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WO2009031999A1 - Fr901464 et analogues présentant une activité antitumorale, et procédé de préparation de ces composés - Google Patents

Fr901464 et analogues présentant une activité antitumorale, et procédé de préparation de ces composés Download PDF

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Publication number
WO2009031999A1
WO2009031999A1 PCT/US2007/019550 US2007019550W WO2009031999A1 WO 2009031999 A1 WO2009031999 A1 WO 2009031999A1 US 2007019550 W US2007019550 W US 2007019550W WO 2009031999 A1 WO2009031999 A1 WO 2009031999A1
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alkyl
compound
formula
group
halo
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PCT/US2007/019550
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English (en)
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Kazunori Koide
Brian J. Albert
Ananthapadmanabhan Sivaramakrishnan
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University Of Pittsburgh-Of The Commonwealth System Of Higher Education
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Priority to PCT/US2007/019550 priority Critical patent/WO2009031999A1/fr
Publication of WO2009031999A1 publication Critical patent/WO2009031999A1/fr

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    • 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
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the natural product FR901464 isolated from the broth of a Pseudomonas sp. No.2663 culture, is a transcriptional activator. It lowers the mRNA levels of p53, p21, c-myc, and E2F-1 in MCF-7 cells at 20 nM, and it induces apparent apoptosis in MCF-7 cells with the impressive LC50 of 0.5 nM. FR901464 also exhibits an antitumor activity in a mouse model at remarkably low concentrations (0.056-0.18 mg/kg).
  • the present invention relates to compounds and pharmaceutical compositions containing them, to their preparation, to intermediates useful in their preparation, and to uses for the compounds, primarily but not exclusively in treating cancer.
  • a compound, stereoisomer, or pharmaceutically acceptable salt or ester thereof is provided that conforms to Formula I:
  • R 1 and R 8 are independently selected from the group consisting of H, Ci- ⁇ -alkyl, halo(C,. 6 -alkyl), C(O)R 11 , C(O)OR 11 , and C(O)NR 12 R 13 , wherein each R 11 is independently H, d- ⁇ -alkyl or halo(Ci_6-alkyl) 5 and wherein R 12 and R 13 are selected independently from the group consisting of H, d- 6 -alkyl, and halo(Ci -6 -alkyl);
  • R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of H, d-e-alkyl, and halo(C 1 . 6 -alkyl);
  • R 7 is selected from the group consisting of Ci- 6 -alkyl and halo(C ⁇ - 6 -alkyl); and R and R 10 are independently selected from the group consisting of H 5 Ci- 6 -alkyl, and Ci-6-alkyl substituted with one to three groups independently selected from halo, hydroxy, and C ⁇ -alkoxy,
  • R 10 is not hydrogen or OH.
  • FIGURE 1 is a graph that compares the viability of cells, over a 48-hour period, when they are treated with FR901464 (10 nM, compound X) versus 1,1- dimethyl-desoxy analog (10 nM compound IX).
  • cellular proliferative disorder refers to a disease or pathology that is characterized by abnormal, uncontrolled cell division.
  • disorders and pathologies are neoplasia, including cancers, hyperplasias such as endometrial hyperplasia and benign prostatic hyperplasia, restenosis, cardiac hypertrophy, immune disorders characterized, for example, by a dysfunctional proliferation response of the cellular immune system, and inflammation.
  • Illustrative cancers in this regard are acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute monocytic leukemia, acute myeloblastic leukemia, acute myelocytic leukemia, acute myelomonocytic leukemia, acute promyelocytic leukemia, acute erythroleukemia, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, colon cancer, colon carcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endotheliosarcoma, ependymoma, epithelial carcinoma, Ewing's
  • Ci- ⁇ -alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CHaCH 2 -), «-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), rc-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CHs) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), r-butyl ((CH 3 ) 3 C-), ⁇ -pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CHs) 3 CCH 2 -).
