WO2010138686A1 - Agents s'opposant au gène mdr1 - Google Patents

Agents s'opposant au gène mdr1 Download PDF

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WO2010138686A1
WO2010138686A1 PCT/US2010/036348 US2010036348W WO2010138686A1 WO 2010138686 A1 WO2010138686 A1 WO 2010138686A1 US 2010036348 W US2010036348 W US 2010036348W WO 2010138686 A1 WO2010138686 A1 WO 2010138686A1
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cancer
compound
subject
compounds
cells
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PCT/US2010/036348
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Gergely Szakacs
Matthew D. Hall
Michael M. Gottesman
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The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
Institute Of Enzymology, Biological Research Center, Hungarian Academy Of Sciences
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Definitions

  • MDRl for example, exhibits wide substrate specificity for structurally different drugs. This wide specificity mediates drug resistance to a variety of drugs, including Vinca alkaloids, anthracyclines, epipodophyllotoxins, taxols, actinomycin D, cardiac glycosides, immunosuppressive agents, glucocorticoids, and anti-HIV protease inhibitors. Since many drugs are substrates of MDRl, its degree of expression and functionality directly affects the therapeutic effectiveness of these agents.
  • the multidrug resistant phenotype of malignant cells is the main obstacle in the chemotherapeutic treatment of subjects having hyperproliferative disorders.
  • MDRl expression is well characterized in hematological malignancies, sarcomas, and other solid cancers, and is frequently correlated with poor clinical response to chemotherapy for those tumors.
  • Strategies employed to circumvent the reduced drug accumulation conferred by these poly- specific efflux transporters have relied heavily on the development of clinical inhibitors of MDRl for concurrent administration with chemotherapeutics. Although a number of these inhibitors have shown promise in vitro, translation to the clinic has taken longer than may have been expected, possibly due to side effects caused by inhibition of endogenous function, and alternative strategies are required.
  • a method for inhibiting the growth of drug resistant cells in a subject comprising identifying a subject having drug resistant cells; and administering to the subject a compound or a pharmaceutically acceptable salt or ester thereof, as described below in more detail.
  • a method of inhibiting cancer in a subject comprising administering to the subject an antiproliferative agent, wherein the antiproliferative effect of the agent is potentiated by P- glycoprotein and the agent is a compound, or a pharmaceutically acceptable salt or ester thereof, as described in more detail below.
  • the compounds are particularly effective against cells that exhibit multidrug resistance.
  • treatment regimens employing the disclosed compounds typically involve first identifying a subject having a multidrug resistant disorder, such as a multidrug resistant tumor or infection.
  • a multidrug resistant disorder such as a multidrug resistant tumor or infection.
  • Certain examples of the compounds described above are not particularly cytotoxic, particularly to cells that are not multidrug resistant.
  • the disclosed compounds effectively re-sensitize multidrug resistant cells to anti-proliferative agents that are substrates for an MDR transporter.
  • the disclosed compounds are co-administered with another chemotherapeutic agent, such as an antibiotic or antineoplastic agent.
  • the disclosed compounds are both cytotoxic and render multidrug resistant cells susceptible to one or more additional chemotherapeutic agents by inhibiting an MDR transporter.
  • treatment regimens and compositions formulated for combination therapy are also disclosed herein.
  • FIG. 1 Identification of candidate MDR-inverse compounds.
  • Figure 3 Dendrogram showing the average-linkage hierarchical clustering of the 37 confirmed MDRl-invese compounds.
  • the distance matrix is derived from Tanimoto similarity indices. Numbers represent NSC codes.
  • the two major clusters are colored green ("TSC-cluster") and yellow ("10580-cluster”).
  • Pharmacophore models derived from the two sets are shown.
  • Figure 4. QSAR analysis of the thiosemicarbazone MDR-inverse compounds identified in the NCI DTP drug library. Scatter plot and comparison of the calculated and measured MDR-inverse ratios.
  • SOM cluster anlaysis of the activity of the 22 DTP compounds verified to demonstrate MDR-inverse activity.
  • SOM clustering of the DTP drug response data defines six major response categories: mitosis (M), membrane function (N), nucleic acid metabolism (S), metabolic stress and cell survival (Q), and two unexplored regions P and R. Each of these regions is further divided into a total of 51 sub-regions. Larger hexagons (yellow) represent a greater number of compounds.
  • Clusters represent the following compounds (1) NSC695331, NSC695333, (2) NSC697125, (3) NSC672036, (4) NSC673999, NSC713048, (5) NSC716765, (6) NSC641208, (7) NSC716766, NSC716768, (8) NSC43320, NSC73306, NSC693871, NSC693872, NSC697124, (9) NSC2924508, (10) NSC168468, (11) NSC1580, (12) NSC356777, (13) NSC649816, 716772, (14) NSC710857.
  • Red hexagon is the SOM cluster overlay of NSC4265, 1,10- phenanthroline.
  • Table 1 lists examples of compounds identified as having MDRl- selective activity.
  • ABSC transporters are transporter proteins belonging to the ABC protein superfamily and are capable of, in their native, active, wild type form, extruding drugs from the cells expressing them.
  • ABSC transporter also covers mutant variants of the wild type proteins retaining at least one function of the wild type, even if lacking another.
  • acyl refers group of the formula RC(O)- wherein R is an organic group.
