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WO2005019181A1 - Analogues de la migrastatine, inhibiteurs de la migration des cellules - Google Patents

Analogues de la migrastatine, inhibiteurs de la migration des cellules Download PDF

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Publication number
WO2005019181A1
WO2005019181A1 PCT/US2004/009211 US2004009211W WO2005019181A1 WO 2005019181 A1 WO2005019181 A1 WO 2005019181A1 US 2004009211 W US2004009211 W US 2004009211W WO 2005019181 A1 WO2005019181 A1 WO 2005019181A1
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compound
compounds
crf
chem
halo
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Xin-Yun Huang
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Cornell Research Foundation Inc
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Cornell Research Foundation Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/02—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention relates to novel compositions and methods for inhibiting cell migration. Such compositions and methods can be used for treating and preventing metastasis in vivo.
  • Background of the Invention Malignant cancer tumors shed cells which migrate to new tissues and create secondary tumors; a benign tumor does not generate secondary tumors. The process of generating secondary tumors is called metastasis and is a complex process in which tumor cells colonize sites distant from the primary tumor. Tumor metastasis remains the major cause of morbidity and death for patients with cancer.
  • metastasis i.e., what controls the spread of tumor cells through the blood and lymphatic systems and what allows tumor cells to populate and flourish in new locations. While surgery and chemotherapy are routinely used for treating cancer, such treatments typically involve removal or ablation of significant tissue giving rise to undesirable side effects. Moreover, the surgeon is rarely certain that all malignant tissues are removed. Hence, new compositions and methods for halting the spread, or metastasis of cancer cells are needed.
  • the present invention provides compounds that act as potent inhibitors of cell migration and can be used for treating and preventing metastasis in vivo. Accordingly there is provided a compound of the invention, which is a compound of formula I:
  • the invention also provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a pharmaceutical composition comprising a combination of compounds, each of formula I, or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • the invention further provides a method for inhibiting migration of mammalian cells either in vitro or in vivo, such as a human, comprising contacting the mammalian cells with an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the invention provides a therapeutic method for preventing or treating metastasis in a mammal, such as a human, comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of formula I for use in medical therapy
  • the invention also provides processes and intermediates disclosed herein that are useful for preparing compounds of formula (I) or salts thereof.
  • FIG. 1 illustrates that treatment of mice with compounds of the invention almost completely blocked 4T1 tumor lung metastasis.
  • 4T1 tumor cells (10 5 ) were injected subcutaneously into the abdominal mammary gland using 0.1 ml of a single-cell suspension.
  • the mice were sacrificed.
  • Each group was comprised of five mice.
  • Lung metastasis was measured by the 6-thioguanine clonogenic assay. The mean and standard deviation are presented in the figure. As shown, the compounds substantially reduced metastasis of tumor cells.
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as "propyl” embraces only the straight chain radical, a branched chain isomer such as "isopropyl” being specifically referred to. It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
  • the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine the cell migration inhibitory activity of such forms using the standard tests described herein, or using other similar tests which are well known in the art.
  • (Ci-C ⁇ jalkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C 3 -Ce)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2- cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl,
  • Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate.
  • Suitable inorganic 5 salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically0 acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a5 variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • compositions and preparations should contain at least 0.1% of active5 compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid CRF D-3406 6 and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • binders such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid CRF D-3406 6 and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, fructo
  • the unit dosage form When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a 5 vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such 10 as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally 15 by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of 25 manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the 30 required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial conditions
  • CRF D-3406 7 and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying 5 absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of 10 preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to 15 the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • a dermatologically acceptable carrier which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present 20 compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the 30 compounds of formula I to the skin are known to the art; for example, see Jacquet et al.
  • the concentration of the compound(s) of formula I in a liquid composition will be from about 0.01-25 wt-%, preferably from about 0.1-10 wt-%.