  • Halo or "halogen” refers to fluoro, chloro, bromo and iodo.
  • Halo(Ci -6 -alkyl) refers to Ci. 6 -alkyl groups substituted with 1 to 3 or 1 to 2 halo groups, wherein Ci- 6 -alkyl and halo are as defined herein.
  • the term includes, for example, CF 3 .
  • heteroaryl refers to an aromatic heterocycle ring of 5 to 14 members, such as 5 to 6 members, having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom. Heteroaryls may be monocyclic, bicyclic, or tricyclic ring systems.
  • heteroaryls are triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, azepinyl, oxepinyl, and quinoxalinyl.
  • heterocycle refers to 5- to 14-membered ring systems, such as 5- to 6-membered ring systems, which are either saturated, unsaturated, and which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized.
  • Heterocycles may be monocyclic, bicyclic, or tricyclic ring systems.
  • the bicyclic or tricyclic ring systems may be spiro-fused.
  • the bicyclic and tricyclic ring systems may encompass a heterocycle or heteroaryl fused to a benzene ring.
  • heterocycles include heteroaryls as defined above.
  • Representative examples of heterocycles include, but are not limited to, aziridinyl, oxiranyl, thiiranyl, triazolyl, tetrazolyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetidinonyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, dioxanyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl, furazanyl, pyridinyl, ox
  • Haldroxy refers to the group -OH.
  • Hydroxy protecting group refers to protecting groups for an OH group. Suitable hydroxy protecting groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous such protecting groups are described in T. W. Greene and P. G. M. Wuts, PROTECTING GROUPS IN ORGANIC SYNTHESIS, 3 rd ed., Wiley, New York. Such hydroxy protecting groups include Ci -6 alkyl ethers, benzyl ethers, p-methoxybenzyl ethers, silyl ethers, and the like.
  • C 1-6 -alkoxy refers to the group -O-(Ci -6 -alkyl) wherein Ci -6 -alkyl is defined herein.
  • C ⁇ -alkoxy includes, by way of example, methoxy, ethoxy, «-propoxy, isopropoxy, «-butoxy, /-butoxy, sec-butoxy, and n-pentoxy.
  • Patient refers to mammals and includes humans and non-human mammals.
  • ester refers to esters, which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate.
  • Red-Al refers to sodium bis(2-methoxyethoxy)aluminum hydride.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers, diastereomers, and racemates.
  • TES triethylsilyl
  • Treating" or “treatment” of a disease in a patient refers to (1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; (2) inhibiting the disease or arresting its development; or (3) ameliorating or causing regression of the disease.
  • the present invention provides a compound, stereoisomer, or pharmaceutically acceptable salt or ester thereof having Formula I as described generally hereinabove:
  • R 1 is C(O)R 11 and R 11 is Ci -6 -alkyl or halo(Ci- 6 -alkyl). In some aspects, R 1 is C(O)CH 3 .
  • At least one of R 2 , R 3 , R 5 , and R 6 is CWalkyl. In some aspects, at least one of R 2 , R 3 , R 5 , and R 6 is CH 3 . In some aspects, R 3 and R 5 are CH 3 .
  • R 2 is hydrogen.
  • R is hydrogen.
  • R 6 is hydrogen
  • R 7 is CH 3 or CF3
  • At least one of R 9 and R 10 is independently selected from the group consisting of Ci. 6 -alkyl aind C ⁇ -allcyl substituted with one to three groups independently selected from halo, hydroxy, and Cj-6-alkoxy. In other embodiments, at least one of R 9 and R 10 is independently selected from the group consisting of CH 3 , CH 2 I, and CH 2 OH.
  • Exemplary compounds of the present invention include:
  • composition comprising a compound, stereoisomer, or pharmaceutically acceptable salt or ester thereof of Formula I, (Ib), or (Ic) and a pharmaceutically acceptable carrier.
