WO2007006143A1 - Compositions and methods for detecting transformed cells - Google Patents
Compositions and methods for detecting transformed cells Download PDFInfo
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- WO2007006143A1 WO2007006143A1 PCT/CA2006/001125 CA2006001125W WO2007006143A1 WO 2007006143 A1 WO2007006143 A1 WO 2007006143A1 CA 2006001125 W CA2006001125 W CA 2006001125W WO 2007006143 A1 WO2007006143 A1 WO 2007006143A1
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- Prior art keywords
- alkyl
- group
- alkoxy
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- compound
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
Definitions
- This invention relates to the use of styrylacrylonitrile compounds for detecting transformed cells.
- This application relates to diagnostic uses of styrylacrylonitrile compounds, e.g., for detecting cancer, as a consequence of the fluorescent properties of these compounds and their selective uptake by cells that are transformed or otherwise cancerous.
- compositions for use in detecting cancer comprising such a compound and a physiologically acceptable carrier, diluent, excipient and/or adjuvant.
- Another embodiment provides a method of detecting and/or assessing the degree of invasiveness of a cancer comprising contacting with a suspected cancer and/or cancer cell with a compound as disclosed herein, followed by detection of the compound.
- Figure 1 is a histogram comparing the effect of a compound as disclosed herein on cell fluorescence in solid tumour cells versus normal cells.
- Figure 2 is a histogram showing the effect of a compound as disclosed herein on cell fluorescence in non-solid tumour cells versus normal cells.
- Figure 3 is a histogram showing the effect that treating normal bone marrow cells with 0 ⁇ M, 25 ⁇ M and 50 ⁇ M of a compound as disclosed herein has on the number of BFU-E, CFU-C and CFU-GEMM colonies on the bone marrow cells.
- Figure 4 is a histogram demonstrating that enhanced fluorescence of cells treated with a compound as disclosed herein is easily detected up to 18 hours from treatment.
- Figure 5 is a histogram demonstrating that a compound as disclosed herein is stable in vivo. The presence of a compound as disclosed herein is detected by HPLC of the acetylated derivative of the compound.
- Cancer cells and cell lines originating from both solid and non-solid tumours selectively uptake, relative to normal (untransformed and/or non-cancerous) cells, certain styryl acrylonitrile compounds as described in greater detail below. Moreover, once in the cancer cells, the fluorescent property of these compounds is enhanced relative to extracellularly located compound. This fortuitous combination of properties enables the detection of cancer and/or cancer cells, which have selectively or preferentially taken up the compound.
- X is selected from O, S , NH and N-C i -6 alkyl;
- R 5 is selected from the group consisting OfNH 2 , OH, NH(CH 2 ) p Ar, NH(CH 2 ) p 0H, (CH 2 ) p OC 1-6 alkyl, C 1-6 alkyl, C, -6 aIkoxy, NHNH 2 , NHC(O)NH 2 , NHC(O)C 1-6 alkoxy, N- mo ⁇ holino, and N-pyrrolidino;
- Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, C 1-6 alkyl, Ci -6 alkoxy, NH 2 , NH-Ci -6 alkyl, N(C ]-6 alkyl)(Ci -6 alkyl), and SH,
- suitable compounds include compounds of Formula II or a salt, solvate, or hydrate thereof
- Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, Ci -6 alkyl, Q-ealkoxy, NH 2 , NH-C 1-6 alkyl, N(Ci -6 alkyl)(C 1-6 alkyl), SH, S-Ci -6 alkyl, NO 2 , CF 3 , OCF 3 , and halo;
- R 6 is selected from the group consisting of Ar, OH, and OCi -6 alkyl; X is selected from O and S; n is 0-4; and p is 1-4.
- Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, C 1-6 alkyl, C 1-6 alkoxy, NH 2 , NH-C 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), SH, S-C 1-6 alkyl, NO 2 , CF 3 , OCF 3 , and halo;
- R 7 is selected from the group consisting of OH, NH 2 , and OC 1-6 alkyl; X is selected from O and S; and n is 0-4.
- compounds suitable for use in the subject methods include compounds of Formula IV or a salt, solvate, or hydrate thereof
- R 4 is unsubstituted Ar, or Ar substituted with 1-4 substituents, independently selected from C 1-6 alkyl, C 1-6 alkoxy, and halo;
- X is selected from (CH 2 CH 2 O) n and (CH 2 ) n ; and n is 1-4.
- X is (CH 2 ) n .
- the present invention also provides compounds of Formula V and salts, solvates, and hydrates thereof
- R , 4 is Ci -6 alkyl; and n is 1-4.
- Suitable compounds also include prodrugs of the above compounds.
- prodrugs will be functional derivatives of a compound of the invention which are readily convertible in vivo into the compound from which it is notionally derived, e.g., by hydrolysis or enzymatic cleavage of a substituent (e.g., of an ester or amide).
- a substituent e.g., of an ester or amide.
- Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985.
- Prodrugs of the compounds of the invention may be conventional esters formed with available hydroxy, amino or carboxyl group.
- R 1 , R 2 or R 3 when R 1 , R 2 or R 3 is OH in a compound as described herein it may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g., an acid chloride in pyridine).
- Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C 8 -C 24 ) esters, acyloxymethyl esters, carbamates and amino acid esters.
- the compound does not demonstrate appreciable toxicity to normal cells at concentrations employed for diagnostic purposes, and/or has high in vivo stability both in living cells and upon intravenous injection in an animal, particularly in a mammal (see, for example, Fig. 3).
- a compound as set forth above may be advantageously used in in vitro and/or in vivo methods for detecting cancer in cells or animals, particularly mammals, preferably humans.
- a compound as set forth above may be particularly useful in methods for diagnosing cancer in vivo, methods for detecting metastases, and/or methods for staging of cancer diseases. Such a compound may also be used in selecting treatment options for cancer patients in need thereof.
- a compound as set forth above may be labelled with radioactive or fluorescent ligands. The selective uptake by cancer cells of such a radioactively or fluorescently labelled compound provides a method for not only detecting cancer and/or cancer cells but also provides a method for assessing the degree of invasiveness of a cancer. In certain embodiments, however, the present invention contemplates the use of compounds that are not radioactive, not fluorescently labelled, or preferably neither radioactive nor fluorescently labelled.
- the change in the fluorescent property of a compound as set forth above may be obtained even with short-term (1-5 hours) exposure of cells, to the compound and is obtained without specifically labelling the compound with a fluorescent ligand.
- a compound as set forth above is particularly useful in fluorescence-based detection of cancer and/or cancer cell cells.
- FACS Fluorescent Activated Cell Sorter
- selective uptake of a compound as set forth above by cancer cells may permit direct observation of malignancies in vivo.
- skin cancers e.g., melanoma
- malignancies of the mouth, throat, stomach, bronchi, colon, prostate and breast may all be directly detected.
- a compound as set forth above may also be used in vitro to provide an inexpensive, fast, simple and reliable way of detecting malignant cells that does not require special training or equipment and can thus be performed in practically any local hospital facility.
- a suspected cancer and/or cancer cell may be detected by administering a compound as set forth above, e.g., alone or in a composition comprising the compound, to a site containing the suspected cancer.
- Administration may be in vivo, ex vivo or in vitro.
- any excess compound may then be removed or washed off from the site containing the suspected cancer.
