WO1990005731A1 - Macromolecules cytotoxiques - Google Patents

Macromolecules cytotoxiques Download PDF

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Publication number
WO1990005731A1
WO1990005731A1 PCT/AU1989/000505 AU8900505W WO9005731A1 WO 1990005731 A1 WO1990005731 A1 WO 1990005731A1 AU 8900505 W AU8900505 W AU 8900505W WO 9005731 A1 WO9005731 A1 WO 9005731A1
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WO
WIPO (PCT)
Prior art keywords
substantially pure
compounds
bistratene
lissoclinamide
cells
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PCT/AU1989/000505
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English (en)
Inventor
Clifford J. Hawkins
Diane J. Watters
Martin F. Lavin
David L. Parry
Elizabeth J. Mccaffrey
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University Of Queensland
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Publication of WO1990005731A1 publication Critical patent/WO1990005731A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • THE PRESENT INVENTION relates to the isolation, identification and preparation of cytotoxic macromolecules and their application in therapy.
  • the invention is directed to novel cyclic peptides and macrocyclic ethers which should be of use in the treatment of cancer and related diseases.
  • Chemotherapy is now a widely accepted form of cancer treatment, although many forms of cancer are still poorly controlled by drugs.
  • search for new pharmaceuticals it has been recognised that, as terrestrial and marine invertebrates do not have a thymus system for immunological protection, these life forms must have developed sophisticated chemical mechanisms for their protection and, therefore, such chemical protective agents should also prove useful in the treatment of a variety of human medical problems.
  • Recent research has indeed confirmed that marine organisms are a valuable source of organic compounds with antineoplastic activity.
  • the present inventors have now isolated and identified a number of macrocyclic compounds from the marine organisms Lissoclinum patella and Lissoclinum bistratum which exhibit appreciable cytotoxic activity. In view of the in vitro and in vivo activity of these cyclic compounds, they should find use in the treatment of cancer and related diseases.
  • a series of compounds each compound being separably isolable - hereinafter referred to as trisoxazoline, patellamide D, lissoclinamide 4, lissoclinamide 5, lissoclinamide 7, lissoclinamide 8, bistratamide B, bistratamide A, bistratene A and bistratene B, the structures of which are depicted in FIG 1.
  • Trisoxazoline, bistratamide A, bistratamide B, bistratene A and bistratene B were all isolated from the aplousobranch ascidian Lissoclinum bistratum, and patellamide D, lissoclinamide 4, lissoclinamide 5, lissoclinamide 7 and lissoclinamide 8 were all isolated from the aplousobranch Lissoclinum patella.
  • a method for the isolation of the afore-defined series of compounds comprising: 1) homogenising the cleaned ascidian with an alcohol/hydrocarbon solution;
  • the ascidian is homegenised with an alcohol/aromatic hydrocarbon solution, more preferably methanol/toluene solution; (2) the filtrate is extracted with sodium nitrate solution; and (3) the aqueous layer is extracted with chloroform.
  • an alcohol/aromatic hydrocarbon solution more preferably methanol/toluene solution
  • the filtrate is extracted with sodium nitrate solution
  • the aqueous layer is extracted with chloroform.
  • the compounds of the present invention have been screened for in vitro and in vivo antitumour activity and positive results have been obtained. Thus the compounds should find a use in the control of cancer and similar diseases.
  • a pharmaceutical composition containing one or more of the above-described compounds, or a non-toxic salt thereof, optionally in association with any carrier or diluent which is suitable for its administration.
  • a non-toxic salt denotes salts which do not produce undesired side effects when administered at effective dosage levels.
  • non-toxic acid addition salts include the hydrohalic, sulphuric, nitric, phosphoric, citric, acetic and oxalic acid salts.
  • the term "effective amount” is understood as meaning a sufficient amount to enable the control of cancer and similar diseases of the patient. However, it will be appreciated that, the doses used can very within wide limits, according to the disease to be treated, the response of the patient and the particular compound employed.
  • PLC protein kinase C
  • Structural identification of each compound of the invention was determined by two-dimensional NMR techniques and each compound was tested for cytotoxicity toward human fibroblast and tumour cell lines.
  • Spectra were obtained using a C-5 dual 1 H, 13 C probe in a JEOL GX400 NMR spectrometer. Compounds were dissolved in deuterated chloroform (Merck) and chemical shifts were derived relative to tetramethylsilane (TMS).