  • the composition comprises a compound or pharmaceutically acceptable ester or ester thereof of Formula (IX):
  • inventions are methods for treating a cellular proliferative disorder in a patient, comprising administering to the patient a therapeutically effective amount of any of the embodiments of a compound, stereoisomer, or pharmaceutically acceptable salt or ester thereof of Formula I 5 (Ib), or (Ic).
  • the compound is of Formula (IX) or a pharmaceutically acceptable salt or ester thereof.
  • RNA splicing-related conditions are cystic fibrosis, Duchenne muscular dystrophy, Fanconi anemia, and neurofibromatosis, among other genetic diseases, as well as a cellular proliferative disorder described above, e.g., breast cancer, ovarian cancer, and prostate cancer.
  • Dysfunctional RNA splicing is understood also to play a role in various inflammatory diseases, such as rheumatoid arthritis and psoriasis, in certain cardiovascular disorders, and in the pathology of infections by oncogenic viruses and other virus types, such as Borna disease virus and HIV, by parasitic infections and fungal infections.
  • the present invention encompasses the combination of a compound of the invention, as described above, with an antibody that targets the impact of the compound when the combination is administered in vivo.
  • a conjugate of an antibody with an inventive compound is a conjugate of an antibody with an inventive compound.
  • Such conjugates have a recognized usefulness for the targeted administration of the compounds. That is, the antibody has a binding specificity for an epitope that is characteristic of a target cell or tissue, whereby the antibody directs the drug (here, a compound of the invention) to that cell or tissue where the compound is needed.
  • the drug here, a compound of the invention
  • Antibodies that are suitable for this purpose, in accordance with the invention may be monoclonal or polyclonal, so long as the requisite specificity is achieved for the in vivo target.
  • the targeting component of the combination also can be an antibody fragment, such as an Fab fragment, or a single-chain binding molecule, produced recombinantly, as well as a a chimeric or humanized antibody. Many such antibodies and binding molecules are known, as evidenced, for example, by U.S. Patent Application Publication No. 2005/0276812.
  • the targeting component can be linked to the compound of the invention via a linker moiety.
  • the linker moiety is bound to a compound of the present invention through hydroxyl or amino groups.
  • Synthetic approaches for attaching the targeting component through a linker moiety are conventional in the field. Exemplary linker moieties and related attachment chemistries are described, for instance, in the above-mentioned published '812 application,in U.S. Patents No. 5,010,176, No. 5,156,840, No. 5,272,253, No. 5,514,794, 5,643,573, No. 5,665,358 and No. 5,795,56O 5 and in C. F. McDonagh et al, Protein Eng'rg Design & Selection 19: 299-308 (2006).
  • the compounds of this invention are administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of the compound of this invention, as the active ingredient, will depend upon numerous factors, such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
  • the drug can be administered more than once a day, preferably once or twice a day. Assessing each of these factors is within the skill of the attending clinician.
  • Therapeutically effective amounts of the compounds can range from approximately 0.05 to 50 mg per kilogram body weight of the recipient per day; such as about 0.1-25 mg/kg/day, or from about 0.5 to 10 mg/kg/day. Thus, for administration to a 70 kg person, for instance, the dosage range can be about 35-70 mg per day.
  • the compounds can be used alone or in compositions together with a pharmaceutically acceptable carrier or excipient.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
  • Other suitable, pharmaceutically acceptable excipients are described in REMINGTON'S PHARMACEUTICAL SCIENCES, Mack Pub. Co., New Jersey (1991), incorporated herein by reference,
  • compositions are administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), parenteral (e.g., intramuscular, intravenous or subcutaneous), or intrathecal administration.
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), parenteral (e.g., intramuscular, intravenous or subcutaneous), or intrathecal administration.
  • routes e.g., oral, using a convenient daily dosage regimen that is adjusted according to the degree of affliction.
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, ointments, or any other appropriate compositions.