  • alkoxy refers to a group of the formula -OR, wherein R is an organic group.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, w-propyl, isopropyl, w-butyl, isobutyl, £-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
  • a “lower alkyl” group is a saturated branched or unbranched hydrocarbon having from 1 to 10 carbon atoms.
  • alkenyl refers to a hydrocarbon group of 2 to 24 carbon atoms and structural formula containing at least one carbon-carbon double bond.
  • alkynyl refers to a hydrocarbon group of 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond.
  • aliphatic is defined as including alkyl, alkenyl, alkynyl, halogenated alkyl and cycloalkyl groups as described above.
  • a "lower aliphatic” group is a branched or unbranched aliphatic group having from 1 to 10 carbon atoms.
  • amine refers to a group of the formula -NRR', where R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described herein.
  • amide group is represented by the formula -C(O)NRR', where R and R' independently can be a hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described herein.
  • Carboxyl refers to a -COOH radical. Substituted carboxyl refers to -COOR where R is aliphatic, heteroaliphatic, alkyl, heteroalkyl, or a carboxylic acid or ester.
  • aryl refers to any carbon-based aromatic group including, but not limited to, benzene, naphthalene, etc.
  • aromatic also includes "heteroaryl group,” which is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorous.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl group can be unsubstituted.
  • alkyl amino refers to alkyl groups as defined above where at least one hydrogen atom is replaced with an amino group.
  • co-administration refers to administration of the compound disclosed herein with at least one other therapeutic agent within the same general time period, and does not require administration at the same exact moment in time (although co-administration is inclusive of administering at the same exact moment in time). Thus, co-administration may be on the same day or on different days, or in the same week or in different weeks.
  • hydroxyl is represented by the formula -OH.
  • alkoxy group is represented by the formula -OR, where R can be an alkyl group, optionally substituted with an alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group as described above.
  • halogenated alkyl or “haloalkyl group” refer to an alkyl group as defined above with one or more hydrogen atoms present on these groups substituted with a halogen (F, Cl, Br, I).
  • cycloalkyl refers to a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • heterocycloalkyl group is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorous.
  • Carbonyl refers to a radical of the formula -C(O)-.
  • Carboxyl refers to a -COOH radical.
  • Substituted carboxyl refers to -COOR where R is aliphatic, heteroaliphatic, alkyl, heteroalkyl, or a carboxylic acid or ester.
  • Multidrug resistance refers to the ability of target cells and microorganisms, particularly cancer cells and mycobacterial cells, to resist the effects of different -often structurally and functionally unrelated- cytotoxic compounds. MDR can develop after sequential or simultaneous exposure to various drugs. MDR also can develop before exposure to many compounds to which a cell or microorganism may be found to be resistant. Although MDR may be caused by a variety of factors, most commonly MDR is associated with overexpression of P- glycoprotein (P-gp).
  • P-gp P- glycoprotein
  • P-gp is a member of a superfamily of membrane proteins, termed adenosine triphosphate (ATP)-binding cassette (ABC) proteins, which behave as ATP-dependent transporters and/or ion channels for a wide variety of substrates.
  • ATP adenosine triphosphate
  • ABSC adenosine triphosphate-binding cassette
  • tumor refers to an abnormal cellular proliferation, which includes benign and malignant tumors, as well as other proliferative disorders.
  • salts or esters refers to salts or esters prepared by conventional means that include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethane sulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like.
  • basic salts of inorganic and organic acids including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethane sulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid,
  • “Pharmaceutically acceptable salts” of the presently disclosed compounds also include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N- methyl-glutamine, lysine, arginine, ornithine, choline, N,N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N- methyl-glutamine, lysine, arginine, ornithine, choline, N,N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine
  • any chemical compound recited in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof.
  • “Pharmaceutically acceptable salts” are also inclusive of the free acid, base, and zwitterionic forms. Descriptions of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). When compounds disclosed herein include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. Such salts are known to those of skill in the art. For additional examples of "pharmacologically acceptable salts,” see Berge et al., J.
  • esters includes those derived from compounds described herein that are modified to include a hydroxy or a carboxyl group.
  • An in vivo hydrolysable ester is an ester, which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include C 1 - O alkoxymethyl esters for example methoxy- methyl, C 1 - O alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 -S cycloalkoxycarbonyloxyCi-6 alkyl esters for example 1- cyclohexylcarbonyl-oxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5- methyl-l,3-dioxolen-2-onylmethyl; and C 1 - O alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyl-oxyethyl which may be formed at any carboxy group in the compounds.
  • An in vivo hydrolysable ester containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxy-methoxy and 2,2-dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
  • salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • the term "addition salt” as used hereinabove also comprises the solvates which the compounds described herein are able to form. Such solvates are for example hydrates, alcoholates and the like.
  • quaternary amine as used hereinbefore defines the quaternary ammonium salts which the compounds are able to form by reaction between a basic nitrogen of a compound and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • an appropriate quaternizing agent such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p- toluenesulfonates.
  • a quaternary amine has a positively charged nitrogen.
  • Pharmaceutically acceptable counterions include chloro, bro
  • the compounds described herein may have metal binding, chelating, complex forming properties and therefore may exist as metal complexes or metal chelates.
  • Transport protein refers to a protein that acts to remove chemotherapeutic substances from cells.