  • TMS tetramethylsilane
  • Bistratamide A spectral width 3076.9 Hzdata matrix 512 x 1024, scans 32, recycle time 3 s, with zero filling in the V 1 domain
  • bistratamide B spectral width 3450.7 Hz, data matrix 512 x 2048, scans 32, recycle time 3.23 s with zero filling in the V 1 domain.
  • Sine-bell apodization functions were used.
  • bistratamide A data matrix 128 x 4096, scans 592, recycle time 1.6 s
  • bistratamide B data matrix 128 x 4096, scans 2000, recycle time 1.7 s
  • bistratene A data matrix 128 x 4096, scans 320, recycle time 1.9 s.
  • ⁇ 1 and ⁇ 2 1/2 J and 1/3 J, respectively
  • a typical sample size for extraction 250g (wet weight) of frozen ascidian, was homogenized in a Waring Blendor with IL of a 3:1 methanol:toluene solution. The homogenate was filtered and the filtrate was extracted with 1M sodium nitrate solution (800 mL). The aqueous layer was extracted with chloroform (6 x 100 mL) and the chloroform dried over anhydrous sodium sulphate. The chloroform was evaporated to dryness yielding a brownish oil.
  • Peptides (0.3 ⁇ mol) were hydrolysed in 6 M HCl (1 mL) and mercaptoethane (100 ⁇ L) in vacuo for 24 h at 110°. Mercaptoethane was added to prevent oxidation of cysteine during hydrolysis. After evaporation to dryness, the amino acids were converted to their N- pentafluoropropionyl isopropyl esters and applied to a Chirasil-Val GC column for separation of D and L isomers.
  • Frozen L. bistratum was processed following the general extraction procedure described above to yield a dark green-brown oil. Chromatography of the oil on a preparative reverse phase C-18 column (Whatman ODS-3) yielded pure trisoxazoline detected by its absorbance at 210 nm.
  • Cytotoxicity was examined in vitro using two cell lines - an SV40 transformed fibroblast cell line (MRC5CV1) and a transitional cell carcinoma of the bladder (T24). Cells were incubated for 1 hour with varying concentrations of trisoxazoline and after 5 days the incorporation of [methyl - 3 H] thymidine into DNA was determined, as a measure of cell viability. The results are shown in FIG.2.
  • the IC 50 value (concentration required to inhibit growth by 50%) was determined as 0.5 ⁇ g/ml. Cell viability was also determined by measuring the colony formation in agar at various doses of trisoxazoline. From these experiments an IC 50 value of 1.2 ⁇ g/ml was obtained, in good agreement with the value obtained from thymidine incorporation.
  • the assay used to assess the in vivo antitumour properties of a single concentration of trisoxazoline was the P-338 system in Balb/C mice as recommended by the Guidelines of the National Cancer Insititute.
  • mice 22-24g were weighed and randomly assorted into three groups. These groups were:-
  • TEST (trisoxazoline) 2.75 g.
  • the mean survival time of untreated controls was 9.5 days.
  • T/C index of 125 is considered significant.
  • a total of 7kg of L. patella was processed following the general extraction procedure described above to yield approximately 10g of crude extract.
  • the crude extract was dissolved in methanol:water (77:23) and applied to a Whatman Partisil ODS-3 9mm x 500mm preparative HPLC column. Elution was effected by means of a concave gradient from 77 to 100% methanol over 120 min. and the absorbance of the eluate was monitored using a Waters 990 Photodiode Array detector.
  • Patellamide D (C 38 H 48 N 8 O 6 S 2 ) is very similar in structure to the known patellamide B except that a leucine is replaced by an isoleucine at position 6.
  • HREI mass spectroscopy gave a molecular weight of 776.3138 (calc'd 776.3128).
  • Positive ion FAB-MS gave (M+H) + 777.
  • the structure was unambiguously assigned from detailed analysis of 1 H and 13 C NMR spectra and 2D COSY 45 and 1 H - 13 C shift correlation experiments.
  • Lissoclinamides 4, 5, 7 and 8 All four peptides are cyclic heptapeptides which have the same sequence of amino acids around the ring and differ from one another only in their stereochemistry or the number of thiazole and thiazoline rings.
  • valine residue is at position 31 - the same sequence as occurs in lissoclinamide 4. Therefore, the only difference between lissoclinamides 4 and 8 must reside in the stereochemistry of one or two of the amino acids.
  • the D configuration has been tentatively assigned for lissoclinamide 8.
  • Lissoclinamides 7 and 8 comprised 0.4% and 0.5% of the dried crude extract respectively.
  • MRC5CV1 SV40- transformed human fibroblasts
  • T24 transitional cell carcinoma of the bladder
  • cytotoxicities of these two compounds were examined in vitro using transitional bladder carcinoma cells (T24), SV40 transformed fibroblasts (MRC5CV1) and normal peripheral blood lymphocytes.