  • Another manner for administering an inventive compounds is inhalation, which delivers a therapeutic agent directly to the respiratory tract (see U.S. patent No. 5,
  • the choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.
  • the compound can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • MDFs metered dose inhalers
  • DPI dry powder inhalers
  • Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract.
  • MDFs typically are formulation packaged with a compressed gas.
  • the device Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
  • DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device.
  • the therapeutic agent In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose.
  • a measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation contains, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of the compound of based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt%.
  • the compounds of this invention may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. AU such stereoisomers and enriched mixtures are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) are prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds are separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • R 1 and R 8 are independently selected from the group consisting of H, Pg 3 C h alky!, halo(Ci -6 -alkyl), C(O)R 11 , C(O)OR 11 , and C(O)NR 12 R 13 ,
  • each R 11 is independently H, Ci- 6 -alkyl, or halo(C 1 ⁇ -alkyl), and
  • R 12 and R 13 are selected independently from the group consisting of H, Ci- 6 -alkyl, and halo(Ci. 6 -alkyl);
  • R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of H 5 Ci. 6 -alkyl, and halo(Ci. 6 -alkyl);
  • R 7 is selected from the group consisting of H, Ci-e-alkyl and halo(Ci- 6 -alkyl);
  • R 9 and R 10 are independently selected from the group consisting of H, Ci- 6 -alkyl, and Ci ⁇ -alkyl substituted with one to three groups independently selected from halo, hydroxy, Ci- ⁇ -alkoxy, and OPg;
  • R 14 and R 15 are selected independently from the group consisting of halo(Ci. 6 -alkyl), C(O)R 11 , F, Cl, NO 2 , and B(OR 1 %, wherein R 11 is as defined above;
  • each Pg is independently a hydroxy protecting group
  • the compound of Formula (Id) is compound (IX):
  • R 1 and R 8 are independently selected from the group consisting of H, Pg, Q. 6 - alkyl, halo(C]. 6 -alkyl), C(O)R 11 , C(O)OR 11 , and C(O)NR 12 R 13 ,
  • each R 1 , 1 is independently H, Ci- 6 -alkyl, or halo(C]- 6 -alkyl), and
  • R 12 and R 13 are selected independently from the group consisting of H, Ci -5 -alkyl 5 and halo(C 1-6 -alkyl);
  • R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of H, Ci-6-alkyl, and halo(d -6 -alkyl);
  • R 7 is selected from the group consisting of H 3 Q- 6 -alkyl and halo(Ci-6-alkyl);
  • R 9 and R 10 are independently selected from the group consisting of H, Ci- 6 -alkyl, and Cj- ⁇ -alkyl substituted with one to three groups independently selected from halo, hydroxy, Cj- 6 -alkoxy, and OPg;
  • R 14 and R 15 are selected independently from the group consisting of halo(C 1-6 -alkyl), C(O)R 11 , F, Cl, NO 2 , and B(OR 1 ') ⁇ , wherein R u is as defined above;
  • This process comprises:
  • the cyclization conditions of part (c) comprise treatment of a compound of Formula (V) with Hg(OAc) 2 /NaBH 4 / ⁇ t 3 B.
  • the cyclization conditions comprises treatment with NaI and Pb(OAc) 4 .
  • the oxidative conditions of part (d) comprise treatment with OsO-j, an oxidant such as NMO, and Pb(OAc) 4 .
  • the cyclization conditions of part (d) comprise treatment of a compound of Formula (VI) with an acidic solution, such as AcOH/THF/H 2 O.
  • the hydroxy protection groups of compounds of Formulae (V) and (VI) are silyl protecting groups such as triethylsilyl.
  • the reducing agent of part (d) is diisobutylaluminum hydride.
  • the selenide forming conditions of part (e) comprise treatment of a compound of Formula (IVb) with a phosphine and an oxidizing agent.