- Detection of the compound may then be performed to determine whether the compound has been selectively taken up by the suspected cancer. The results may be compared against a standard involving known normal cells and a conclusion drawn as to whether the suspected cancer and/or cancer cell is indeed a cancer. Since the fluorescence of the compounds disclosed herein is selectively enhanced in cancer cells, fluorescence-based detection methods may be conveniently used in an assay.
- detecting fluorescence can be performed by irradiating the cells with light including the excitation wavelength of the compound being used, followed by detection of light emitted by the cells at the emission wavelength of the compound.
- a compound's excitation and emission wavelengths can readily be determined using techniques well established in the art.
- a compound as set forth above may be administered alone or in a composition or formulation comprising the compound and a physiologically acceptable carrier, diluent, excipient and/or adjuvant either in vitro or in vivo to bring the compound into contact with cancer cells.
- a physiologically acceptable carrier, diluent, excipient and/or adjuvant either in vitro or in vivo to bring the compound into contact with cancer cells.
- the route of administration and the type of composition or formulation used generally depend on the type of cancer and/or cancer cell being detected and whether the compound is to be used in vitro or in a patient.
- Formulations comprise the active compound in combination with one or more physiologically acceptable ingredients, such as carriers (including implant carriers or microcapsules), excipients, diluents and/or adjuvants.
- physiologically acceptable ingredients such as carriers (including implant carriers or microcapsules), excipients, diluents and/or adjuvants.
- Such ingredients generally refer to inert, non-toxic solid materials that do not react with the active compound of the invention.
- the active compound may be formulated into a formulation for enteral (e.g., oral), buccal, topical, transdermal (e.g., patch), intranasal, intraperitoneal, ophthalmic, intraocular, parenteral (e.g., intravenous, intraarterial, intramuscular, intrathecal or infusion or subcutaneous), rectal, administration, or in a form suitable for administration by inhalation or insufflation, or another mode of administration.
- enteral e.g., oral
- buccal topical
- transdermal e.g., patch
- intranasal e.g., intraperitoneal
- ophthalmic e.g., intraocular
- parenteral e.g., intravenous, intraarterial, intramuscular, intrathecal or infusion or subcutaneous
- rectal e.g., administration by inhalation or insufflation, or another mode of administration.
- Formulations may be prepared, for example, in unit dose forms, such as dragees, tablets, capsules, suppositories or ampoules. They may be prepared in a conventional manner, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
- the compounds of the present invention may take the form of, for example, granules, tablets, capsules, liquids or dragees prepared together with physiologically acceptable carriers, excipients and/or diluents.
- physiologically acceptable ingredients include:
- binding agents such as starch (e.g., pregelatinised maize starch, wheat starch paste, rice starch paste, potato starch paste), polyvinylpyrrolidone, hydroxypropyl methylcellulose, gum tragacanth and/or gelatin;
- fillers such as sugars (e.g., lactose, saccharose, mannitol, sorbitol), amylopectin, cellulose preparations (e.g., microcrystalline cellulose), calcium phosphates (e.g., tricalcium phosphate, calcium hydrogen phosphatelactose) and/or titanium dioxide;
- sugars e.g., lactose, saccharose, mannitol, sorbitol
- amylopectin e.g., microcrystalline cellulose
- calcium phosphates e.g., tricalcium phosphate, calcium hydrogen phosphatelactose
- titanium dioxide e.g., titanium dioxide
- lubricants such as stearic acid, calcium stearate, magnesium stearate, talc, silica, silicic acid, polyethylene glycol and/or waxes;
- disintegrants such as the above-mentioned starches, carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof (e.g., sodium alginate) and/or sodium starch glycollate;
- wetting agents such as sodium lauryl sulphate
- Soft gelatin capsules may be prepared with capsules containing a mixture of the compound together with paraffin oil, liquid polyethylene glycols, vegetable oil, fat and/or another suitable vehicle for soft gelatin capsules. Plasticizers such as glycerol or sorbitol may also be used. Hard gelatin capsules may contain granules of the compound. Hard gelatin capsules may also contain the compound in combination with solid powdered ingredients such as those listed above. Liquid formulations for oral administration may be prepared in the form of solutions, syrups or suspensions.
- Liquid formulations typically comprise the compound together with an excipient such as sugar or sugar alcohols, and a carrier such as ethanol, water, glycerol, propylene glycol, polyethylene glycol, almond oil, oily esters or mixtures thereof.
- a carrier such as ethanol, water, glycerol, propylene glycol, polyethylene glycol, almond oil, oily esters or mixtures thereof.
- such liquid formulations may also contain coloring agents, flavoring agents, saccharine, thickening agents (e.g., carboxymethyl cellulose), suspending agents (e.g., sorbitol syrup, methyl cellulose, hydrogenated edible fats), emulsifying agents (e.g. lecithin, acacia), and/or preservatives (e.g., methyl p-hydroxybenzoates, propyl p- hydroxybenzoates, sorbic acid).
- Liquid formulations for oral administration may also be prepared in the form of a dry powder to be re
- Dragee cores are provided with suitable coatings that may be resistant to gastric juices, there being used, inter alia, concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colourings or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active compound.
- the formulation may take the form of tablets of lozenges formulated in conventional manner.
- the active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
- Formulations for injection may be presented in unit dosage form (e.g., in ampoules or in multi-dose containers) with an added preservative.
- the formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
- aqueous solutions of the active compound in water-soluble form for example a water-soluble salt, are particularly suitable for parenteral administration.
- Suspensions of the active compound are also suitable.
- Oily injection suspensions using suitable lipophilic solvents or vehicles such as fatty oils (e.g., sesame oil, synthetic fatty acid esters like ethyl oleate or triglycerides) may be used.
- fatty oils e.g., sesame oil, synthetic fatty acid esters like ethyl oleate or triglycerides
- Aqueous injection suspensions that contain viscosity- increasing substances for example sodium carboxymethylcellulose, sorbitol and/or dextran and optionally also stabilisers may also be used.
- the active compound may be in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.
- Rectally administrable formulations for example, suppositories that comprise a combination of the active compound and a suppository base are also provided.
- Suitable as suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher alkanols. It is also possible to use gelatin rectal capsules that comprise a combination of the active compound and a base material.
- Suitable base materials are, for example, liquid triglycerides, polyethylene glycols and paraffin hydrocarbons.
- the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).
- a suitable propellant e.g., dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- the pressurized container or nebulizer may contain a solution or suspension of the active compound.
- Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
- a compound as set forth above may be applied or administered at a concentration in a range of about 10 nM to about 50 ⁇ M.
- the active compound is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual animal, the site and method of administration, scheduling of administration, animal age, sex, body weight and other factors known to practitioners.
- An effective dose of the compound may depend on various factors, such as the method of administration, species of animal, age and/or individual condition.
- C 1-6 alkyl as used herein means, unless otherwise stated, straight and/or branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
- d- ⁇ alkoxy as used herein means, unless otherwise stated, straight and/or branched chain alkoxy radicals containing from one to six carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
- C 1-4 alkyl as used herein means, unless otherwise stated, straight and/or branched chain alkyl radicals containing from one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
- Ci -4 alkoxy as used herein means, unless otherwise stated, straight and/or branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
- halo as used herein means halogen and includes chloro, fluoro, bromo, iodo and the like.
