" ring.
- the compounds of the invention lack a 4-methoxy group in the ring corresponding to the "B" ring of combretastatin A4.
- substituting alternative groups for the 4-methoxy group in the B-ring of combretastatin A4 would considerably reduce biological activity:
- Woods et al. disclose analogues of combretastatin with reduced potency.
- the 4-methyl compound shows 3.5 to 36-fold reduction in potency against four cell lines compared to the 4-methoxy compound.
- R',R 2 and R 3 are each independently alkyl
- R 4 is alkyl, haloalkyl, alkenyl, alkynyl, alkylthio, alkylsulphinyl, alkylsulphonyl or halo
- R 5 is hydrogen, alkoxy, alkyl, alkylthio, hydroxy or halo, and the pharmaceutically acceptable salts, solvates, hydrates and prodrugs thereof.
- alkyl alone or in combinations, means a straight or branched-chain alkyl group containing from one to seven, preferably a maximum of four, carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl and pentyl.
- alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy.
- halogen means fluorine, chlorine, bromine or iodine.
- An alkenyl group may be for example an olefinic group containing from two to seven carbon atoms for example methylene, ethylene, n-propylene, i-propylene, n-butylene, i- butylene, s-butylene and t-butylene.
- An alkynyl group may be for example an ethynyl , propynyl or butynyl group.
- salts include pharmaceutically acceptable salts for example acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates and tartrates, salts derived from inorganic bases including alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and salts derived from organic amines such as morpholine, piperidine or dimethylamine salts.
- acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates and tartrates
- salts derived from inorganic bases including alkali metal salt
- Prodrugs of the invention are compounds which upon administration to a mammal produce compounds of formula (1). Such prodrugs can be for example converted within the mammal by hydrolysis. Prodrugs are preferably ester derivatives of the phenolic hydroxy group contained in compounds of formula (1) such as, for example, phosphate esters, carboxylate esters, sulphate esters and carbonates.
- Preferred compounds of the invention are those of formula 1 in which R 1 , R 2 and R 3 are all methyl, and prodrugs thereof Further preferred compounds of the invention are those of formula 1 in which R 1 , R 2 and R 3 are all methyl and R 5 is hydrogen and prodrugs thereof
- Still further preferred compounds of the invention are those of formula 1 in which R 1 , R 2 and R 3 are all methyl, R 5 is hydrogen and R 4 is alkyl or halo and prodrugs thereof
- Preferred prodrugs of the invention are phosphate esters Particularly preferred prodrugs of the invention are dihydrogen phosphate esters
- compounds of formula (1) can be prepared by Wittig olefin synthesis involving reaction of a phosphonium salt of formula (2) with a strong base, for example an alkyllithium such as n-butyllithium or t-butyllithium or a metal hydride such as sodium hydride in a solvent such as an ether solvent for example diethyl ether or tetrahydrofuran or in a solvent such as a hydrocarbon solvent for example toluene at a temperature of between about -100°C to about 30°C followed by treatment with an aldehyde of formula (3) in which R 6 is a protecting group, to give an intermediate of formula (4) The synthesis of compounds of formula (1) is then completed by removal of the group R 6 .
- a strong base for example an alkyllithium such as n-butyllithium or t-butyllithium or a metal hydride such as sodium hydride in a solvent such as an ether solvent for example diethyl
- Suitable protecting groups R 6 include trialkylsilyl, for example t- butyldimethylsilyl, and allyl
- R 6 is a trialkylsilyl group it may be removed, for example, by treatment with a quaternary ammonium fluoride such as tetrabutylammonium fluoride in an ether solvent such as tetrahydrofuran at a temperature of about -30°C to about 40°C conveniently at or near ambient temperature
- R 6 is an allyl group it may be removed for example by treatment with a palladium(O) complex such as tetrakis(triphenylphosphine)Pd(0) in a solvent such as a chlorinated solvent, for example dichloromethane, at a temperature of about - 40°C to about 40°C conveniently at or near ambient temperature, in the presence of an allyl scavenger such as morpholine.
- Aldehydes of formula (3) can be prepared by any process known to a person skilled in the art.
- an aldehyde of formula (3) can be prepared from an alcohol of formula (5) by oxidation with a suitable oxidising agent Suitable oxidising agents include the Dess-Martin reagent and manganese dioxide Alcohols of formula (5) can be prepared by application of standard methods of organic synthesis including the selective protection of phenols of formula (6).