  • Suitable phosphines and oxidizing agents include tributylphosphine and hydrogen peroxide.
  • the compound of Formula (Ie) is compound (X):
  • Y is selected from the group consisting of MeO 2 C-, ⁇ -O 2 N-PhSeCH 2 -, and HOCH 2 -;
  • R 9 is selected from the group consisting of Cj- 6 -alkyl and Ci- 6 -alkyl substituted with one to three groups independently selected from halo, hydroxy,
  • Ci-6-alkoxy, and OPg; R 14 and R 15 are selected independently from the group consisting of halo(Ci -6 -alkyl), C(O)R 11 , F 5 Cl, NO 2 , and B(OR ll ) 2 , wherein each R 1 ' is independently H, Ci- 6 -alkyl, or halo(Ci- 6 -alkyl),
  • P 1 and Pg are independently a hydroxy protecting group.
  • the intermediate compound is selected from the group consisting of:
  • the olefin metathesis catalyst is a Ruthenium catalyst.
  • the Ruthenium catalyst is:
  • NMR spectra were recorded on AM300 or AM500 (Bruker) instruments and calibrated using a solvent peak or tetramethylsilane as an internal reference. The following abbreviations are used to indicate the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. High-resolution mass spectra were obtained by using EBE geometry.
  • Recrystallization of a batch of 7 of lower enantiopurity was accomplished by dissolving 7 (1.80 g, 64% ee) in Et 2 O (5 mL), then diluting the resulting solution with hexanes (15 mL) at 23 0 C. The resulting solution was then cooled to -20 0 C. After 10 h at the same temperature, the solution was filtered, washed with hexanes, and cold 5% EtOAc/hexanes (5 mL) to afford 7 (664 mg, 95% ee 2 ) as colorless needles, which was used for the subsequent steps.
  • reaction mixture was cooled to 23 0 C, diluted with H 2 O (100 mL) then aqueous 1 N HCl (300 mL), and the layers were separated.
  • the aqueous residue was extracted with EtOAc (4 x 200 mL).
  • the combined organic layers were washed with brine (1 x 500 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the resulting residue was purified by flash chromatography (1 -> 5% EtOAc in hexanes) on silica gel (800 mL) to afford 12 (13.91 g, 77%) as a colorless oil.
  • reaction mixture was diluted with Et 2 O (15 mL), dried over anhydrous Na 2 SO 4 , filtered through a pad of Celite 545 ® , rinsed with Et 2 O (3 x 25 mL), and concentrated under reduced pressure.
  • the resulting residue was purified by flash chromatography (5 — > 20% EtOAc in hexanes) on silica gel (40 mL) to afford 27 (838 mg, 95%) as a colorless oil.
  • the reaction mixture was cannulated into a flask containing AcOH (120 mL) and H 2 O (60 mL) 0 0 C, the reaction container was rinsed with Et 2 O (50 mL), and then the resulting layers were separated. The organic layer was washed with saturated aqueous NaHCO 3 (30O mL). The combined aqueous layers were extracted with Et 2 O (50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (2.5 — > 10% EtOAc in hexanes) on silica gel (600 mL) to afford 35 (7.141 g, 78%) as a colorless oil.
  • reaction was allowed to warm to 23 °C and was stirred for 17 hours at the same temperature at which time it was quenched with saturated NH 4 Cl (5 mL). To the reaction mixture was added hexanes (25 mL) and the mixture was dried over anhydrous Na 2 SO4, filtered through cotton, and concentrated under reduced pressure.
  • FR901464 (compound X) and its dimethyl analog (compound IX) were prepared synthetically and dissolved in dimethyl sulfoxide (DMSO) as 10 ⁇ M stocks and stored at -80 0 C.
  • DMSO dimethyl sulfoxide
  • aliquots were thawed at room temperature and dilutions were prepared in RPMI 1640 medium containing 2 % DMSO at 2X the desired concentration prior to addition to the cells.