- pharmaceutically acceptable salt means an acid addition salt which is suitable for or compatible with the treatment of patients.
- pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of any base compounds represented by Formulae I-V, or their intermediates.
- Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
- Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p- toluenesulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
- mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulf
- the acid addition salts of compounds as set forth herein are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
- the selection of the appropriate salt will be known to one skilled in the art.
- Other non-pharmaceutically acceptable salts e.g. oxalates, may be used, for example, in the isolation of compounds of Formulae I- V for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
- solvate means a compound of Formulae I- V, or a pharmaceutically acceptable salt of a compound of Formulae I- V, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
- a suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate”.
- an "effective amount” or a "sufficient amount " of an agent as used herein is that amount sufficient to effect beneficial or desired results, including clinical results, and, as such, an "effective amount” depends upon the context in which it is being applied and would be understood by a person skilled in the art.
- an effective amount of an agent is, for example, an amount sufficient to achieve such a modulation in cell proliferation as compared to the response obtained without administration of the agent.
- animal as used herein includes all members of the animal kingdom including human.
- the animal is preferably a human.
- a cell as used herein includes a plurality of cells. Administering a compound to a cell includes in vivo, ex vivo and in vitro administration.
- Example CR4 ((E,E)-2-(Benzylaminocarbonyl)-3-(3,4- dihydroxystyryl)acrylonitrile) may be prepared by methods described in WO 01/79158. The synthesis is described below.
- the compound was prepared as described in Example A 1 by adding methyl cyanoacetate (1.3 mL, 14 mmol) to benzylamine (1.5 mL, 14 mmol). The compound was distilled in vacuo directly from the reaction mixture (Kugelrohr apparatus (Aldrich), 0.1 mm Hg, T. oven 180-190 °C) to give an off-white solid (2.34 g, 95%).
- Example A 7 The compound was prepared as described in Example CRl 1, by adding 3,4- dimethoxycinnamaldehyde (Example A 7 , 0.04 g, 0.2 mmol) to N-(cyanoacetyl)benzylamide (Example A 3 , 0.036 g, 0.2 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.045 g, 62%).
- Example A 8 Methyl ester of 3,4-bis(t-butyldimethylsilyloxy)cinnamic acid (A 8 )
- Example A 9 The compound was prepared as described in Example A 6 by treating of 3,4- dihydroxycinnamic acid bis(BDMS) ether methyl ester (Example A 9 , 0.42 g, 1.0 mmol) with IM THF solution of diisobutylaluminum hydride (4.0 mmol) in absolute THF (25 mL) at 2O 0 C for 1 h. After distilling in vacuo (Kugelrohr apparatus (Aldrich), 0.1 mm Hg, T. oven 185-200 0 C) a white viscous oil was obtained, yield 0.33 g (85%).
- Example A 10 3,4-Bis(t-butyldimethylsilyloxy)cinnamaldehyde (Ai 0 )
- Example A 7 The compound was prepared as described in Example A 7 by adding 3,4-bis(t- butyldimethylsilyloxy)cinnamyl alcohol (Example A 9 , 0.2 g, 0.5 mmol) in 5 mL Of CH 2 Cl 2 to a mixture of pyridinium dichromate (0.38 g, 1 mmol) and 1 g molecular sieves 3 A in 20 mL OfCH 2 Cl 2 . The residue was passed through silica gel and washed with 300 mL of EtOAc-hexane, 1 :1. After evaporation the compound was purified by silica gel chromatography (hexane-EtOAc, 5:1) to provide an oil (0.15 g, 76%).
- Example A 10 The compound was prepared as described in Example CRl 1 by adding 3,4-bis(Y- butyldimethylsilyloxy) cinnamaldehyde (Example A 10 , 0.100 g, 0.26 mmol) to N- (cyanoacetyl)benzylamide (Example A 3 , 0.044 g, 0.26 mmol. After refluxing for 2.5 h purification by silica gel chromatography (hexane-EtOAc, 15:1) provided a yellow solid (0.090 g, 64%).
- Example 1 The fluorescence of compound of formula (I) is enhanced in solid tumor cells, but not normal cells.
- Normal human fibroblasts or transformed human embryonic kidney cells or various human cancer cells were cultured in an appropriate medium with 10% FCS.
- Subconfluent cell cultures were incubated in complete medium with or without 50 ⁇ M of CR4.
- the cells were incubated with the compound for 2.5 hours at 37 °C under 5% CO 2 . At the end of this period, the cells were thoroughly washed in medium to remove CR4, detached and analysed by flow cytometry.
- the results are shown in Figure 1. The results demonstrate that the fluorescence CR4 is enhanced in solid tumor cancer cells, but not normal cells.
- Example 2 The fluorescence of CR4 is specifically enhanced in non-solid human cancer cells.
- Example 3 Treatment of normal bone marrow with high dose of CR4 does not demonstrate toxicity of the compound.
- Bone marrow cells were layered over PercollTM and centrifuged at 400 g at 4 0 C for 10 minutes to remove neutrophils and red blood cells (RBCs). The cells were resuspended at lxlO 6 /mL in complete medium with or without 50 ⁇ M of CR4. The cells were incubated with the compound for 2.5 hours at 37 0 C under 5% CO 2 .
- the cells were thoroughly washed in medium to remove CR4 and then cultured at 2x10 5 cells/mL in IMDM containing 0.9% (v/v) methylcellulose supplemented with 30% FCS or normal human plasma, and a cocktail of cytokines, containing G-CSF (10 ng/mL), IL-3 (40 LVmL), MGF (50 ng/mL), Erythropoietin (2 LVmL) or TPO (10 ng/mL) and 5xlO- 5 M ⁇ -2- mercaptoethanol.
- the culture mixture was plated in 1 mL volumes into 35 mL dishes and incubated at 37 0 C under 5% CO 2 in a humidified atmosphere.
- BFU-B colonies defined as aggregates of more than 500 hemaglobinized eels or 3 or more erythroid subcolonies
- CFU-C colonies defined as granulocyte or monocyte-macrophage cells or both
- CFU-GEMM colonies a mixed population comprising of all elements.
- CR4 displayed negligible toxicity upon normal bone marrow at doses up to 50 ⁇ M, as illustrated in Figure 3.
- Example 4 CR4 is stable in living cells. Cl pre-B ALL cells were treated with 50 ⁇ M of CR4 as in Example 2, washed, incubated in the absence of the compound in complete medium at 37 0 C for time periods indicated in Figure 4, and analysed by flowcytometry. Increased fluorescence in cells treated with CR4 but not in control cells was easily detected even upon 18 hours of incubation free from the compound. The results are illustrated in Figure 4.
- Example 5 CR4 is stable in vivo.
- mice Nine week old BALBc mice were injected intravenously with 100 ⁇ M of CR4 in 250 ⁇ L of 0.1% DMSO, or, with 250 ⁇ L of 0.1% DMSO alone. Blood samples were taken after the time periods indicated in Figure 5, plasma was prepared and analysed by HPLC.