- alcohols of formula (5) may be prepared, for example, by treatment of a phenol of formula (6) with a strong base, for example an alkyllithium such as n-butyllithium or t-butyllithium or a metal hydride such as sodium hydride in a solvent such as an ether solvent for example diethyl ether or tetrahydrofuran or in a solvent such as a hydrocarbon solvent for example toluene at a temperature of between about -100°C to about 40°C followed by treatment with tert- butylchlorodimethylsilane.
- a strong base for example an alkyllithium such as n-butyllithium or t-butyllithium or a metal hydride such as sodium hydride in a solvent such as an ether solvent for example diethyl ether or tetrahydrofuran or in a solvent such as a hydrocarbon solvent for example toluene at a temperature of between about
- Phenols of formula (6) are either known or may be prepared from known compounds using standard methods of organic synthesis.
- Compounds of formula ( 1) may also be prepared from other compounds of formula (1) by chemical modification. Examples of such chemical modifications that may be applied are standard alkylation, halogenation, oxidation and coupling reactions. These reactions may be used to add new substituents or to modify existing substituents.
- Prodrugs of compounds of formula (1) can be prepared by any process known to a person skilled in the art. Processes for the preparation of prodrugs of compounds of formula 1 include standard acylation, sulphation and phosphorylation reactions.
- dihydrogen phosphate esters of compounds of formula (1) can be prepared by treatment of the corresponding di-t-butylphosphate esters with an acid, for example hydrochloric acid or trifluoroacetic acid, in a solvent such as a chlorinated solvent, for example dichloromethane, at a temperature of from about -20°C to about 40°C, conveniently at room temperature.
- Compounds according to the invention are able to destroy tumour vasculature and vasculature that has been newly formed while leaving unaffected normal, mature vasculature.
- the ability of the compounds to act in this way may be determined by the tests described hereinafter.
- the compounds according to the invention are thus of particular use in the prophylaxis and treatment of cancers involving solid tumours and in the prophylaxis and treatment of diseases where inappropriate angiogenesis occurs such as diabetic retinopathy, psoriasis, rheumatoid arthritis, atherosclerosis and macular degeneration.
- compositions for the treatment of neovascularisation which compositions contain an effective amount of a cis-stilbene or prodrugs thereof as hereinbefore defined.
- the invention also includes the use in the preparation of a composition for the treatment of neovascularisation of a cis-stilbene or prodrugs therof as hereinbefore defined.
- compounds of the invention may be administered in combination with radiotherapy or in combination with other anti-tumour substances for example those selected from mitotic inhibitors, for example vinblastine, vincristine, vinorelbine, paclitaxel and docetaxel; platinum derivatives for example cisplatin and carboplatin; alkylating agents, for example melphalan, chlorambucil, busulphan, ifosfamide and cyclophosphamide; antimetabolites, for example methotrexate, 5-fluorouracil, cytosine arabinoside, gemcitabine and hydroxyurea; antitumour antibiotics for example bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,mitomycin-C, dactinomycin and mithramycin ; enzymes, for example aspariginase; topoisomerase inhibitors for example etoposide,teniposide, topotecan and
- Such combination treatment may involve simultaneous or sequential application of the individual components of the treatment.
- the compounds according to the invention may be administered as pharmaceutical compositions selected with regard to the intended route of administration and standard pharmaceutical practice.
- Such pharmaceutical compositions may take a form suitable for oral, buccal, nasal, topical, rectal or parenteral administration and may be prepared in a conventional manner using conventional excipients
- the pharmaceutical compositions may take the form of tablets or capsules
- Topical administration may be as an ointment or cream and rectal administration may be as a suppository
- parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
- the composition may take the form of, for example, a sterile solution, suspension or emulsion
- the dose of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, the route of administration, the form and severity of the condition and whether the compound is to be administered alone or in combination with another drug Thus the precise dose will be determined by the administering physician but in general daily dosages may be in the range 0 001 to l OOmg/kg preferably 0 1 to lOmg/kg
- Tumour functional vascular volume in CaNT tumour-bearing mice was measured using the fluorescent dye Hoechst 33342 according to the method of Smith et al (Brit J Cancer 57, 247-253, 1988) At least three animals were used in control and treated groups.
- the fluorescent dye was dissolved in saline at 6.25 mg/ml and injected intravenously at 10 mg/kg 24 hours after intraperitoneal drug treatment. One minute later, animals were killed and tumours excised and frozen; 10 ⁇ m sections were cut at 3 different levels and observed under UV illumination using an Olympus microscope equipped with epifluorescence.