  • transport proteins include, without limitation, P- glycoprotein, the protein product of the MDRl gene. Expression of such transport proteins confers resistance to numerous chemotherapeutic agents and sometimes entire classes of chemotherapeutic s, including Vinca alkaloids, anthracyclines, epipodophyllotoxins, actinomycin D and taxanes.
  • P-glycoprotein is over-expressed in certain chemotherapy resistant tumors and is upregulated during disease progression following chemotherapy in other malignancies.
  • MRPs also belonging to the ABC family, confer a multidrug resistance phenotype that includes many natural product drugs, but is distinct from the resistance phenotype associated with P-gP- In addition to P-gp and the MRPs there may be other transporters that are involved in cytotoxic drug resistance.
  • P-gP- the resistance phenotype associated with P-gP-
  • P-gp the resistance phenotype associated with P-gP-
  • P-gp the resistance phenotype associated with P-gP-
  • Treatment refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop.
  • the term “ameliorating,” with reference to a disease or pathological condition refers to any observable beneficial effect of the treatment.
  • the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
  • treating a disease refers to inhibiting the full development of a disease or condition, for example, in a subject who is at risk for a disease such as cancer, particularly a metastatic cancer.
  • coadminister is meant that each of at least two compounds be administered during a time frame wherein the respective periods of biological activity overlap. Thus, the term includes sequential as well as coextensive administration of two or more drug compounds.
  • Treating multidrug resistance means increasing or restoring sensitivity of multidrug resistant cells to therapeutic agents. Treating multidrug resistance also may include inhibiting the development of multidrug resistance in nonresistant cells.
  • prodrug also is intended to include any covalently bonded carriers that release a disclosed compound or a parent thereof in vivo when the prodrug is administered to a subject. Since prodrugs often have enhanced properties relative to the active agent pharmaceutical, such as, solubility and bioavailability, the compounds disclosed herein can be delivered in prodrug form. Thus, also contemplated are prodrugs of the presently claimed compounds, methods of delivering prodrugs and compositions containing such prodrugs. Prodrugs of the disclosed compounds typically are prepared by modifying one or more functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound. In particular, ester prodrugs are specifically contemplated herein.
  • prodrugs include compounds having an amino or sulfhydryl group functionalized with any group that is cleaved to yield the corresponding free amino or free sulfhydryl group.
  • examples of prodrugs include, without limitation, compounds having a hydroxy, amino and/or sulfhydryl group acylated with an acetate, formate, or benzoate group.
  • protecting group or “blocking group” refers to any group that when bound to a functional group prevents or diminishes the group's susceptibility to reaction.
  • Protecting group generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like.
  • deprotecting “deprotected,” or “deprotect,” as used herein, are meant to refer to the process of removing a protecting group from a compound.
  • MDR-inverse compounds target multidrug resistant cycling cells, avoiding side effects associated with the damage of resting cells that constitutively express Pgp. It has been determined that a positive correlation between a compound's cytotoxicity profile and the expression of Pgp in the NCI-60 cell panel may be the result of a causal interaction, where the activity of Pgp sensitizes the cell to the cytotoxicity of the compound.
  • MDRl -inverse compounds are represented by the formula:
  • R 1 and R 2 are each independently H, alkyl (particularly lower alkyl), cycloalkyl, aryl, or substituted alkyl, or R 1 and R 2 together with the N form a heterocyclic ring such as a pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperzinyl, indolinyl, morpholinyl, pyrrolyl, pyrazolyl, or pyrazinyl;
  • R 3 is alkyl (particularly lower alkyl), substituted alkyl, alkyl amino, hydroxyl, amino, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; and a is 0 to 5, with the proviso that the following compounds are not included
  • Lanthanoid metal(s) complexed to bidentate 1,10-phenanthroline or 2,2'- bipyrdiyl ligands are further examples of MDRl -inverse agents.
  • the chelating ligands alone may possess response profiles similar to their metal chelates indicating that the active metal complexes may serve as carriers for chelators, which themselves are the active drug molecules. While chelation is probably key to the cytotoxicity of at least a subset of the MDR-inverse compounds disclosed herein, data presented in Figure 6 indicate that metal chelation alone is not sufficient for Pgp potentiated activity. Since metal complexes were as active as the ligands alone ( Figure 6), chelates may serve as chaperones facilitating free diffusion of the ligands into the cells.
  • compositions and Methods for their Use Another aspect of the disclosure includes pharmaceutical compositions prepared for administration to a subject and which include a therapeutically effective amount of one or more of the currently disclosed compounds.
  • the therapeutically effective amount of a disclosed compound will depend on the route of administration, the species of subject and the physical characteristics of the subject being treated. Specific factors that can be taken into account include disease severity and stage, weight, diet and concurrent medications. The relationship of these factors to determining a therapeutically effective amount of the disclosed compounds is understood by those of skill in the art.
  • compositions for administration to a subject can include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice.
  • Pharmaceutical compositions can also include one or more additional active ingredients such as antimicrobial agents, antiinflammatory agents, anesthetics, and the like.
  • Pharmaceutical formulations can include additional components, such as carriers.
  • the pharmaceutically acceptable carriers useful for these formulations are conventional. Remington's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 19th Edition (1995), describes compositions and formulations suitable for pharmaceutical delivery of the compounds herein disclosed. In general, the nature of the carrier will depend on the particular mode of administration being employed.