- the 3,4-diacetate derivative was prepared by treating CR4 (10 mg, 31.3 ⁇ mol) with 70 ⁇ L of pyridine and 70 ⁇ L of acetic anhydride at 20 0 C for 1 hour:
- HPLC analyses were performed on a WatersTM 600 chromatograph (USA) with a PDA detector using a Nova-PakTM C18 3.9x300 mm column (WatersTM, USA), with 60:40 MeCN-H 2 O as eluent, at a flow rate of 1.0 mL/min and detecting at a UV wavelength of 340 nm.
- the compound standard showed a peak at RT 8.9 min, ⁇ max 338 nm.
- the plasma samples were taken to dryness by evaporating water with acetonitrile and derivatized with 200 ⁇ L pyridine and 200 ⁇ L acetic anhydride at 2O 0 C for 12 hours.
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Abstract
The invention relates to the use of fluorescent styryl acrylomtrile compounds that are selectively taken up by cancer cells relative to normal cells. The fluorescent properties of these compounds are enhanced in cancer cells. Such compounds may be used for detecting cancer and/or transformed cells both in vitro and in vivo.
Description
COMPOSITIONS AND METHODS FOR DETECTING TRANSFORMED CELLS
REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the filing date of U.S. Provisional Application U.S.S.N. 60/699,012 filed on July 13, 2005. The teachings of the referenced application are incorporated herein by reference.
FIELD OF THE INVENTION
This invention relates to the use of styrylacrylonitrile compounds for detecting transformed cells.
BACKGROUND OF THE INVENTION
Early detection of tumors and cancers can significantly improve the prospects for successful treatment and long-term survival. Many early detection techniques rely heavily on crude physical methods, invasive biopsies, harsh X-rays, or blood tests that are specific for only particular types of cancer, and many of these tests are ineffective or unreliable for early-stage cancer detection. There remains a need for improved methods for detecting malignant cells, particularly in the early stages of cancer development.
SUMMARY OF THE INVENTION
This application relates to diagnostic uses of styrylacrylonitrile compounds, e.g., for detecting cancer, as a consequence of the fluorescent properties of these compounds and their selective uptake by cells that are transformed or otherwise cancerous.
One embodiment provides a composition for use in detecting cancer comprising such a compound and a physiologically acceptable carrier, diluent, excipient and/or adjuvant.
Another embodiment provides a method of detecting and/or assessing the degree of invasiveness of a cancer comprising contacting with a suspected cancer and/or cancer cell with a compound as disclosed herein, followed by detection of the compound.
There is also provided a commercial package comprising a compound as described herein together with instructions for its use in detecting cancer.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described by way of example having regard to the appended drawings in which:
Figure 1 is a histogram comparing the effect of a compound as disclosed herein on cell fluorescence in solid tumour cells versus normal cells.
Figure 2 is a histogram showing the effect of a compound as disclosed herein on cell fluorescence in non-solid tumour cells versus normal cells.
Figure 3 is a histogram showing the effect that treating normal bone marrow cells with 0 μM, 25 μM and 50 μM of a compound as disclosed herein has on the number of BFU-E, CFU-C and CFU-GEMM colonies on the bone marrow cells.
Figure 4 is a histogram demonstrating that enhanced fluorescence of cells treated with a compound as disclosed herein is easily detected up to 18 hours from treatment.
Figure 5 is a histogram demonstrating that a compound as disclosed herein is stable in vivo. The presence of a compound as disclosed herein is detected by HPLC of the acetylated derivative of the compound.
DETAILED DESCRIPTION
Cancer cells and cell lines originating from both solid and non-solid tumours selectively uptake, relative to normal (untransformed and/or non-cancerous) cells, certain styryl acrylonitrile compounds as described in greater detail below. Moreover, once in the cancer cells, the fluorescent property of these compounds is enhanced relative to extracellularly located compound. This fortuitous combination of properties enables the detection of cancer and/or cancer cells, which have selectively or preferentially taken up the compound.
Compounds suitable for use in the present methods include compounds of Formula I or a salt, solvate, or hydrate thereof:
I wherein
R1 and R2 are each independently selected from the group consisting of H, OH, C1- 6alkyl, Ci-6alkoxy, Ci-6alkylCO2, NH2, NH-C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), C1. 6alkyl(C=O)NH, C1-6alkyl(C==O)N(Ci-6alkyl), SH, S-Ci-6alkyl, O-SiCd^alky^Cd. 6alkyl)(Ci-6alkyl), NO2, CF3, OCF3, and halo; or R1 and R2 together represent O-Ci-6alkyl- O, thereby forming a ring;
R3 is selected from the group consisting of H, OH, C1-6alkyl, Ci-όalkoxy, C1- 6alkylCO2, NH2, NH-C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), Ci-6alkyl(C=O)NH, C1-
6alkyl(C=O)N(Ci-6alkyl), SH, S-Ci-6alkyl, O-Si(Ci-6alkyl)(Ci-6alkyl)(C1-6alkyl), NO2, halo, and CH2-S-(CH2)nAr;
R4 is selected from the group consisting of C(X)R5, SO3Ar, NH2, NH-Ci-6alkyl, N(Ci-6alkyl)(C1-6alkyl), P(O)(OH)2, P(O)(OC1 -6alkyl)2, and C(NH2)=C(CN)2; X is selected from O, S , NH and N-C i -6alkyl;
R5 is selected from the group consisting OfNH2, OH, NH(CH2)pAr, NH(CH2)p0H, (CH2)pOC1-6alkyl, C1-6alkyl, C,-6aIkoxy, NHNH2, NHC(O)NH2, NHC(O)C 1-6alkoxy, N- moφholino, and N-pyrrolidino;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, C1-6alkyl, Ci-6alkoxy, NH2, NH-Ci-6alkyl, N(C]-6alkyl)(Ci-6alkyl), and SH,
S-Ci-6alkyl, NO2, CF3, OCF3, and halo; n is O to 4; and p is 1-4.
In other embodiments, suitable compounds include compounds of Formula II or a salt, solvate, or hydrate thereof
II wherein
R1 and R2 are each independently selected from the group consisting of H, OH, C1. 6alkyl, Ci-6alkoxy, C1-6alkylCO2, NH2, NH-Ci-6alkyl, N(C1-6alkyl)(C1-6alkyl), C1- 6alkyl(C=O)NH, C1-6alkyl(C=O)N(C1-6alkyl), SH, S-C1-6alkyl, O-SKd-ealkylXd. 6alkyl)(C1-6alkyl), NO2, CF3, OCF3, and halo; or R1 and R2 together represent O-C1-6alkyl- O, thereby forming a ring;
R3 is selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, C1- 6alkylCO2, NH2, NH-C1-6alkyl, N(Ci-6alkyl)(Ci-6alkyl), C1-6alkyl(C=O)NH, C1- 6alkyl(C=O)N(C1-6alkyl), SH, S-C1-6alkyl, O-Si(C1-6alkyl)(C1-6alkyl)(C1.6alkyl), NO2, halo, and CH2-S-(CH2)nAr; Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, Ci-6alkyl, Q-ealkoxy, NH2, NH-C1-6alkyl, N(Ci-6alkyl)(C1-6alkyl), SH, S-Ci-6alkyl, NO2, CF3, OCF3, and halo;
R6 is selected from the group consisting of Ar, OH, and OCi-6alkyl; X is selected from O and S; n is 0-4; and p is 1-4.