  • concentration in a semi-solid or solid composition such as a gel or a 10 powder will be about 0.01-10 wt-%, preferably about 0.1 -5 wt-%.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose will be in the range of from about 1.0 to about 200 mg/kg, e.g., from about 2.0 to about 100 mg/kg of body weight per day, such as about 3.0 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of about 5 to 20 mg/kg/day.
  • the compositions can be administered five times a week on five consecutive days with a two day rest, or four 20 times a week on four consecutive days with a three day rest, or every other day.
  • the compound is conveniently administered in unit dosage form; for example, containing 45 to 3000 mg, conveniently 90 to 2250 mg, most conveniently, 450 to 1500 mg of active ingredient per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma 25 concentrations of the active compound of from about 0.5 nM to about 10 ⁇ M, preferably, about 1 nM to 1 ⁇ M, most preferably, about 10 nM to about 0.5 ⁇ M.
  • This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 20- 2000 mg of the active ingredient. Desirable blood levels may be maintained by 30 continuous infusion to provide about 0.2 to 1.0 mg/kg/hr or by intermittent infusions containing about 0.4 to 20 mg/kg of the active ingredient(s).
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub- doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by 5 application of a plurality of drops into the eye.
  • the ability of a compound of the invention to act as an inhibitor of cell migration or metastasis may be determined using pharmacological models that are well known to the art, or using the wound healing, chamber cell migration assay or tumor metastasis assays described below.
  • the Wound-Healing Assay involves observing whether confluent cells can migrate across a scrape or wound in the cell layer.
  • tumor cells can be plated in standard media containing 10% fetal bovine serum (FBS).
  • FBS fetal bovine serum
  • wounds are made in the confluent layer of cell using a sterile instrument such as a sterile pipette tip.
  • the cells can be washed with Phosphate Buffered Saline 15 (PBS) or other sterile solutions and then growth medium can be added that contains different concentrations of the compounds to be tested. After overnight incubation at 37°C, cells can be fixed and the plates can be photographed.
  • PBS Phosphate Buffered Saline 15
  • the Chamber Cell Migration Assay assesses whether cell can migrate through a filter having pores of known sizes. For example, cell migrations can be assayed with Boyden chambers having filters with about 8.0 ⁇ m pore size. Briefly, cells in serum-free medium are added to the first chamber and 500 ⁇ l of medium with 10% fetal bovine serum (FBS) is added to the second chamber. The chamber is incubated for about 6-8 25 hours at 37°C with different concentrations of chemical compounds in both of the two chambers.
  • FBS fetal bovine serum
  • CRF D-3406 10 invention can inhibit cell migration at lower concentrations than currently available compounds, including migrastatin.
  • the compounds of the invention can be tested in appropriate animal models.
  • the compounds of the invention can be tested in animals with 5 known tumors, or animals that have been injected with tumor cells into a localized area. The degree or number of secondary tumors that form over time is a measure of metastasis and the ability of the compounds to inhibit such metastasis can be evaluated relative to control animals that have the primary tumor but receive no test compounds.
  • Experimental results from this type of in vivo testing are shown in FIG. 1 and further 10 described in the Examples. These results demonstrate that the compounds of the invention substantially reduce or eliminate tumor metastasis.
  • cancers include but are not limited to, cancers involving the animal's head, neck, lung, mesothelioma, 15 mediastinum, esophagus, stomach, pancreas, hepatobihary system, small intestine, colon, colorectal, rectum, anus, kidney, ureter, bladder, prostate, urethra, penis, testis, gynecological organs, ovaries, breast, endocrine system, skin, or central nervous system.
  • the cancer can be a breast cancer, a leukemia, a lung cancer, a colon cancer, a central nervous system cancer, a melanoma, an ovarian cancer, a renal cancer, 20 or a prostate cancer.
  • compounds of the invention may be useful as pharmacological tools for the further investigation of the inhibition of cell migration.
  • the compounds of the invention can also be administered in combination with other therapeutic agents that are effective for treating or controlling the spread cancerous 25 cells or rumor cells.
  • the invention will now be illustrated by the following non-limiting Examples.
  • CRF D-3406 13 The reagents and conditions employed were as follows: (a) Yamaguchi acylation (48%); (b) Et 3 N, DMAP, 6-heptenoyl chloride (89%); (c) Grubbs catalyst, toluene and reflux (47 and 73%); (d) HF-pyridine, THF (78 and 90%); (e) diphenylphosphoryl azide (87%); (f) PPh 3 , H 2 O (90%); (g) CBr 4 , PPh 3 (95%); (h) EDCI, 6-heptenioc acid (70%); (i) 1- 5 benzenesulfonyl-oct-7-en-one, DBU (75%); (j) Na/Hg (79%); (k) Grubbs catalyst, toluene, reflux (70 and 75%); (1) HF-pyridine, THF (90 and 95%).
  • Coupling constants (J) (H,H) are given in Hz
  • spectral splitting patterns were 15 designated as singlet (s), doublet (d), triplet (t), quadruplet (q), multiplet or more overlapping signals (m), apparent (app), broad signal (br).
  • Low resolution mass spectra ionspray, a variation of electrospray
  • Samples were introduced by direct infusion.
  • High resolution mass spectra (fast atom bombardment, FAB) were acquired on a Micromass 70-SE-4F spectrometer.
  • Example 2 In Vitro Assay Procedures 20 The efficacy of the compounds of the invention for inhibiting cell migration was initially assessed using two procedures, a wound healing assay and a chamber cell migration assay.