  • parenteral formulations usually contain injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • compositions disclosed herein include those formed from pharmaceutically acceptable salts and/or solvates of the disclosed compounds.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Particular disclosed compounds possess at least one basic group that can form acid-base salts with acids. Examples of basic groups include, but are not limited to, amino and imino groups. Examples of inorganic acids that can form salts with such basic groups include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
  • Basic groups also can form salts with organic carboxylic acids, sulfonic acids, sulfo acids or phospho acids or N-substituted sulfamic acid, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2- acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, and, in addition, with amino acids, for example with ⁇ -amino acids, and also with methanesulfonic acid, ethanesulfonic acid, 2-hydroxymethanesulfonic acid, ethane- 1,2-disulfonic
  • suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.
  • Certain compounds include at least one acidic group that can form an acid- base salts with an inorganic or organic base.
  • salts formed from inorganic bases include salts of the presently disclosed compounds with alkali metals such as potassium and sodium, alkaline earth metals, including calcium and magnesium and the like.
  • salts of acidic compounds with an organic base such as an amine
  • an organic base such as an amine
  • an organic base such as an amine
  • salts formed with basic amino acids aliphatic amines, heterocyclic amines, aromatic amines, pyridines, guanidines and amidines.
  • aliphatic amines the acyclic aliphatic amines, and cyclic and acyclic di- and tri- alkyl amines are particularly suitable for use in the disclosed compounds.
  • quaternary ammonium counterions also can be used.
  • Suitable amine bases for use in the present compounds include, without limitation, pyridine, iV,./V-dimethylaminopyridine, diazabicyclononane, diazabicycloundecene, jV-methyl-iV-ethylamine, diethylamine, triethylamine, diisopropylethylamine, mono-, bis- or tris- (2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, tris(hydroxymethyl)methylamine, iV,./V-dimethyl-./V-(2- hydroxyethyl)amine, tri-(2- hydroxyethyl) amine and jV-methyl-D-glucamine.
  • compositions disclosed herein can be crystallized and can be provided in a single crystalline form or as a combination of different crystal polymorphs. As such, the compounds can be provided in one or more physical form, such as different crystal forms, crystalline, liquid crystalline or non-crystalline (amorphous) forms. Such different physical forms of the compounds can be prepared using, for example different solvents or different mixtures of solvents for recrystallization.
  • polymorphs can be prepared, for example, by performing recrystallizations at different temperatures and/or by altering cooling rates during recrystallization.
  • the presence of polymorphs can be determined by X- ray crystallography, or in some cases by another spectroscopic technique, such as solid phase NMR spectroscopy, IR spectroscopy, or by differential scanning calorimetry.
  • the presently disclosed compounds are useful for the treatment of hyperproliferative disorders wherein the hyperproliferative cells exhibit MDR or are likely to develop MDR.
  • MDR is likely to develop in proliferative disorders being treated with an MDR-inducing chemotherapeutic agent.
  • Chemotherapeutic s that tend to induce MDR are known to those of skill in the arts of pharmacology and oncology and include, for example Vinca alkaloids, anthracyclines, epipodophyllotoxins, taxols, actinomycin D, cardiac glycosides, immunosuppressive agents, glucocorticoids, and anti-HIV protease inhibitors.
  • proliferative disorders that can be so treated include solid tumors, such as sarcomas and carcinomas, include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, and other sarcomas, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer, lung cancers, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, medullary carcinoma, bronchogenic
  • the present disclosure also provides methods to treat hyperproliferative disorders that are characterized by multidrug resistance.
  • the presently disclosed compounds and compositions can be used to inhibit multidrug resistant prostate, breast, colon, bladder, cervical, skin, testicular, kidney, ovarian, stomach, brain, liver, pancreatic or esophageal cancer, or lymphoma, leukemia or multiple myeloma.
  • the disclosed compounds and compositions are used to treat a subject is at risk of developing a metastatic proliferative disorder.
  • leukemias examples include leukemias, including acute leukemias (such as acute lymphocytic leukemia, acute myelocytic leukemia, acute myelogenous leukemia and myeloblasts, promyelocytic, myelomonocytic, monocytic and erythroleukemia), chronic leukemias (such as chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia), polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (indolent and high grade forms), multiple myeloma, Waldenstrom's macro globulinemia, heavy chain disease, myelodysplastic syndrome, hairy cell leukemia and myelodysplasia.
  • acute leukemias such as acute lymphocytic leukemia, acute myelocytic leukemia, acute mye
  • the therapeutically effective amount of the compound or compounds administered can vary depending upon the desired effects and the factors noted above. Typically, dosages will be between about 0.01 mg/kg and 250 mg/kg of the subject's body weight, and more typically between about 0.05 mg/kg and 100 mg/kg, such as from about 0.2 to about 80 mg/kg, from about 5 to about 40 mg/kg or from about 10 to about 30 mg/kg of the subject's body weight.
  • unit dosage forms can be formulated based upon the suitable ranges recited above and a subject's body weight.
  • the term "unit dosage form" as used herein refers to a physically discrete unit of therapeutic agent appropriate for the subject to be treated.
  • dosages are calculated based on body surface area and from about 1 mg/m to about 200 mg/m , such as from about 5 mg/m to about 100 mg/m will be administered to the subject per day.