III wherein
R1 and R2 are each independently selected from the group consisting of H, OH, C1. 6alkyl, C1-6alkoxy, C1-6alkylCO2, NH2, NH-C,-6alkyl, N(C1-6alkyl)(C1-6alkyl), C1- 6alkyl(C=O)NH, Ci-6alkyl(C=O)N(C1-6alkyl), SH, S-Ci-6alkyl, O-Si(C1-6alkyl)(Ci. 6alkyl)(C1-6alkyl), NO2, CF3, OCF3, and halo; or R1 and R2 together represent O-C1-6alkyl- O, thereby forming a ring;
R3 is selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, C1- 6alkylCO2, NH2, NH-C1-6alkyl, N(Ci-6alkyl)(C1-6alkyl), Ci-6alkyl(C=O)NH, C1-
6alkyl(C=O)N(C1-6alkyl), SH, S-C1-6alkyl, O-Si(Ci-6alkyl)(C1-6alkyl)(C1-6alkyl), NO2, halo, and CH2-S-(CH2)nAr;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, C1-6alkyl, C1-6alkoxy, NH2, NH-C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), SH, S-C1-6alkyl, NO2, CF3, OCF3, and halo;
R7 is selected from the group consisting of OH, NH2, and OC1-6alkyl; X is selected from O and S; and n is 0-4.
In yet other embodiments, compounds suitable for use in the subject methods include compounds of Formula IV or a salt, solvate, or hydrate thereof
R1, R2, and R3 are each independently selected from H, OH, Ci-6alkyl, Ci-6alkoxy, Ci-6alkyl(CO)O, NH2, NH-C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), C1-6alkyl(C=O)NH, C1- 6alkyl(C=O)N(C1-6alkyl), SH, S-Ci-6alkyl, NO2, CF3, OCF3, and halo;
R4 is unsubstituted Ar, or Ar substituted with 1-4 substituents, independently selected from C1-6alkyl, C1-6alkoxy, and halo;
X is selected from (CH2CH2O)n and (CH2)n; and n is 1-4.
In certain embodiments, X is (CH2)n.
The present invention also provides compounds of Formula V and salts, solvates, and hydrates thereof
R1, R2, and R3 are each independently selected from H, OH, C1-6alkyl, C1-6alkoxy, Ci-6alkyl(CO)O, NH2, NH-C1-6alkyl, N(Ci-6alkyl)(C1-6alkyl), C1-6alkyl(C=O)NH, C1- 6alkyl(C=O)N(C1-6alkyl), SH, S-C1-6alkyl, NO2, CF3, OCF3, and halo;
R ,4 is Ci-6alkyl; and
n is 1-4.
Compounds of the above formulae, including the particular compounds disclosed in PCT CA04/001431, WO 03/062190, WO 01/79158, and U.S. Provisional Application 60/649211, all of which are hereby incorporated herein in their entireties, are useful in the various methods and compositions disclosed herein.
Suitable compounds also include prodrugs of the above compounds. In general, such prodrugs will be functional derivatives of a compound of the invention which are readily convertible in vivo into the compound from which it is notionally derived, e.g., by hydrolysis or enzymatic cleavage of a substituent (e.g., of an ester or amide). Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985.
Prodrugs of the compounds of the invention may be conventional esters formed with available hydroxy, amino or carboxyl group. For example, when R1, R2 or R3 is OH in a compound as described herein it may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g., an acid chloride in pyridine). Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C8-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.
In certain embodiments, the compound does not demonstrate appreciable toxicity to normal cells at concentrations employed for diagnostic purposes, and/or has high in vivo stability both in living cells and upon intravenous injection in an animal, particularly in a mammal (see, for example, Fig. 3).
Accordingly, a compound as set forth above may be advantageously used in in vitro and/or in vivo methods for detecting cancer in cells or animals, particularly mammals, preferably humans. A compound as set forth above may be particularly useful in methods for diagnosing cancer in vivo, methods for detecting metastases, and/or methods for staging of cancer diseases. Such a compound may also be used in selecting treatment options for cancer patients in need thereof.
A compound as set forth above may be labelled with radioactive or fluorescent ligands. The selective uptake by cancer cells of such a radioactively or fluorescently labelled compound provides a method for not only detecting cancer and/or cancer cells but also provides a method for assessing the degree of invasiveness of a cancer. In certain embodiments, however, the present invention contemplates the use of compounds that are not radioactive, not fluorescently labelled, or preferably neither radioactive nor fluorescently labelled.
The change in the fluorescent property of a compound as set forth above may be obtained even with short-term (1-5 hours) exposure of cells, to the compound and is obtained without specifically labelling the compound with a fluorescent ligand. Thus, a compound as set forth above is particularly useful in fluorescence-based detection of cancer and/or cancer cell cells.
Methods of detecting fluorescence both in vitro and in vivo are well known in the art and include inter alia the use of a Fluorescent Activated Cell Sorter (FACS), a fluorimeter or a fluorescence microscope.
In another beneficial aspect, selective uptake of a compound as set forth above by cancer cells may permit direct observation of malignancies in vivo. For example, skin cancers (e.g., melanoma) where precise in vivo diagnostics are particularly neede, and malignancies of the mouth, throat, stomach, bronchi, colon, prostate and breast may all be directly detected.
A compound as set forth above may also be used in vitro to provide an inexpensive, fast, simple and reliable way of detecting malignant cells that does not require special training or equipment and can thus be performed in practically any local hospital facility.
Generally, a suspected cancer and/or cancer cell may be detected by administering a compound as set forth above, e.g., alone or in a composition comprising the compound, to a site containing the suspected cancer. Administration may be in vivo, ex vivo or in vitro. After a period of time sufficient to allow the compound to be taken up by the cancer and/or cancer cells, any excess compound may then be removed or washed off from the site containing the suspected cancer. Detection of the compound may then be performed to
determine whether the compound has been selectively taken up by the suspected cancer. The results may be compared against a standard involving known normal cells and a conclusion drawn as to whether the suspected cancer and/or cancer cell is indeed a cancer. Since the fluorescence of the compounds disclosed herein is selectively enhanced in cancer cells, fluorescence-based detection methods may be conveniently used in an assay.
In certain embodiments, detecting fluorescence can be performed by irradiating the cells with light including the excitation wavelength of the compound being used, followed by detection of light emitted by the cells at the emission wavelength of the compound. A compound's excitation and emission wavelengths can readily be determined using techniques well established in the art.
A compound as set forth above may be administered alone or in a composition or formulation comprising the compound and a physiologically acceptable carrier, diluent, excipient and/or adjuvant either in vitro or in vivo to bring the compound into contact with cancer cells. The route of administration and the type of composition or formulation used generally depend on the type of cancer and/or cancer cell being detected and whether the compound is to be used in vitro or in a patient.
Formulations comprise the active compound in combination with one or more physiologically acceptable ingredients, such as carriers (including implant carriers or microcapsules), excipients, diluents and/or adjuvants. Such ingredients generally refer to inert, non-toxic solid materials that do not react with the active compound of the invention.
The active compound may be formulated into a formulation for enteral (e.g., oral), buccal, topical, transdermal (e.g., patch), intranasal, intraperitoneal, ophthalmic, intraocular, parenteral (e.g., intravenous, intraarterial, intramuscular, intrathecal or infusion or subcutaneous), rectal, administration, or in a form suitable for administration by inhalation or insufflation, or another mode of administration.