  • Cell viability assays were performed using a colorimetric assay which relies on the conversion of MTT (3- (4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide to a blue formazan dye by live mitochondria. This assay has been shown to give identical results to the [methyl- 3 H]thymidine incorporation assay.
  • SV40 transformed fibroblasts (MRC5CV1) and transitional bladder carcinoma cells (T24) were maintained in RPMI 1640 medium (Commonwealth Serum Laboratories) containing 10% foetal calf serum, at 37° in a humidified atmosphere of 5% CO 2 in air.
  • Human lymphocytes were isolated from whole blood using Ficoll Paque (Pharmacia-LKB) as recommended by the manufacturer.
  • Phytohaemagglutinin [PHA, (GIBCO)] was added at 1 ⁇ L/mL. the lymphocytes were plated into 96 well microtitre plates at a density of 1x10 5 /mL.
  • the lissoclinamides were added in a range from 100 ⁇ g/mL to 0.1 ⁇ g/mL. After 24 h, the surviving cells were assayed.
  • MRC5CV1 and T24 cells were plated at a density of 1x10 4 /100 ⁇ L in 96 well microtiter plates . After overnight incubation, the cells were exposed to varying concentrations of the lissoclinamides for 1 h. After a 48 h incubation, 10 ⁇ L of MTT (5 mg/mL) were added per well and the cultures incubated for 4 h at 37°.
  • Lissoclinamide 7 was the most cytotoxic with an IC 50 value of 0.04 ⁇ g/mL for a 1 h exposure.
  • bistratamide B bistratamide A
  • bistratene A bistratene B
  • Bistratamides A and B were obtained in approximately equal amounts comprising 0.3% of dried extract each (equivalent to 5mg/kg wet weight).
  • the yields of bistratenes A and B were 10% and 2.8% of the dried extract, respectively (equivalent to 0.56 g/kg and 0.15 g/kg wet weight, respectively).
  • the structures of the compounds were determined unambiguously from detailed analyses of 1 H and 13 C NMR spectra and from 2D COSY 45 and 1 H- 13 C shift correlation experiments.
  • cytotoxicity of these compounds towards human cell lines, MRC5CV1 fibroblasts and T24 bladder carcinoma cells was determined.
  • the cells were maintained in RPMI-1640 medium (Commonwealth Serum Laboratories) containing 10% foetal calf serum at 37° in a humidified atmosphere of 5% CO 2 in air.
  • Cells were plated at a density of 5x10 3 cells/16mm well, 24 h prior to labelling with [methyl- 3 H] thymidine (10 ⁇ Ci/mL, 40 Ci/mmol, Amersham).
  • Bistratamide A has an IC 50 value of about 60 ⁇ g/mL and bistratamide B an IC 50 value greater than 100 ⁇ g/mL. Their toxicity is similar to that of patellamide D. The conversion of one thiazoline in bistratamide A to a thiazole in bistratamide B results in a less toxic compound.
  • bistratenes are among the most cytotoxic compounds yet discovered in the ascidians, in particular, bistratene A with an IC 50 value of 0.07 ⁇ g/mL. (see FIG 5) and bistratene B, with an IC 50 value of 0.09 ⁇ g/mL.
  • Results are reported for T24 Bladder Carcinoma Cells and a 1-hour exposure.
  • the compounds induce, at nanomolar concentrations, the property of differentiation in HL-60, human leukaemia cells along the monocyte/macrophages pathway. They do not have calcium ionophore activity but do activate the enzyme protein kinase C (PKC) at micromolar concentrations.
  • PKC protein kinase C
  • a monoclonal antibody against OKM-1 (a macrophage- granulocyte cell surface glycoprotein) was obtained from Ortho Diagnostics.
  • Phycoerythrin labelled antibodies to Leu-M3 (CDw14), the granulocyte marker Leu-lla (CD16), Leu-7 (HNK-1) and HLA-DR were purchased from Becton Dickinson.
  • HL-60 cells were cultured in RPMI 1640 medium containing 10% foetal calf serum.
  • the cytotoxicity of the bistratenes to HL-60 cells was determined using a colorimetric assay based on conversion of MTT to a blue formazan product by live mitochondria. Adherence was assessed by visual examination after gently shaking the cultures and aspirating non- adherent cells . Cytocentrifuge smears were assayed for nonspecific esterase (NSE) 48 h after treatment with bistratene A. Phagocytosis was determined by incubating differentiated HL-60 cells with 0.8 ⁇ polystyrol-latex beads (Boehringer Mannheim).