  • administration of the therapeutically effective amount of the compound or compounds involves administering to the subject from about 5 mg/m 2 to about 50 mg/m 2 , such as from about 10 mg/m 2 to about 40 mg/m 2 per day. It is currently believed that a single dosage of the compound or compounds is suitable, however a therapeutically effective dosage can be supplied over an extended period of time or in multiple doses per day.
  • unit dosage forms also can be calculated using a subject's body surface area based on the suitable ranges recited above and the desired dosing schedule.
  • the disclosed compounds are used in combination with other types of treatments, such as cancer treatments.
  • the disclosed inhibitors may be used with other chemotherapies, including those employing an anti-proliferative agent, such as, without limitation, microtubule binding agent, a toxin, a DNA intercalator or cross-linker, a DNA synthesis inhibitor, a DNA and/or RNA transcription inhibitor, an enzyme inhibitor, a gene regulator, enediyne antibiotics and/or an angiogenesis inhibitor.
  • an anti-proliferative agent such as, without limitation, microtubule binding agent, a toxin, a DNA intercalator or cross-linker, a DNA synthesis inhibitor, a DNA and/or RNA transcription inhibitor, an enzyme inhibitor, a gene regulator, enediyne antibiotics and/or an angiogenesis inhibitor.
  • the presently disclosed compounds are used to render a neoplasm susceptible to one or more anti-proliferative compounds to which it is resistant.
  • the disclosed compounds can be used in combination
  • Microtubule binding agent refers to an agent that interacts with tubulin to stabilize or destabilize microtubule formation thereby inhibiting cell division.
  • microtubule binding agents that can be used in conjunction with the presently disclosed compounds include, without limitation, paclitaxel, docetaxel, vinblastine, vindesine, vinorelbine (navelbine), the epothilones, colchicine, dolastatin 15, nocodazole, podophyllotoxin and rhizoxin. Analogs and derivatives of such compounds also can be used and will be known to those of ordinary skill in the art.
  • epothilones and epothilone analogs for incorporation into the present compounds are described in International Publication No. WO 2004/018478, which is incorporated herein by reference.
  • Taxoids such as paclitaxel and docetaxel are currently believed to be particularly useful as therapeutic agents in combination with the presently disclosed compounds.
  • Examples of additional useful taxoids, including analogs of paclitaxel are taught by U.S. Patent Nos. 6,610,860 to Holton, 5,530,020 to Gurram et al. and 5,912,264 to Wittman et al. Each of these patents is incorporated herein by reference.
  • Suitable DNA and/or RNA transcription regulators for use with the disclosed compounds include, without limitation, actinomycin D, daunorubicin, doxorubicin and derivatives and analogs thereof also are suitable for use in combination with the presently disclosed compounds.
  • DNA intercalators, cross-linking agents and alkylating agents that can be used in combination therapy with the disclosed compounds include, without limitation, cisplatin, carboplatin, oxaliplatin, mitomycins, such as mitomycin C, bleomycin, chlorambucil, cyclophosphamide, isophosphoramide mustard and derivatives and analogs thereof.
  • DNA synthesis inhibitors suitable for use as therapeutic agents include, without limitation, methotrexate, 5-fluoro-5'-deoxyuridine, 5-fluorouracil and analogs thereof.
  • suitable enzyme inhibitors for use in combination with the presently disclosed compounds include, without limitation, camptothecin, etoposide, formestane, trichostatin and derivatives and analogs thereof.
  • Suitable therapeutics for use with the presently disclosed compounds that affect gene regulation include agents that result in increased or decreased expression of one or more genes, such as, without limitation, raloxifene, 5-azacytidine, 5-aza-2'- deoxycytidine, tamoxifen, 4-hydroxytamoxifen, mifepristone and derivatives and analogs thereof.
  • angiogenesis inhibitor is used herein, to mean a molecule including, but not limited to, biomolecules, such as peptides, proteins, enzymes, polysaccharides, oligonucleotides, DNA, RNA, recombinant vectors, and small molecules that function to inhibit blood vessel growth.
  • Angiogenesis inhibitors are known in the art and examples of suitable angiogenesis inhibitors include, without limitation, angiostatin Kl-3, staurosporine, genistein, fumagillin, medroxyprogesterone, SFTI-I, suramin, interferon-alpha, metalloproteinase inhibitors, platelet factor 4, somatostatin, thromobospondin, endostatin, thalidomide, and derivatives and analogs thereof.
  • Other therapeutic agents particularly anti-tumor agents, that may or may not fall under one or more of the classifications above, also are suitable for administration in combination with the presently disclosed compounds.
  • such agents include adriamycin, apigenin, erlotinib, gefitinib, temozolomide, rapamycin, topotecan, carmustine, melphalan, mitoxantrone, irinotecanetoposide, tenoposide, zebularine, cimetidine, and derivatives and analogs thereof.
  • Suitable dosages and treatment regimes for administering the above- identified therapeutic agents are known to those of ordinary skill in the art of oncology and also are described, for example, in Physicians' Cancer Chemotherapy Drug Manual 2005 By Edward Chu and Vincent T. DeVita (ISBN 0763734616), which is incorporated herein by reference. Such dosages and treatment regimens can be used in combination with a presently disclosed MDR-inverse compound.