Formulations may be prepared, for example, in unit dose forms, such as dragees, tablets, capsules, suppositories or ampoules. They may be prepared in a conventional manner, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
To prepare formulations of the present invention in the form of dosage units for oral administration, the compounds of the present invention may take the form of, for example, granules, tablets, capsules, liquids or dragees prepared together with physiologically acceptable carriers, excipients and/or diluents. Typical physiologically acceptable ingredients include:
(a) binding agents such as starch (e.g., pregelatinised maize starch, wheat starch paste, rice starch paste, potato starch paste), polyvinylpyrrolidone, hydroxypropyl methylcellulose, gum tragacanth and/or gelatin;
(b) fillers such as sugars (e.g., lactose, saccharose, mannitol, sorbitol), amylopectin, cellulose preparations (e.g., microcrystalline cellulose), calcium phosphates (e.g., tricalcium phosphate, calcium hydrogen phosphatelactose) and/or titanium dioxide;
(c) lubricants such as stearic acid, calcium stearate, magnesium stearate, talc, silica, silicic acid, polyethylene glycol and/or waxes;
(d) disintegrants such as the above-mentioned starches, carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof (e.g., sodium alginate) and/or sodium starch glycollate;
(e) wetting agents such as sodium lauryl sulphate; and/or
(f) stabilizers.
Soft gelatin capsules may be prepared with capsules containing a mixture of the compound together with paraffin oil, liquid polyethylene glycols, vegetable oil, fat and/or another suitable vehicle for soft gelatin capsules. Plasticizers such as glycerol or sorbitol may also be used. Hard gelatin capsules may contain granules of the compound. Hard gelatin capsules may also contain the compound in combination with solid powdered ingredients such as those listed above. Liquid formulations for oral administration may be prepared in the form of solutions, syrups or suspensions. Liquid formulations typically comprise the compound together with an excipient such as sugar or sugar alcohols, and a carrier such as ethanol, water, glycerol, propylene glycol, polyethylene glycol, almond oil, oily esters or mixtures
thereof. If desired, such liquid formulations may also contain coloring agents, flavoring agents, saccharine, thickening agents (e.g., carboxymethyl cellulose), suspending agents (e.g., sorbitol syrup, methyl cellulose, hydrogenated edible fats), emulsifying agents (e.g. lecithin, acacia), and/or preservatives (e.g., methyl p-hydroxybenzoates, propyl p- hydroxybenzoates, sorbic acid). Liquid formulations for oral administration may also be prepared in the form of a dry powder to be reconstituted with water or another suitable vehicle prior to use.
Dragee cores are provided with suitable coatings that may be resistant to gastric juices, there being used, inter alia, concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colourings or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active compound.
For buccal administration the formulation may take the form of tablets of lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form (e.g., in ampoules or in multi-dose containers) with an added preservative. The formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. For example, aqueous solutions of the active compound in water-soluble form, for example a water-soluble salt, are particularly suitable for parenteral administration. Suspensions of the active compound are also suitable. Oily injection suspensions using suitable lipophilic solvents or vehicles, such as fatty oils (e.g., sesame oil, synthetic fatty acid esters like ethyl oleate or triglycerides) may be used. Aqueous injection suspensions that contain viscosity- increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran
and optionally also stabilisers may also be used. Alternatively, the active compound may be in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.
Rectally administrable formulations, for example, suppositories that comprise a combination of the active compound and a suppository base are also provided. Suitable as suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher alkanols. It is also possible to use gelatin rectal capsules that comprise a combination of the active compound and a base material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols and paraffin hydrocarbons.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
Generally, a compound as set forth above may be applied or administered at a concentration in a range of about 10 nM to about 50 μM. However, if used for the diagnosis of cancer in an animal, the active compound is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual animal, the site and method of administration, scheduling of administration, animal age, sex, body weight and other factors known to practitioners. An effective dose of the compound may depend on various factors, such as the method of administration, species of animal, age and/or individual condition.
DEFINITIONS
The term "C1-6alkyl" as used herein means, unless otherwise stated, straight and/or branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like. The term "d-βalkoxy" as used herein means, unless otherwise stated, straight and/or branched chain alkoxy radicals containing from one to six carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
The term "C1-4alkyl" as used herein means, unless otherwise stated, straight and/or branched chain alkyl radicals containing from one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
The term "Ci-4alkoxy" as used herein means, unless otherwise stated, straight and/or branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
The term "halo" as used herein means halogen and includes chloro, fluoro, bromo, iodo and the like.
The term "pharmaceutically acceptable salt" means an acid addition salt which is suitable for or compatible with the treatment of patients.
The term "pharmaceutically acceptable acid addition salt" as used herein means any non-toxic organic or inorganic salt of any base compounds represented by Formulae I-V, or their intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p- toluenesulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds as set forth herein are more soluble in water
and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, e.g. oxalates, may be used, for example, in the isolation of compounds of Formulae I- V for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
The term "solvate" as used herein means a compound of Formulae I- V, or a pharmaceutically acceptable salt of a compound of Formulae I- V, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate".
The term an "effective amount" or a "sufficient amount " of an agent as used herein is that amount sufficient to effect beneficial or desired results, including clinical results, and, as such, an "effective amount" depends upon the context in which it is being applied and would be understood by a person skilled in the art. For example, in the context of administering an agent that modulates cell proliferation, an effective amount of an agent is, for example, an amount sufficient to achieve such a modulation in cell proliferation as compared to the response obtained without administration of the agent.
The term "animal" as used herein includes all members of the animal kingdom including human. The animal is preferably a human. The term "a cell" as used herein includes a plurality of cells. Administering a compound to a cell includes in vivo, ex vivo and in vitro administration.
EXAMPLES
Synthesis Examples
Example CR4 ((E,E)-2-(Benzylaminocarbonyl)-3-(3,4- dihydroxystyryl)acrylonitrile) may be prepared by methods described in WO 01/79158. The synthesis is described below.
To 3,4-dimethoxybenzylamine (2.7 mL, 18 mmol) methyl cyanoacetate was added (1.6 mL, 18 mmol). The reaction was heated for 14 h at 100 °C. Cooling gave a dark brown solid which was recrystallized from ethanol to give 2.90 g of the product (69% yield).
Example A2: N-(Cyanoacetyl)3,4-dihydroxybenzylaminocarbonyl (A2)
To N-(cyanoacetyl)3,4-dimethoxybenzylaminocarbonyl (Example A1, 0.2 g, 0.85 mmol) in 20 mL Of CH2Cl2 boron tribromide was added under argon at -78 °C (0.24 mL, 2.56 mmol) in 2.5 mL Of CH2Cl2. After 2 h the reaction was brought to room temperature and stirred overnight. The reaction was cooled to 0 °C, 10 mL of IN HCl was added, the solution was extracted with 3 x 50 mL of ethyl acetate, the organic phase was washed to neutral pH, dried with MgSO4, and taken to dryness. The residue was purified by silica gel chromatography (CHCl3-MeOH, 20:1) to give a yellow solid (0.07 g, 40% yield).