  • MCF-7 cells were used in this experiment. The cells were grown at 37 0 C in an atmosphere containing 5% carbon dioxide in corning cell culture dishes (150 mm) in RPMI 1640 cell culture medium containing 10% fetal bovine serum and 5mL of gultamine pen-strep solution (Invitrogen) per 500 mL of medium.
  • Cells were plated in 96 well plates at an initial density of 25,000 cells/well and were incubated for 24 hours prior to compound addition. The compound was added to the cells at 2 x the desired concentration into an equal volume of cell culture medium. The cells were then incubated for an additional 24 to 48 hours. Cell proliferation was measured by manual counting using a hemacytometer by trypsinizing and staining with trypan blue. Each compound treatment was done in quadruplets and the final counts were averaged.
  • the cells were grown at 37 0 C in an atmosphere containing 5% carbon dioxide in corning cell culture flasks (25 cm 2 ) in RPMI 1640 cell culture medium containing 10% fetal bovine serum, 1% Penicillin/Streptomycin, and 1% L- Glutamine.
  • Cells were plated in 96 well plates at an initial density of 2,000 cells per well in 100 ⁇ L of medium and were incubated for 24 hours prior to compound addition. Serial two-fold dilutions were used in this experiment from 100 nM to 0.000191 nM. The compound was added to the cells at 2* the desired concentration in 100 ⁇ L cell culture medium. The cells were then incubated for an additional 3 to 5 days. Cell proliferation was measured using a commercial MTS solution (20 ⁇ L per well). The absorbance (at 490 run and 630 run) was measured by a Spectromax M2 plate reader (Molecular Devices). Each concentration treatment was done in quadruplets and the final numbers were averaged.
  • Cells were plated in 96 well plates at an initial density of 2,000 cells per well in 100 ⁇ L of medium and were incubated for 24 hours prior to compound addition. One concentration was used in each experiment for all times examined. The compound was added to the cells at 2* the desired concentration in 100 ⁇ L cell culture medium. At the desired time intervals, the media containing the drug was removed, the wells were washed 5 times with new media and 200 ⁇ L of new media containing 1% DMSO was added. At the last time interval, after washing and replacing the media, cell proliferation was measured using a commercial MTS solution (20 ⁇ L per well). The absorbance (at 490 run and 630 nm) was measured by a Spectromax M2 plate reader (Molecular Devices). Each concentration treatment was done in quadruplets and the final numbers were averaged.
  • AU cells were treated at the same time meayamycin at 1 nM concentration. At the given time interval, the drug-containing media was removed and replaced with ftesh media. Cell proliferation was measured at the last time interval (72 h).
  • IMR-90 cell line normal lung cells
  • reaction mixture was then heated to 42 0 C. After 3 h at the same, temperature, additional Grela catalyst (1.5 mg, 2.2 ⁇ mol) and (3/?,4i?,5i?)-5-ethenyl- 7,7-dimethyl-l,6-dioxaspiro[2.5]octan-4-ol (100 ⁇ L) were added. After 1 1 total hours, the reaction was concentrated under reduced pressure.
  • High-content analysis is an analysis tool designed to yield information about the activity and spatial regulation of multiple targets in individual cells rather than in a cell population as a whole ( Giuliano,K.A., DeBiasio,R.L., Dunlay,T., Gough,A., Volosky,J.M., Zock,J., Pavlakis,G.N., and TaylorJD.L. (1997).
  • High-Content Screening A new aproach to easing key bottlenecks in the drug discovery process. J. Biomol. Screen. 2, 249-259.; Taylor,D.L., Woo,E.S., and Giuliano,K.A. (2001).
  • HCA encompasses the automated acquisition, analysis, and archiving of fluorescence micrographs of monolayer cell populations with fluorescently labeled cellular constituents of interest.
  • the multiparametric, automated nature of HCA enables the simultaneous, rapid and quantitative analysis of many cellular phenotypes.