  • the compounds disclosed herein may be administered orally, topically, transdermally, parenterally, via inhalation or spray and may be administered in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • oral administration or administration via implantation or intravenously, such as via injection is preferred.
  • the particular mode of administration employed may be dependent upon the particular disease, condition of patient, toxicity of compound and other factors as will be recognized by a person of ordinary skill in the art.
  • MDRl MM Retrachloro-2-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)
  • Such antibodies can be directly labeled with fluorescent probe, or detected using subsequent reagents such as goat anti-mouse IgG-FITC.
  • Flow cytometry allows for direct quantitative determinations of the full spectrum of MDRl expression using channel number or fluorescence intensity. Microscopic examination of the slide preparations can give qualitative results (-, +, ++, and the like) or, in conjunction with an image analyzer, quantitative evaluations typically expressed in pixels.
  • ICC immunocytochemistry
  • IHC immunohistochemistry
  • ICC immunocytochemistry
  • IHC immunohistochemistry
  • the detection techniques are the same as described for fixed leukemia cells on microscope slides.
  • Expression of MDRl can also be monitored by the measurement of specific mRNA levels.
  • Cell slides can be processed, and levels of mRNA discerned using basic molecular biology techniques such as quantitative fluorescent PCR.
  • the cells of interest can be lysed, processed, and following PCR of the mRNA, the product can be detected and quantitated following gel electrophoresis.
  • Anti-sense targeting of MDRl mRNA is also possible, followed by standard techniques for quantitative determinations.
  • Radio-labeled probes followed by autoradiography or other radiodetection techniques can also be used to obtain a relative estimate of MDRl protein or mRNA expression.
  • MDRl-specific antibodies labeled with any number of detectable markers such as radioactive compounds detectable with positron emission tomography (PET), single- photon emission computed tomography (SPECT) or compounds detectable with magnetic resonance imaging (MRI) can be used to assess MDRl expression in a subject having cancer or an MDRl-expressing infection, such as multidrug resistant tuberculosis.
  • PET positron emission tomography
  • SPECT single- photon emission computed tomography
  • MRI magnetic resonance imaging
  • MDRl function i.e., functional expression of MDRl also can be evaluated.
  • MDRl functions as a cytoplasmic membrane pump, effluxing compounds such as drugs and toxins from the cytoplasm to the exterior of the cell.
  • Compounds acted on by MDRl are termed MDRl substrates.
  • Detection of MDRl function therefore involves detection of substrate efflux, such as the efflux of a particular drug, or alternatively, detection of efflux of surrogate fluorescent dye markers that also are MDRl substrates, such as DiOC2 (3,3'-diethyloxacarbocyanine iodide) or Rhodamine 123 (Rhl23, or 2-(6-amino-3-imino-3H-xanthen-9-yl)benzoic acid, methyl ester).
  • substrate efflux such as the efflux of a particular drug
  • surrogate fluorescent dye markers that also are MDRl substrates, such as DiOC2 (3,3'-diethyloxacarbocyanine iodide) or Rhodamine 123 (Rhl23, or 2-(6-amino-3-imino-3H-xanthen-9-yl)benzoic acid, methyl ester).
  • the cells are exposed in tissue culture to a substrate for MDRl, such as the aforementioned dye markers, radiolabeled drugs, or drugs that can be detected and/or quantitated by other means such as fluorescence.
  • a substrate for MDRl such as the aforementioned dye markers, radiolabeled drugs, or drugs that can be detected and/or quantitated by other means such as fluorescence.
  • the substrate for MDRl At physiological temperature (37° C) the net accumulation of the substrate over time, in the presence or absence of specific MDRl inhibitors, gives an indication of the MDRl functional activity exhibited by the cells.
  • the single cell suspension can be exposed to the substrate and subsequent efflux of the substrate over time monitored at physiological temperature in the presence or absence of specific MDRl inhibitors. PET, SPECT, and MRI techniques also can be used to assess MDRl function in cancer patients.
  • small organic molecules as well as metal complexes that serve as MDRl substrates can be labeled with radionuclides or other detectable markers.
  • functional expression in solid tumors can be more efficiently ascertained by ICC/IHC techniques with prior labeling of the tumor cells in the patient.
  • Diagnostic testing methods for MDRl expression and efflux pump activity can be used to prospectively stratify patients for treatment optimization in treating malignancies exhibiting MDRl expression or function, such as acute myelogenous leukemia, most solid tumors, lymphomas, bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, myeloma, lymphocytic leukemia, and sarcoma.
  • the disclosed techniques for identifying subjects having MDR-resistant cells are applicable to any therapeutic drug that is a substrate for P-gp-mediated efflux.
  • drugs include, but are not limited to, P-glycoprotein substrates; anticancer drugs as described above and including, by way of example Vinca alkaloids such as vinblastine and vincristine; anthracyclines such as doxorubicin, daunorubicin, epirubicin; anthracenes such as bisantrene and mitoxantrone; epipodophyllo-toxins such as etoposide and teniposide; and other anticancer drugs such as actinomyocin D, mithomycin C, mitamycin, methotrexate, docetaxel, etoposide (VP-16), paclitaxel, docetaxel, and adriamycin; immunosuppressants, including cyclosporine A and tacrolimus; steroids, by way of example, dexamethasone, hydrocort
  • a subject having a multidrug resistant disorder such as a multidrug resistant tumor.