  • Cell migrations were assayed with Boyden chambers [8.0 ⁇ m pore size, polyethylene terephthalate membrane, FALCON cell culture insert (Becton-Dickinson)]. Cells were trypisinized and counted. 300 ⁇ l of 5-10 x 10 4 cells in serum-free medium was added to the upper chamber and 500 ⁇ l of medium with 10% 5 fetal bovine serum (FBS) was added to the lower chamber.
  • Transwells were incubated for 6-8 hours at 37°C with different concentrations of chemical compounds in both upper and lower chambers. Cells on the inside of the transwell inserts were removed with a cotton swab, and cells on the underside of the insert were fixed and stained. Photographs of three random regions were taken and the number of cells was counted to calculate the 10 average number of cells that had transmigrated.
  • Example 3 Compounds of the Invention are Potent Cell Migration Inhibitors This Example provides the results of cell migration assays performed as described above, illustrating that several of the compounds of the invention are more potent cell migration inhibitors than previously available compounds like migrastatin. 25 The results of a Chamber Cell Migration Assay for several compounds are provided in Table 1. Table 1
  • Migrastatin (1) is a known inhibitor of cell migration. Nakae et al., J. Antibiot. 2000, 53, 1130; Nakae et al., J. Antibiot. 2000, 53, 1228; Takemoto et al., J Antibiot. 2001, 54, 1104; Nakamura et al., J. Antibiot. 2002, 55, 442; Woo et al. J. Antibiot. 2002, 10 55, 141.
  • the structure of migrastatin is provided below.
  • Epoxyquinols A and B can be isolated as described in Kakeya et al., J. Am. Chem. Soc. 2002, 124, 3496; Kakeya et al., J. Antibiot. 2002, 55, 829. Epoxyquinols A and B can be synthesized as described in Shoji et al., Angew. Chem., Int. Ed. 2002, 41, 3192; Chaomin et al. Org. Lett. 2002, 4, 3267; Mehta, G.; Islam, K.
  • Evodiamine is a potent anti-invasive and anti-metastatic agent: Ogasawara et al., Biol. Pharm. Bull. 2001, 24, 720; Ogasawara et al., Biol. Pharm. Bull. 2001, 24, 917; 10 Ogasawara et al, Biol. Pharm. Bull.20 2, 25, 1491.
  • Evodiamine is commercially available from Wako Pharmaceuticals. The structures of epoxyquinol A and evodiamine are provided below.
  • Example 4 Compounds of the Invention Inhibit Tumor Metastasis In Vivo This Example illustrates that the compounds of the invention inhibit metastasis of 10 breast tumors in mice.
  • 4T1 mouse breast tumor cells were employed for in vivo testing of the compounds of the invention.
  • the 4T1 mouse breast tumor cell line was isolated from a single 15 spontaneously arising mammary tumor from a BALB/BfC3H mouse (MMTV+). See, Miller, F.R., Miller, B.E., and Heppner, G.H. 1983. Characterization of metastatic heterogeneity among subpopulations of a single mouse mammary tumor: heterogeneity in phenotypic stability. Invasion Metastasis 33: 22-31.
  • the 4T1 tumor closely mimics human breast cancer in its anatomical site, immunogenecity, growth characteristics, and 20 metastatic properties.
  • mice Female BALB/c mice (6-8 week old) were purchased from the Jackson Laboratory (Bar Harbor, Maine). All mice were housed at the Weill Medical College of Cornell University Animal Facilities in accordance with the Principles of Animal Care. 4T1 tumor cells (1 x 10 s ) were injected subcutaneously into the abdominal mammary 5 gland area of mice using 0.1 ml of a single-cell suspension in phosphate buffered saline (PBS) on Day 0. The dosage of rumor implantation was empirically determined to give rise to tumor of about 10 mm in diameter in untreated wild type mice within 21-23 days.
  • PBS phosphate buffered saline
  • test compounds or control PBS saline were given every day by intraperitoneal injection at 10 mg/kg or 20 10 mg/kg per mouse until Day 25.
  • the mice were sacrificed. This dosage regiment employed of the compounds was well tolerated with no signs of overt toxicity. Every group included five mice. Primary tumors were measured using electronic calipers on the day when the mice were sacrificed. Tumor size was the square root of the product of two perpendicular 15 diameters. Numbers of metastatic 4T 1 cells in lung were determined by the clonogenic assay as described in Pulaski, B.A., and Ostrand-Rosenberg, S. 1998.
  • lungs were removed from each mouse on Day 28, finely 20 minced and digested in 5 ml of enzyme cocktail containing lxPBS and 1 mg/ml collagenase type IV for 2 hours at 37°C on a platform rocker. After incubation, samples were filtered through 70 uM nylon cell strainers and washed twice with PBS. Resulting cells were suspended and plated serially diluted in 10 cm tissue culture dishes in medium RPMI1640 containing 60 ⁇ M thioguanine for clonogenic growth.
  • 6-Thioguanine- 25 resistant tumor cells formed foci after 14 days, at which time they were fixed with methanol and stained with 0.03% methylene blue for counting.
  • the results are provided in FIG. 1.
  • the compounds had only a small, rather insignificant effect on tumor size.
  • both the macroketone (14) and the macrolactam (13) substantially reduced the number of 30 metastatic tumors.
  • the control group diaily PBS injection
  • the group treated with 10 mg/kg of macroketone there were
  • CRF D-3406 27 invention illustratively described herein suitably may be practiced in the absence of any element or elements, or limitation or limitations, which is not specifically disclosed herein as essential.
  • the methods and processes illustratively described herein suitably may be practiced in differing orders of steps, and that they are not necessarily restricted 5 to the orders of steps indicated herein or in the claims.
  • the singular forms "a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.
  • a reference to "a host cell” includes a plurality (for example, a culture or population) of such host cells, and so forth.