  • HCA has proven exeptionally valuable in cases where compound supply is limited (Wipf,P., Graham,T.H., Vogt,A., SikorskijR.P., Ducruet,A.P., and Lazo,J.S. (2006). Cellular analysis of disorazole Cl and structure-activity relationship of analogs of the natural product. Chem. Biol. Drug Des. 67, 66-73). [0209] High-content analysis of mitotic arrest by meayamycin and FR 901464.
  • FR 901464 caused cell cycle arrest in both Gl and G2 (Kaida,D., Motoyoshi,H., Tashiro,E., Nojima,T. s Hagiwara,M., Ishigami,K., Watanabe,H. 3 Kitahara,T., Yoshida,T., Nakajima,H., Tani,T., Horinouchi,S., and Yoshida,M. (2007).
  • Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat. Chem. Biol. 3 > 576-583).
  • a multiparameter high-content analysis investigated the effects of meayamycin and FR 901464 on G2/M arrest and cellular microtubule perturbation as previously described (Wipf et al., 2006; Wang,Z., McPherson,P.A., Raccor,B.S., Balachandran 3 R., Zhu,G., Day,B-W., Vogt,A., and Wipf,P. (2007). Structure-activity and High-content Imaging Analyses of Novel Tubulysins. Chem. Biol. Drug £>es 70, 75-86).
  • VCRd-5L cells were >250-fold resistant to vincristine and 60-fold resistant to paclitaxel.
  • FR 901464 and meayamycin potently inhibited the growth of the parental DC3F cells (Table 2), with meayamycin being active in the subnanomolar range. While FR 901464 was about an order of magnitude less active in the multidrug resistant cells, meayamycin retained picomolar activity, suggesting that it is not a substrate for p-gp (Table 2).
  • Table 2 Antiproliferative activity of FR901464 and meayamycin in cultured cell lines a
  • IMR-90 human lung fibroblasts were chosen because they are a well characterized normal cell line that is resistant to a variety of cytotoxic and antisignaling agents ( Erickson,L.C, Bradley,M.O., Ducore,J.M., Ewig,R.A., and Kohn,K.W. (1980). DNA crosslinking and cytotoxicity in normal and transformed human cells treated with antitumor nitrosoureas. Proc. Natl. Acad. Sci. U. S. A 77, 461-471., Dusre,L., CoveyJ.M., CoIHnS 5 C 5 and Sinha,B.K. (1989). DNA damage, cytotoxicity and free radical formation by mitomycin C in human cells. Chem.
  • Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis. Cancer Res. 63, 5054-5059.).
  • the cells have a finite lifespan of approximately 60 population doublings ( Nichols,W.W., Murphy,D-G., CristofalOjV.J., Toji,L.H. 5 Greene,A.E., and Dwight,S.A. (1977). Characterization of a new human diploid cell strain, EVIR-90. Science 196, 60-63) before entering crisis, which was confirmed.
  • Cells were plated at high density (10,000 per well) in 384 well plates and treated for 24 h with vehicle (DMSO) or ten two-fold concentration gradients of meayamycin. At the end of the study, cells were fixed and immunostained with antibodies against p53 and the cleaved form of caspase-3. Nuclei were counterstained with Hoechst 33342 and enumerated.
  • meayamycin (10 nM) consistently caused a more pronounced cell loss in the A-549 lung cancer cells compared with normal cells. Both cell lines responded to meayamycin with p53 induction, although the magnitude of response was smaller in the normal cells. A low level of caspase cleavage that appeared to be selective for A-549 cells was observed in some experiments. Meayamycin did not cause nuclear fragmentation but instead enlarged nuclei. Thus, meayamycin preferentially affects the survival of lung cancer cells compared with normal lung fibroblasts.