  • IL-1 interleukin-1
  • mAb monoclonal antibody
  • PKC was isolated from bovine spleen (1000 g) by sequential chromatographies on DEAE-cellulose, phenyl-Sepharose, threonine-Sepharose and hydroxylapatite. The final preparation yielded 4.3 mg of type II PKC and 2.0 mg of type III PKC in electrophoretically pure form.
  • Assays of enzyme activity were carried out using lysine-rich histone as substrate, and measuring the rate of incorporation of [ 32 P] phospate from [ - 32 PZATP (50 ⁇ M, 4 x 10 dpm/assay) into histone (lmg/mL). All assays contained 10 mM MgCl 2 and 5 mM dithiothreitol. The concentrations of calcium ions, phosphatidylserine, oleic acid, diolein, TPA and bistratene included in the assays are given in Table 2.
  • Phosphatidylserine was added as a sonicated vesicle preparation. Other compounds were added as solutions in either ethanol or methanol. The concentration of organic solvent, which was always less than 2% (v/v), was shown to have no effect on the enzyme activity.
  • TPA-treated cells were more strongly adherent and showed greater clumping.
  • the morphology of bistratene-treated HL-60 cells is typical of cells in the process of differentiation along the monocyte/macrophage pathway.
  • the nature of the differentiated cells was investigated in greater detail using a variety of cell surface and other differentiation markers (table 3).
  • the concentration required to produce half-maximal expression was less than 50 nM for both OKM-1 and Leu-M3. These cells show some of the characteristics of macrophages, for example adherence to plastic and expression of OKM-1 and Leu-M3 antigens, but do not appear to be activated since they lack HLA-DR expression, and nonspecific esterase activity, do not phagocytose and fail to produce IL-1.
  • the enzyme is fully activated in the presence of either 16 nM TPA or 35 ⁇ M bistratene B, an enhancement of 30-fold over the activity in the presence of 600 ⁇ M fatty acid alone.
  • bistratenes can induce some differentiation of HL-60 cells at nanomolar concentrations and that, like diacylglycerols and phorbol esters, are capable of enhancing the activity of type II PKC from bovine spleen in the presence of suboptimal concentrations of oleic acid.
  • bistratenes induce the incomplete differentiation of HL-60 cells and enhance PKC activity in vitro, thus representing a new type of PKC modulator which should find use in the investigation of the role of PKC in cell growth and differentiation.
  • the compounds of the present invention do exhibit appreciable in vitro anti-tumour activity, they are thus potential anti-tumour agents. Accordingly, these compounds should be useful in the treatment of cancer and related diseases.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Un certain nombre de peptides cycliques et d'éthers macrocycliques ont été isolés et identifiés à partir des organismes marins Lissoclinum patella et Lissoclinum bistratum. Ces composés se caractérisent par une activité cytotoxique et peuvent être utiles dans le traitement du cancer et des maladies associées. Ces composés peuvent également servir de modulateurs pour une protéine cellulaire (PKC) pour la détection et le contrôle de la croissance et de la différentiation cellulaires. Les composés préférés sont lissoclinamide 7, bistratène A et bistratène B.
PCT/AU1989/000505 1988-11-24 1989-11-23 Macromolecules cytotoxiques WO1990005731A1 (fr)

Applications Claiming Priority (2)

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AUPJ1653 1988-11-24
AUPJ165388 1988-11-24

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WO1990005731A1 true WO1990005731A1 (fr) 1990-05-31

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994020503A1 (fr) * 1993-03-08 1994-09-15 Institut Francais De Recherche Scientifique Pour Le Developpement En Cooperation (Orstom) Bistramides biologiquement actifs, leur obtention et leurs applications en therapeutique
FR2702478A1 (fr) * 1993-03-08 1994-09-16 Orstom Nouveaux dérivés de bistramides, leur obtention et leurs applications en thérapeutique.
FR2707644A1 (fr) * 1993-06-29 1995-01-20 Orstom Bistramides biologiquement actifs, leur préparation et leurs applications biologiques.
EP0730446A1 (fr) * 1993-09-21 1996-09-11 The Trustees of Columbia University in the City of New York Activateurs de proteine kinase c et leur utilisation pour reduire l'expression d'antigenes cellulaires
WO1997039025A1 (fr) * 1996-04-18 1997-10-23 Pharma Mar, S.A. Heptapeptide cyclique obtenu a partir d'une ascidie coloniale, a savoir le lissoclinum.