Example CRl 1 : (E,E)-2-(3,4-Dihydroxybenzylaminocarbonyl)-3-(3,5-dimethoxy-4- hydroxystyryl)acrylonitrile (CRl 1 )
To 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.042 g, 0.2 mmol) and N- (cyanoacetyl)3,4-dihydroxybenzylamide (Example A2, 0.042 g, 0.2 mmol) in 10 mL of ethanol 3 mg of β-alanine was added and the reaction was refluxed for 6 h. Water was
added and the solid was recrystallized from 5 niL of ethanol twice to give 0.06 g (75%) of a red solid.
Example A3: N-(Cyanoacetyl)benzylamide (A3)
The compound was prepared as described in Example A1 by adding methyl cyanoacetate (1.3 mL, 14 mmol) to benzylamine (1.5 mL, 14 mmol). The compound was distilled in vacuo directly from the reaction mixture (Kugelrohr apparatus (Aldrich), 0.1 mm Hg, T. oven 180-190 °C) to give an off-white solid (2.34 g, 95%).
Example A6: 3,4-Dimethoxycinnamyl alcohol (A6)
To a solution of 0.42 g (2.0 mmol) of 3,4-dimethoxycinnamic acid in 50 mL MeOH was added SOCl2 (50 μL) and the mixture was stirred at 60 °C for 5 h. The mixture was taken to dryness and the obtained 3,4-dimethoxycinnamic acid methyl ester was reduced with IM THF solution of diisobutylaluminum hydride (8.0 mmol) in absolute THF (50 mL) at 20 0C for 1 h. Water was added, the mixture was extracted with EtOAc, dried with
MgSO4 and distilled in vacuo (Kugelrohr apparatus (Aldrich), 0.1 mm Hg, T. oven 185-190 °C) giving an off-white solid, yield 0.36 g (92%), m.p. 70-71 °C.
Example A7: 3,4-Dimethoxycinnamaldehyde (A7)
To a mixture of pyridinium dichromate (3.88 g, 10.3 mmol) and 4 g of finely grounded freshly activated molecular sieves 3 A in 20 mL Of CH2Cl2 3,4- dimethoxycinnamyl alcohol in 10 mL OfCH2Cl2 (Example A6, 1.00 g, 5.1 mmol) was
added. The reaction was stirred for 2 h, 0.5 mL of methanol was added, the residue was passed through silica gel and washed with 300 mL of ethyl acetate. After evaporation the compound was purified by silica gel chromatography (hexane-EtOAc, 5:1) leading to a crystallizing oil (0.62 g, 63%).
Example CR2: (E,E)-2-(Benzylaminocarbonyl)-3-(3,4-dimethoxystyryl) acrylonitrile (CR2)
The compound was prepared as described in Example CRl 1, by adding 3,4- dimethoxycinnamaldehyde (Example A7, 0.04 g, 0.2 mmol) to N-(cyanoacetyl)benzylamide (Example A3, 0.036 g, 0.2 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.045 g, 62%).
Example IA: (E,E)-2-(Benzylaminocarbonyl)-3-(3,4-dihydroxystyryl)acrylonitrile (I) - Method A
Boron tribromide (0.033 mL, 0.34 mmol) was added to (E,E)-2-
(benzylaminocarbonyl)-3-(3,4-dimethoxystyryl)acrylonitrile (Example CR2, 0.04 g, 0.11 mmol). The residue was purified by silica gel chromatography (CHCl3-MeOH, 10:1) to give an orange solid (0.02 g, 55% yield).
Example A8: Methyl ester of 3,4-bis(t-butyldimethylsilyloxy)cinnamic acid (A8)
BDMS COOCH3
BDMSO
To a solution of 3.6 g (20 mmol) of 3,4-dihydroxycinnamic acid in 300 mL MeOH was added SOCl2 (100 μL) and the mixture was stirred at 60 0C for 5 h. Methanol was taken to dryness and the obtained methyl ester was treated up with 10.2 g (68 mmol) of t- BuMe2SiCl and 9.2 g (136 mmol) of imidazole in 100 mL DMF at 50 °C for 0.5 h. The mixture was diluted with water and extracted with hexane. Hexane was taken to dryness. The residue was distilled in vacuo (Kugelrohr apparatus (Aldrich), 0.1 mm Hg, T. oven 200-210 °C) and crystallized from hexane at -2O0C giving a white solid, yield 7.5 g (89%), m.p. 57-58 0C.
Example A9: 3,4-Bis(t-butyldimethylsilyloxy)cinnamyl alcohol (A9)
The compound was prepared as described in Example A6 by treating of 3,4- dihydroxycinnamic acid bis(BDMS) ether methyl ester (Example A9, 0.42 g, 1.0 mmol) with IM THF solution of diisobutylaluminum hydride (4.0 mmol) in absolute THF (25 mL) at 2O0C for 1 h. After distilling in vacuo (Kugelrohr apparatus (Aldrich), 0.1 mm Hg, T. oven 185-200 0C) a white viscous oil was obtained, yield 0.33 g (85%).
Example A10: 3,4-Bis(t-butyldimethylsilyloxy)cinnamaldehyde (Ai0)
The compound was prepared as described in Example A7 by adding 3,4-bis(t- butyldimethylsilyloxy)cinnamyl alcohol (Example A9, 0.2 g, 0.5 mmol) in 5 mL Of CH2Cl2 to a mixture of pyridinium dichromate (0.38 g, 1 mmol) and 1 g molecular sieves 3 A in 20 mL OfCH2Cl2. The residue was passed through silica gel and washed with 300 mL of EtOAc-hexane, 1 :1. After evaporation the compound was purified by silica gel chromatography (hexane-EtOAc, 5:1) to provide an oil (0.15 g, 76%).
Example CRl 8: (E,E)-2-(Benzylaminocarbonyl)-3-(3,4- bis(t-butyldimethylsilyloxystyryl))acrylonitrile (CRl 8)
The compound was prepared as described in Example CRl 1 by adding 3,4-bis(Y- butyldimethylsilyloxy) cinnamaldehyde (Example A10, 0.100 g, 0.26 mmol) to N- (cyanoacetyl)benzylamide (Example A3, 0.044 g, 0.26 mmol. After refluxing for 2.5 h purification by silica gel chromatography (hexane-EtOAc, 15:1) provided a yellow solid (0.090 g, 64%).
Example IB: (E,E)-2-(Benzylaminocarbonyl)-3-(3,4-dihydroxystyryl)acrylonitrile (I) - Method B
(E,E)-2-Benzylaminocarbonyl-3-[3,4-bis(t-butyldimethylsilyloxystyryl)] acrylonitrile (Example CRl 8, 0.028 g, 0.052 mmol) was treated with 60 μL of a 1 M THF solution of tetra-n-butylammonium fluoride in 2 mL of dry THF for 0.5 h at 20 °C. After evaporation the compound was dissolved in 5 mL of chloroform-methanol, 20:1, passed through silica gel and washed with chloroform-methanol, 20:1. The residue was purified by HPLC chromatography (MeCN-H2O, 60:40, UV detection at 340 nm) providing an orange solid (0.010 g, 62%).