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Abstract

L'invention concerne des analogues de FR901464 ainsi qu'un procédé de préparation de FR901464 et d'analogues de ce composé. Ces composés présentent une activité anticancéreuse et constituent des candidats pour traiter des états pathologiques associés à un dysfonctionnement de l'épissage d'ARN.
PCT/US2007/019550 2007-09-07 2007-09-07 Fr901464 et analogues présentant une activité antitumorale, et procédé de préparation de ces composés WO2009031999A1 (fr)

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US20150307512A1 (en) * 2012-12-21 2015-10-29 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Synthesis of fr901464 and analogs with antitumor activity
WO2017214423A3 (fr) * 2016-06-08 2018-01-11 William Marsh Rice University Dérivés de la thailanstatine a, méthodes de traitement et méthodes de synthèse de ceux-ci
JP2019529563A (ja) * 2016-09-23 2019-10-17 パーデュー・リサーチ・ファウンデーションＰｕｒｄｕｅ Ｒｅｓｅａｒｃｈ Ｆｏｕｎｄａｔｉｏｎ 抗がん剤およびその調製方法
CN113384703A (zh) * 2021-06-21 2021-09-14 深圳市第二人民医院(深圳市转化医学研究院) Dhx34基因的表达抑制剂在制备抑制肝癌细胞转移和侵袭的药物中的应用
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H. NAKAJIMA ET AL.: "New antitumor substances, FR901463, FR901464, FR901465. II. Activities against experimental tumors in mice and mechanism of action", JOURNAL OF ANTIBIOTICS., vol. 49, no. 12, 1996, JAPAN ANTIBIOTICS RESEARCH ASSOCIATION, TOKYO; JP, pages 1204 - 1211 *
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014089571A1 (fr) * 2012-12-09 2014-06-12 St. Jude Children's Research Hospital Composés anti-cancer
US9682993B2 (en) 2012-12-09 2017-06-20 St. Jude Children's Research Hospital Anticancer compounds
US20150307512A1 (en) * 2012-12-21 2015-10-29 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Synthesis of fr901464 and analogs with antitumor activity
US9771377B2 (en) * 2012-12-21 2017-09-26 University of Pittsburgh—of the Commonwealth System of Higher Education Synthesis of FR901464 and analogs with antitumor activity
EP3468976A4 (fr) * 2016-06-08 2019-11-27 William Marsh Rice University Dérivés de la thailanstatine a, méthodes de traitement et méthodes de synthèse de ceux-ci
WO2017214423A3 (fr) * 2016-06-08 2018-01-11 William Marsh Rice University Dérivés de la thailanstatine a, méthodes de traitement et méthodes de synthèse de ceux-ci
US11584754B2 (en) 2016-06-08 2023-02-21 William Marsh Rice University Derivatives of thailanstatin A, methods of treatment and methods of synthesis thereof
JP2019529563A (ja) * 2016-09-23 2019-10-17 パーデュー・リサーチ・ファウンデーションＰｕｒｄｕｅ Ｒｅｓｅａｒｃｈ Ｆｏｕｎｄａｔｉｏｎ 抗がん剤およびその調製方法
JP7111722B2 (ja) 2016-09-23 2022-08-02 パーデュー・リサーチ・ファウンデーション 抗がん剤およびその調製方法
US11851441B2 (en) 2016-09-23 2023-12-26 Purdue Research Foundation Anti-cancer agents and preparation thereof
CN115698018A (zh) * 2020-04-09 2023-02-03 百时美施贵宝公司 美亚霉素类似物和使用方法
CN113384703A (zh) * 2021-06-21 2021-09-14 深圳市第二人民医院(深圳市转化医学研究院) Dhx34基因的表达抑制剂在制备抑制肝癌细胞转移和侵袭的药物中的应用
CN113384703B (zh) * 2021-06-21 2023-03-10 深圳市第二人民医院(深圳市转化医学研究院) Dhx34基因的表达抑制剂在制备抑制肝癌细胞转移和侵袭的药物中的应用

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