  • Subjects having such disorders can be identified, for example, as set forth above.
  • a subject having a multidrug resistant disorder is administered an MDR-inverse compound disclosed herein, in an amount sufficient to elevate the target tissue concentration of the MDR-inverse compound in the subject to at least about 10 nM, such as from about 0.1 ⁇ M to about 100 ⁇ M, and typically from about 1 ⁇ M to about 10 ⁇ M.
  • the MDR-inverse compound is administered intravenously in an amount of 400 mg/day or less to about 1,600 mg/day or more, preferably from about 500, 600, or 700 mg/day to about 900, 1000, 1100, 1200, 1300, 1400, or 1500 mg/day, and most preferably about 700 mg/day.
  • the MDR-inverse compound preferably is administered on two, three, or four separate days.
  • the dosage typically is administered in intravenously continuously over the course of about 3 to about 90 hours, more preferably over the course of about 4, 6, 12, 18, 24 or 30, 36, or 42 hours to about 54, 60, 66, 72, 78, or 84 hours, most preferably over about 24 hours, 48 hours, or 72 hours, depending upon the treatment regimen.
  • the MDR-inverse compound is administered on multiple days of the treatment regimen.
  • Combination Therapy using MDR-Inverse Compounds The drugs which are substrates of P-gp are quite varied as are the associated disease states.
  • Chemotherapeutic agents that are P-gp substrates include, without limitation, anthracyclines (for example, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone), Vinca alkaloids (for example, vincristine, vinblastine, vinorelbine, vindesine), Topoisomerase-II inhibitors (for example, etoposide, teniposide), taxanes (e.g., paclitaxel, docetaxel), and others (for example, Gleevec and dactinomycin).
  • the MDRl -inverse compounds disclosed herein can be administered in combination with any of these chemotherapeutic agents.
  • the DTP Human Tumor Cell Line Screen has screened tens of thousands of compounds for growth inhibition of human cancer cell lines. Screening results for -43,000 compounds were downloaded from http://discover.nci.nih.gov (July 2007 Release). Scrutiny of the dataset indicated that it was not immediately amenable to stringent statistical analysis due to missing dose-response values or lack of activity in the dose window tested. Since uninformative drug profiles are not expected to yield useful leads, we selected only those drugs that were measured inside the range of cytotoxicity with no more than 50% missing values, resulting in a higher quality activity dataset.
  • Putative MDR-inverse compounds were identified based on correlation of their cytotoxicity patterns to ABCBl expression, as described in (Szakacs et al., 2004). Evaluation of structural similarity. Structural analogs within the DTP dataset were identified based on Tanimoto coefficients defined by the Leadscope software (LeadScope, Inc, Columbus, OH, USA) (Mutch et al., 2004). Clustering of the Discovery-set was performed using the PubChem Structure Clustering algorithm (http://pubchem.ncbi.nlm.nih.gov/). For additional analysis shown (Figure 3), chemical fingerprints were generated using the Chemaxon GenerateMD software. Structural clustering was performed using the average linkage method with a threshold distance of 0.6 (R package, www.r-project.org).
  • the initial descriptor set was preprocessed in order to eliminate ineffective descriptors (those with too many zero values or with very small standard deviations).
  • the QSAR study was carried out with the enhanced replacement method (Mercader et al., 2008) using the Matlab software (The MathWorks, Inc.).
  • KB-3-1 is the parental human (HeLa) epidermoid carcinoma cell line of KB-Vl cells that overexpress Pgp (MDRl) as a result of long-term selection in vinblastine (Shen et al., 1986).
  • NIH-MDR-G185 is a clone of NIH3T3 cells transfected with wild type pHaMDRl/A (Cardarelli et al., 1995).
  • MES-SA Dx5 a drug resistant cell line expressing high levels of Pgp, was derived from a human uterine sarcoma line (MES-SA) by doxorubicin selection (Wang et al., 2000).
  • KB-3-1, KB-Vl, NIH3T3 and NIH-MDR-G185 cells were grown in DMEM cell culture medium at 37 0 C in 5% CO 2 .
  • MES-SA and MES-SA Dx5 cells were grown in McCoy's medium.
  • NIH-MDR-G 185, KB-V-I and Dx5 cells were maintained in 60 ng/mL colchicine, l ⁇ g/mL vinblastine and 500 nM doxorubicin (adriamycin) respectively to maintain Pgp expression. All cell culture media (GIBCO) was supplemented with 10% fetal bovine serum (FBS, GIBCO), 5 mM glutamine (GIBCO) and 50 unit/ml penicillin and streptomycin (GIBCO).
  • Retroviral expression of ABCBl in A431 cells was achieved by a method described previously (Ujhelly et al., 2003).
  • the human skin-derived, epidermoid carcinoma cells, A431 were maintained in alpha- MEM (Life Technologies, Grand Island, NY) supplemented with 10% FBS, 50 units/mL penicillin, 50 units/mL streptomycin, and 5 mM glutamine at 37 0 C in 5% CO 2 .
  • Cell viability assay Cells were trypsinized, counted and seeded in 100 ⁇ L medium supplemented with 10% FBS at a density of 3,000 per well in 96-well plates and incubated for 24 hours at 37 0 C in a humidified atmosphere with 5% CO 2 and 95% air to allow exponential growth. After 24 h, 100 uL medium containing serially diluted compounds were added to give the indicated final concentrations in three replicated wells. Cells were then incubated for a further 72 hours.