- aqueous phase was extracted with diethylether (5 portions of 20ml) and the combined extracts were washed with aqueous sodium thiosulphate solution (3 portions of 10ml), water (3 portions of 10ml) and brine (2 portions of 10ml), dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. Purification by chromatography on silica gel, eluting with petroleum ether / diethyl ether (50:50) gave 3-tert-butyldimethylsilyIoxy-4- methylbenzaldehyde (85mg).
- Trifluoroacetic acid (0.22mL, 2.95mmol) was added dropwise to a stirred solution of (Z)-2-methyl-5-[2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl di-tcvtbutyl phosphate (401mg, 0.82mmol) and dichloromethane (16mL). The mixture was stirred at room temperature overnight. Solvent was removed in vacuo, and the residue azeotroped four times with toluene. The colourless oil was triturated with ether to give the title compound as a white solid (18 l g, 58%) m.p. 109-1 13°C.
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002379544A CA2379544A1 (en) | 1999-08-12 | 2000-08-09 | New stilbenes with vascular damaging activity |
JP2001516880A JP2003507356A (ja) | 1999-08-12 | 2000-08-09 | 血管損傷活性を有する新しいスチルベン類 |
NZ517069A NZ517069A (en) | 1999-08-12 | 2000-08-09 | New stilbenes with vascular damaging activity |
AU64581/00A AU779980B2 (en) | 1999-02-16 | 2000-08-09 | New stilbenes with vascular damaging activity |
EP00951727A EP1206429A2 (en) | 1999-08-12 | 2000-08-09 | Stilbenes with vascular damaging activity |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9918912.8A GB9918912D0 (en) | 1999-08-12 | 1999-08-12 | New stilbenes with vascular damaging activity |
GB9918912.8 | 1999-08-12 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2001012579A2 true WO2001012579A2 (en) | 2001-02-22 |
WO2001012579A3 WO2001012579A3 (en) | 2001-10-11 |
Family
ID=10858950
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2000/003067 WO2001012579A2 (en) | 1999-02-16 | 2000-08-09 | New stilbenes with vascular damaging activity |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1206429A2 (it) |
JP (1) | JP2003507356A (it) |
CA (1) | CA2379544A1 (it) |
GB (1) | GB9918912D0 (it) |
NZ (1) | NZ517069A (it) |
WO (1) | WO2001012579A2 (it) |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1068870A1 (en) * | 1998-04-03 | 2001-01-17 | Ajinomoto Co., Inc. | Antitumor agents |
WO2002014329A1 (en) * | 2000-08-15 | 2002-02-21 | Angiogene Pharmaceuticals Ltd. | Compositions with vascular damaging activity |
WO2002050007A2 (en) * | 2000-12-21 | 2002-06-27 | Cancer Research Technology Limited | Substituted stilbenes, their reactions and anticancer activity |
WO2004085361A1 (en) * | 2003-03-26 | 2004-10-07 | Angiogene Pharmaceuticals Limited | Bioreductively activated stilbene prodrugs |
EP1631540A2 (en) * | 2003-12-16 | 2006-03-08 | GTX Inc. | Prodrugs of selective androgen receptor modulators and methods of use thereof |
WO2009067706A1 (en) | 2007-11-21 | 2009-05-28 | Oxigene, Inc. | Method for treating hematopoietic neoplasms |
EP2348012A1 (fr) | 2002-04-11 | 2011-07-27 | Aventis Pharma S.A. | Procede de preparation de combretastatine |
US8039513B2 (en) | 2004-07-21 | 2011-10-18 | Institute Of Radiation Medicine, Academy Of Military Medical Sciences, Pla | Cis-1,2-substituted stilbene derivatives and their use in preparation of drugs for treatment and/or prevention of diabetes |
WO2012025638A1 (en) | 2010-08-27 | 2012-03-01 | Universität des Saarlandes | Selective 17beta-hydroxysteroid dehydrogenase type 1 inhibitors |
US10201623B2 (en) | 2013-03-15 | 2019-02-12 | Memorial Sloan Kettering Cancer Center | HSP90-targeted cardiac imaging and therapy |
US10640508B2 (en) | 2017-10-13 | 2020-05-05 | Massachusetts Institute Of Technology | Diazene directed modular synthesis of compounds with quaternary carbon centers |