US5869650A (en) * 1996-06-21 1999-02-09 Fox Chase Cancer Center Dendroamide compounds and their use in chemosensitizing multidrug resistant cells
KR100471727B1 (ko) * 2002-10-14 2005-02-21 학교법인 포항공과대학교 이속사졸린 고리와 불소를 포함하는 거대고리 화합물 및그의 제조방법
EP1998792A2 (fr) * 2006-03-01 2008-12-10 The University of Utah Research Foundation Procedes et compositions relatifs a la synthese de peptides cycliques
US10538535B2 (en) 2017-04-27 2020-01-21 Pharma Mar, S.A. Antitumoral compounds

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY, Volume 32, No. 6, 1989, pages 1349-54, B M DEGNAN et al.: "New Cyclic Peptides with Cytotoxic Activity from the Ascidian Lissoclinum patella". *
JOURNAL OF MEDICINAL CHEMISTRY, Volume 32, No. 6, 1989, pages 1354-59, B M DEGNAN et al.: "Novel Cytotoxic Compounds from the Ascidian Lissoclinum bistratum". *
JOURNAL OF ORGANIC CHEMISTRY, Volume 47, No. 10, 1982, pages 1807-1811, C M IRELAND et al.: "Antineoplastic Cyclic Peptides from the Marine Tunicate Lissochinum patella". *
JOURNAL OF ORGANIC CHEMISTRY, Volume 54, No. 14, 1989, pages 3463-3472, F.J. SCHMITZ et al.: "Cyclic Peptides from the Ascidian Lissoclinum patella: Conformational analysis of Patellamide D by x-ray analysis and molecular modelling". *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2702478A1 (fr) * 1993-03-08 1994-09-16 Orstom Nouveaux dérivés de bistramides, leur obtention et leurs applications en thérapeutique.
AU679501B2 (en) * 1993-03-08 1997-07-03 Institut Francais De Recherche Scientifique Pour Le Developpement En Cooperation (Orstom) Biologically active bistramides, process for their production and their applications in therapy
US5798381A (en) * 1993-03-08 1998-08-25 Institut Francais De Recherche Scientifique Pour Le Development En Cooperation (Orstom) Biologically active bistramides, process for their production and their applications in therapy
WO1994020503A1 (fr) * 1993-03-08 1994-09-15 Institut Francais De Recherche Scientifique Pour Le Developpement En Cooperation (Orstom) Bistramides biologiquement actifs, leur obtention et leurs applications en therapeutique
FR2707644A1 (fr) * 1993-06-29 1995-01-20 Orstom Bistramides biologiquement actifs, leur préparation et leurs applications biologiques.
US6069174A (en) * 1993-09-21 2000-05-30 The Trustees Of Columbia University In The City Of New York Protein kinase C activators and their use in increasing expression of cell antigens
EP0730446A1 (fr) * 1993-09-21 1996-09-11 The Trustees of Columbia University in the City of New York Activateurs de proteine kinase c et leur utilisation pour reduire l'expression d'antigenes cellulaires
EP0730446A4 (fr) * 1993-09-21 1999-01-20 Univ Columbia Activateurs de proteine kinase c et leur utilisation pour reduire l'expression d'antigenes cellulaires
WO1997039025A1 (fr) * 1996-04-18 1997-10-23 Pharma Mar, S.A. Heptapeptide cyclique obtenu a partir d'une ascidie coloniale, a savoir le lissoclinum.
US5869650A (en) * 1996-06-21 1999-02-09 Fox Chase Cancer Center Dendroamide compounds and their use in chemosensitizing multidrug resistant cells
KR100471727B1 (ko) * 2002-10-14 2005-02-21 학교법인 포항공과대학교 이속사졸린 고리와 불소를 포함하는 거대고리 화합물 및그의 제조방법
EP1998792A2 (fr) * 2006-03-01 2008-12-10 The University of Utah Research Foundation Procedes et compositions relatifs a la synthese de peptides cycliques
EP1998792B1 (fr) * 2006-03-01 2015-02-18 The University of Utah Research Foundation Procedes et compositions relatifs a la synthese de peptides cycliques
US10538535B2 (en) 2017-04-27 2020-01-21 Pharma Mar, S.A. Antitumoral compounds
US11332480B2 (en) 2017-04-27 2022-05-17 Pharma Mar, S.A. Antitumoral compounds
US11339180B2 (en) 2017-04-27 2022-05-24 Pharma Mar, S.A. Antitumoral compounds
US11713325B2 (en) 2017-04-27 2023-08-01 Pharma Mar, S.A. Antitumoral compounds

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