  • Antiproliferative activity of drugs was evaluated using the MTT ([3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay (Szakacs et al., 2004). Cytotoxicity assays were performed in triplicate, and curves were fitted by Prism software (GraphPad Software, Inc., San Diego, CA) using nonlinear least-squares regression in a sigmoidal dose-response model with variable slope, also known as the four- parameter logistic equation. Curves were normalized at 100 and 0, the expected upper and lower boundaries of normalized percentage inhibition data, respectively.
  • IC 50 values were determined using the MTT cytotoxicity against the parental KB-3-1 cell line, and the P-glycoprotein expressing cell line KB-Vl.
  • the MDRl selectivity is calculated as the ratio of a compound's IC50 against KB-3-1 cells divided by its IC50 against KB-Vl cells.
  • a value > 1 indicates that the compound kills P-gp-expressing cells more effectively than parental cells, so-called MDRl -inverse activity.
  • a value ⁇ 1 indicates that the P-gp expressing cells are resistant to the compound, relative to parental cells, as is normally observed for P-gp substrates.
  • Compounds with an IC 50 > 50 ⁇ M were considered to be not toxic (NT), and as such their MDRl selectivity could not be determined.

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Abstract

La présente invention concerne un procédé d'inhibition de la croissance de cellules présentant une résistance aux médicaments chez un sujet, cela comprenant l'identification d'un sujet possédant des cellules présentant une résistance aux médicaments; et l'administration audit sujet d'un composé ou d'un ester ou d'un sel pharmaceutiquement acceptable de celui-ci, constituant un agent s'opposant au gène MDR1. L'invention concerne également une méthode d'inhibition du cancer chez un sujet, comprenant l'administration audit sujet d'un agent antiprolifératif, dont l'effet antiprolifératif est potentialisé par la P-glycoprotéine et ledit agent étant un composé ou un ester ou un sel pharmaceutiquement acceptable de celui-ci, constituant un agent s'opposant au gène MDR1.
PCT/US2010/036348 2009-05-29 2010-05-27 Agents s'opposant au gène mdr1 WO2010138686A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103145631A (zh) * 2013-03-18 2013-06-12 广州英赛特生物技术有限公司 抗菌性的喹噁啉-1,4-二氧化物的衍生物及其在动物生产中的应用
WO2017175018A2 (fr) 2016-04-05 2017-10-12 Magyar Tudományos Akadémia Természettudományi Kutatóközpont Dérivés de 8-hydroxy-quinoléine inversant la multirésistance aux médicaments
WO2018187414A1 (fr) * 2017-04-05 2018-10-11 The Regents Of The University Of California Inhibiteurs d'interactions mtor-rictor
CN109776357A (zh) * 2018-08-29 2019-05-21 湖北工业大学 一种含环庚三烯酚酮小分子抑制剂及在抑制鸟氨酸脱羧酶（odc）上的应用
US20190282563A1 (en) * 2016-11-17 2019-09-19 Centre National De La Recherche Scientifique Selective c-FLIP Inhibitors as Anticancer Agents
CN114656417A (zh) * 2022-04-08 2022-06-24 合肥工业大学智能制造技术研究院 一种手性噁唑啉的合成方法及用途

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CN103145631A (zh) * 2013-03-18 2013-06-12 广州英赛特生物技术有限公司 抗菌性的喹噁啉-1,4-二氧化物的衍生物及其在动物生产中的应用
CN103145631B (zh) * 2013-03-18 2015-08-19 广州英赛特生物技术有限公司 抗菌性的喹噁啉-1,4-二氧化物的衍生物及其在动物生产中的应用
WO2017175018A2 (fr) 2016-04-05 2017-10-12 Magyar Tudományos Akadémia Természettudományi Kutatóközpont Dérivés de 8-hydroxy-quinoléine inversant la multirésistance aux médicaments
WO2017175018A3 (fr) * 2016-04-05 2018-01-11 Magyar Tudományos Akadémia Természettudományi Kutatóközpont Dérivés de 8-hydroxy-quinoléine inversant la multirésistance aux médicaments
US10744127B2 (en) 2016-04-05 2020-08-18 Magyar Tudományos Akadémia Természettudományi Kutatóközpont MDR-reversing 8-hydroxy-quinoline derivatives
US20190282563A1 (en) * 2016-11-17 2019-09-19 Centre National De La Recherche Scientifique Selective c-FLIP Inhibitors as Anticancer Agents
WO2018187414A1 (fr) * 2017-04-05 2018-10-11 The Regents Of The University Of California Inhibiteurs d'interactions mtor-rictor
CN109776357A (zh) * 2018-08-29 2019-05-21 湖北工业大学 一种含环庚三烯酚酮小分子抑制剂及在抑制鸟氨酸脱羧酶（odc）上的应用
CN114656417A (zh) * 2022-04-08 2022-06-24 合肥工业大学智能制造技术研究院 一种手性噁唑啉的合成方法及用途
CN114656417B (zh) * 2022-04-08 2023-10-13 合肥工业大学智能制造技术研究院 一种手性噁唑啉的合成方法及用途

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