WO2020092134A1 (en) | 2018-10-29 | 2020-05-07 | Cepheid | Exponential base-3 nucleic acid amplification with reduced amplification time using nested overlapping primers |
WO2020247054A1 (en) | 2019-06-05 | 2020-12-10 | Massachusetts Institute Of Technology | Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof |
US10918627B2 (en) | 2016-05-11 | 2021-02-16 | Massachusetts Institute Of Technology | Convergent and enantioselective total synthesis of Communesin analogs |
US10918735B2 (en) | 2012-12-04 | 2021-02-16 | Massachusetts Institute Of Technology | Substituted pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment |
US11419934B2 (en) | 2015-08-18 | 2022-08-23 | Oncotelic Therapeutics, Inc. | Use of VDAS to enhance immunomodulating therapies against tumors |
US11932650B2 (en) | 2017-05-11 | 2024-03-19 | Massachusetts Institute Of Technology | Potent agelastatin derivatives as modulators for cancer invasion and metastasis |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101085743B (zh) * | 2006-06-06 | 2012-02-15 | 浙江大德药业集团有限公司 | 含氟烷氧基康普立停衍生物及制法和用途 |
JP2011016777A (ja) * | 2009-07-10 | 2011-01-27 | Nipro Corp | 新規システイン誘導体 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992016486A1 (en) * | 1991-03-22 | 1992-10-01 | Aston Molecules Limited | Substituted diphenylethylenes and analogues or derivatives thereof |
EP0641767A1 (en) * | 1993-09-08 | 1995-03-08 | Ajinomoto Co., Inc. | Cytotoxic stilbene derivatives and pharmaceutical composition containing them |
US5561122A (en) * | 1994-12-22 | 1996-10-01 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Combretastatin A-4 prodrug |
WO2000048590A1 (en) * | 1999-02-16 | 2000-08-24 | Angiogene Pharmaceuticals Ltd. | Substituted stilbene compounds with vascular damaging activity |
-
1999
- 1999-08-12 GB GBGB9918912.8A patent/GB9918912D0/en not_active Ceased
-
2000
- 2000-08-09 WO PCT/GB2000/003067 patent/WO2001012579A2/en not_active Application Discontinuation
- 2000-08-09 CA CA002379544A patent/CA2379544A1/en not_active Abandoned
- 2000-08-09 EP EP00951727A patent/EP1206429A2/en not_active Withdrawn
- 2000-08-09 NZ NZ517069A patent/NZ517069A/en unknown
- 2000-08-09 JP JP2001516880A patent/JP2003507356A/ja active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992016486A1 (en) * | 1991-03-22 | 1992-10-01 | Aston Molecules Limited | Substituted diphenylethylenes and analogues or derivatives thereof |
EP0641767A1 (en) * | 1993-09-08 | 1995-03-08 | Ajinomoto Co., Inc. | Cytotoxic stilbene derivatives and pharmaceutical composition containing them |
US5561122A (en) * | 1994-12-22 | 1996-10-01 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Combretastatin A-4 prodrug |
WO2000048590A1 (en) * | 1999-02-16 | 2000-08-24 | Angiogene Pharmaceuticals Ltd. | Substituted stilbene compounds with vascular damaging activity |
Non-Patent Citations (3)
Title |
---|
J. A. WOODS: "The interaction with tubulin of a series of stilbenes based on combretastatin A-4" BRITISH JOURNAL OF CANCER, vol. 71, 1995, pages 705-711, XP000978556 cited in the application * |
K. OHSUMI: "Novel combretastatin analogues effective against murine solid tumors: design and structure-activity relationships" JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, 1998, pages 3022-3032, XP002102895 WASHINGTON US cited in the application * |
M. CUSHMAN: "Synthesis and evaluation of stilbene and dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerization" JOURNAL OF MEDICINAL CHEMISTRY, vol. 34, 1991, pages 2579-2588, XP000571676 WASHINGTON US cited in the application * |
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1068870A1 (en) * | 1998-04-03 | 2001-01-17 | Ajinomoto Co., Inc. | Antitumor agents |
US7655696B2 (en) | 1998-04-03 | 2010-02-02 | Ajinomoto Co., Inc. | Anti-tumor composition |
US7973076B2 (en) | 1998-04-03 | 2011-07-05 | Ajinomoto Co., Inc. | Anti-tumor composition |