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Abstract

L'invention porte sur des compositions et méthodes inhibant la migration des cellules et pouvant en particulier inhiber la métastase des cellules tumorales chez les mammifères. Lesdites compositions se caractérisent en ce qu'elles contiennent un composé de formule (I).
PCT/US2004/009211 2003-08-19 2004-03-25 Analogues de la migrastatine, inhibiteurs de la migration des cellules Ceased WO2005019181A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006001967A3 (fr) * 2004-05-25 2006-07-27 Sloan Kettering Inst Cancer Analogues de migrastatine utilises dans le traitement du cancer
US7943800B2 (en) 2003-03-28 2011-05-17 Sloan-Kettering Institute For Cancer Research Migrastatin analogs and uses thereof
US8188141B2 (en) 2004-09-23 2012-05-29 Sloan-Kettering Institute For Cancer Research Isomigrastatin analogs in the treatment of cancer
US9303009B2 (en) 2011-04-07 2016-04-05 Sloan-Kettering Institute For Cancer Research Migrastatins and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020119937A1 (en) * 2000-08-21 2002-08-29 Chaitan Khosla Fermentation and purification of migrastatin and analog

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020119937A1 (en) * 2000-08-21 2002-08-29 Chaitan Khosla Fermentation and purification of migrastatin and analog

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"MIGRASTATIN, A NOVEL 14-MEMBERED LACTONE FROM STREPTOMYCES SP, MK929-43F1", JOURNAL OF ANTIBIOTICS, JAPAN ANTIBIOTICS RESEARCH ASSOCIATION. TOKYO, JP, vol. 53, no. 10, October 2000 (2000-10-01), pages 1228 - 1230, XP002938945, ISSN: 0021-8820 *
GAUL C ET AL: "Synthesis of the macrolide core of migrastatin", TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 43, no. 50, 9 December 2002 (2002-12-09), pages 9039 - 9042, XP004391896, ISSN: 0040-4039 *

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US7943800B2 (en) 2003-03-28 2011-05-17 Sloan-Kettering Institute For Cancer Research Migrastatin analogs and uses thereof
US8202911B2 (en) 2003-03-28 2012-06-19 Cornell Research Foundation, Inc. Migrastatin analog compositions and uses thereof
US8324284B2 (en) 2003-03-28 2012-12-04 Sloan-Kettering Institute For Cancer Research Migrastatin analogs and uses thereof
US8835693B2 (en) 2003-03-28 2014-09-16 Sloan-Kettering Institute For Cancer Research Migrastatin analogs and uses thereof
WO2006001967A3 (fr) * 2004-05-25 2006-07-27 Sloan Kettering Inst Cancer Analogues de migrastatine utilises dans le traitement du cancer
US8957056B2 (en) 2004-05-25 2015-02-17 Sloan-Kettering Instiute For Cancer Research Migrastatin analogs in the treatment of cancer
US8188141B2 (en) 2004-09-23 2012-05-29 Sloan-Kettering Institute For Cancer Research Isomigrastatin analogs in the treatment of cancer
US9303009B2 (en) 2011-04-07 2016-04-05 Sloan-Kettering Institute For Cancer Research Migrastatins and uses thereof
US9546146B2 (en) 2011-04-07 2017-01-17 Sloan-Kettering Institute For Cancer Research Migrastatins and uses thereof

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