EP1068870A4 (en) * | 1998-04-03 | 2003-02-12 | Ajinomoto Kk | ANTITUMOR AGENTS |
US6992106B2 (en) | 1998-04-03 | 2006-01-31 | Ajinomoto Co., Inc. | Anti-tumor composition |
WO2002014329A1 (en) * | 2000-08-15 | 2002-02-21 | Angiogene Pharmaceuticals Ltd. | Compositions with vascular damaging activity |
US7105501B2 (en) | 2000-08-15 | 2006-09-12 | Angiogene Pharmaceuticals Ltd. | Compositions with vascular damaging activity |
WO2002050007A3 (en) * | 2000-12-21 | 2002-10-17 | Cancer Res Ventures Ltd | Substituted stilbenes, their reactions and anticancer activity |
US8853270B2 (en) | 2000-12-21 | 2014-10-07 | University Of Salford | Substituted stilbenes and their reactions |
WO2002050007A2 (en) * | 2000-12-21 | 2002-06-27 | Cancer Research Technology Limited | Substituted stilbenes, their reactions and anticancer activity |
EP2354118A1 (fr) | 2002-04-11 | 2011-08-10 | Aventis Pharma S.A. | Procédé de préparation de combretastatine |
EP2348012A1 (fr) | 2002-04-11 | 2011-07-27 | Aventis Pharma S.A. | Procede de preparation de combretastatine |
WO2004085361A1 (en) * | 2003-03-26 | 2004-10-07 | Angiogene Pharmaceuticals Limited | Bioreductively activated stilbene prodrugs |
EP1631540A2 (en) * | 2003-12-16 | 2006-03-08 | GTX Inc. | Prodrugs of selective androgen receptor modulators and methods of use thereof |
EP1631540A4 (en) * | 2003-12-16 | 2006-10-04 | Gtx Inc | PRODRUGS OF SELECTIVE ANDROGEN RECEPTOR MODULATORS AND METHOD OF USE THEREOF |
US7595402B2 (en) | 2003-12-16 | 2009-09-29 | Gtx, Inc. | Prodrugs of selective androgen receptor modulators and methods of use thereof |
US8039513B2 (en) | 2004-07-21 | 2011-10-18 | Institute Of Radiation Medicine, Academy Of Military Medical Sciences, Pla | Cis-1,2-substituted stilbene derivatives and their use in preparation of drugs for treatment and/or prevention of diabetes |
WO2009067706A1 (en) | 2007-11-21 | 2009-05-28 | Oxigene, Inc. | Method for treating hematopoietic neoplasms |
US9040500B2 (en) | 2007-11-21 | 2015-05-26 | Oxigene, Inc. | Method for treating hematopoietic neoplasms |
WO2012025638A1 (en) | 2010-08-27 | 2012-03-01 | Universität des Saarlandes | Selective 17beta-hydroxysteroid dehydrogenase type 1 inhibitors |
US10918735B2 (en) | 2012-12-04 | 2021-02-16 | Massachusetts Institute Of Technology | Substituted pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment |
US10201623B2 (en) | 2013-03-15 | 2019-02-12 | Memorial Sloan Kettering Cancer Center | HSP90-targeted cardiac imaging and therapy |
US11419934B2 (en) | 2015-08-18 | 2022-08-23 | Oncotelic Therapeutics, Inc. | Use of VDAS to enhance immunomodulating therapies against tumors |
US10918627B2 (en) | 2016-05-11 | 2021-02-16 | Massachusetts Institute Of Technology | Convergent and enantioselective total synthesis of Communesin analogs |
US11932650B2 (en) | 2017-05-11 | 2024-03-19 | Massachusetts Institute Of Technology | Potent agelastatin derivatives as modulators for cancer invasion and metastasis |
US10640508B2 (en) | 2017-10-13 | 2020-05-05 | Massachusetts Institute Of Technology | Diazene directed modular synthesis of compounds with quaternary carbon centers |
WO2020092134A1 (en) | 2018-10-29 | 2020-05-07 | Cepheid | Exponential base-3 nucleic acid amplification with reduced amplification time using nested overlapping primers |
WO2020247054A1 (en) | 2019-06-05 | 2020-12-10 | Massachusetts Institute Of Technology | Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof |
US11535634B2 (en) | 2019-06-05 | 2022-12-27 | Massachusetts Institute Of Technology | Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
NZ517069A (en) | 2004-04-30 |
EP1206429A2 (en) | 2002-05-22 |
GB9918912D0 (en) | 1999-10-13 |
CA2379544A1 (en) | 2001-02-22 |
JP2003507356A (ja) | 2003-02-25 |
WO2001012579A3 (en) | 2001-10-11 |
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