Biological Examples
Example 1 : The fluorescence of compound of formula (I) is enhanced in solid tumor cells, but not normal cells. Normal human fibroblasts or transformed human embryonic kidney cells or various human cancer cells were cultured in an appropriate medium with 10% FCS. Subconfluent cell cultures were incubated in complete medium with or without 50 μM of CR4. The cells
were incubated with the compound for 2.5 hours at 37 °C under 5% CO2. At the end of this period, the cells were thoroughly washed in medium to remove CR4, detached and analysed by flow cytometry. The results are shown in Figure 1. The results demonstrate that the fluorescence CR4 is enhanced in solid tumor cancer cells, but not normal cells. Example 2: The fluorescence of CR4 is specifically enhanced in non-solid human cancer cells.
Normal human bone marrow cells, or cells from ALL or AML infiltrated human bone marrow were layered over Percoll™ and centrifuged at 400 g at 4 0C for 10 minutes to remove neutrophils and red blood cells (RBCs). Obtained primary cells, or cell lines, were resuspended at 1x106AnL in complete medium with or without 50 μM of CR4. The cells were incubated with the compound for 2.5 hours at 37 0C under 5% CO2. At the end of this period, the cells were thoroughly washed in medium to remove CR4, detached and analysed by flow cytometry (Coulter Elite™). The results are shown in Figure 2. The results demonstrate that the fluorescence of CR4 is enhanced in non-solid tumor cancer cells, but not normal cells.
Example 3: Treatment of normal bone marrow with high dose of CR4 does not demonstrate toxicity of the compound.
Bone marrow cells were layered over Percoll™ and centrifuged at 400 g at 4 0C for 10 minutes to remove neutrophils and red blood cells (RBCs). The cells were resuspended at lxlO6/mL in complete medium with or without 50 μM of CR4. The cells were incubated with the compound for 2.5 hours at 37 0C under 5% CO2. At the end of this period, the cells were thoroughly washed in medium to remove CR4 and then cultured at 2x105 cells/mL in IMDM containing 0.9% (v/v) methylcellulose supplemented with 30% FCS or normal human plasma, and a cocktail of cytokines, containing G-CSF (10 ng/mL), IL-3 (40 LVmL), MGF (50 ng/mL), Erythropoietin (2 LVmL) or TPO (10 ng/mL) and 5xlO-5 M β-2- mercaptoethanol. The culture mixture was plated in 1 mL volumes into 35 mL dishes and incubated at 37 0C under 5% CO2 in a humidified atmosphere. All cultures were evaluated at 14 days for the number of BFU-B colonies (defined as aggregates of more than 500 hemaglobinized eels or 3 or more erythroid subcolonies), CFU-C colonies (defined as
granulocyte or monocyte-macrophage cells or both), and CFU-GEMM colonies (a mixed population comprising of all elements). CR4 displayed negligible toxicity upon normal bone marrow at doses up to 50 μM, as illustrated in Figure 3.
Example 4: CR4 is stable in living cells. Cl pre-B ALL cells were treated with 50 μM of CR4 as in Example 2, washed, incubated in the absence of the compound in complete medium at 37 0C for time periods indicated in Figure 4, and analysed by flowcytometry. Increased fluorescence in cells treated with CR4 but not in control cells was easily detected even upon 18 hours of incubation free from the compound. The results are illustrated in Figure 4. Example 5: CR4 is stable in vivo.
Nine week old BALBc mice were injected intravenously with 100 μM of CR4 in 250 μL of 0.1% DMSO, or, with 250 μL of 0.1% DMSO alone. Blood samples were taken after the time periods indicated in Figure 5, plasma was prepared and analysed by HPLC.
To improve chromatographic properties of CR4, the plasma samples as well as the compound standard were acetylated to obtain the more hydrophobic 3,4-diacetate derivative. The 3,4-diacetate derivative was prepared by treating CR4 (10 mg, 31.3 μmol) with 70 μL of pyridine and 70 μL of acetic anhydride at 20 0C for 1 hour:
Excess of the reagents was evaporated and the target 3,4-diacetate derivative was purified by column chromatography on silica gel using 1% MeOH in CHCl3 as the eluent.
HPLC analyses were performed on a Waters™ 600 chromatograph (USA) with a PDA detector using a Nova-Pak™ C18 3.9x300 mm column (Waters™, USA), with 60:40 MeCN-H2O as eluent, at a flow rate of 1.0 mL/min and detecting at a UV wavelength of 340 nm. The compound standard showed a peak at RT 8.9 min, λmax 338 nm. In a typical experiment, the plasma samples were taken to dryness by evaporating water with
acetonitrile and derivatized with 200 μL pyridine and 200 μL acetic anhydride at 2O0C for 12 hours. The reagents were evaporated, 200 μL of 60:40 MeCN-H2O was added to the samples, the mixtures were vortexed, centrifuged at 2000 rpm for 5 min, and 50 μL aliquots of the supernatants were injected. Results are shown in Figure 5. The results indicate that CR4 is stable in vivo.
REFERENCES
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3. Baker, A., K.H. Gibson, W. Grundy, A.A. Godfrey, JJ. Barlow, M.P. Healy, J.R. Woodburn, S.E. Ashton, BJ. Curry, L. Scarlett, L. Henthorn and L. Richards (2001) "Studies leading to the identification of ZD1839 (iressa): an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer." Bioorg Med Chem Lett 11:1911.
4. Al-Obeidi, F.A. and K.S. Lam (2000) "Development of inhibitors for protein tyrosine kinases. Oncogene 19:5690. 5. Meydan, N., T. Grunberger, H. Dadi, M. Shahar, E. Arpaia, Z. Lapidot, J.S.
Leeder, M. Freedman, A. Cohen, A. Gazit, A. Levitzki and CM. Roifman (1996) "Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor." Nature 379:645.
6. Sausville, E.A. (1999) "A Bcr/Abl kinase antagonist for chronic myelogenous leukemia: a promising path for progress emerges." J Natl Cancer Inst 91 : 102. 7. Sharfe, N., H.K. Dadi and CM. Roifman (1995) "JAK3 protein tyrosine kinase mediates interleukin-7-induced activation of phosphatidylinositol-3' kinase." Blood 86:2077.
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Molecular Imaging." The Journal of Nuclear Medicine 41 :661.
Claims
1. A method for identifying a cancer cell, comprising contacting a cell with a compound having a formula:
R1 and R2 are each independently selected from the group consisting of H, OH, C1-6alkyl, C,-6alkoxy, C1-6alkylCO2, NH2, NH-Ci-6alkyl, N(C1-6alkyl)(C1-6alkyl), C1- 6alkyl(C=O)NH, C1-6alkyl(C=O)N(d-6alkyl), SH, S-C1-6alkyl, O-Si(C1-6alkyl)(Ci. 6alkyl)(C1-6alkyl), NO2, CT3, OCF3, and halo; or R1 and R2 together represent 0-C1- 6alkyl-O, thereby forming a ring;
R3 is selected from the group consisting of H, OH, Ci-6alkyl, C1-6alkoxy, Ci-6alkylCO2, NH2, NH-C,-6alkyl, N(Ci-6alkyl)(C1-6alkyl), C1-6alkyl(C=O)NH, Ci-6alkyl(C=O)N(C,. 6alkyl), SH, S-C1-6alkyl, O-Si(C1-6alkyl)(C1-6alkyl)(C1-6alkyl), NO2, halo, and CH2- S-(CH2)nAr; R4 is selected from the group consisting of C(X)R5, SO3Ar, NH2, NH-Ci-6alkyl, N(C1- 6alkyl)(C1-6alkyl), P(O)(OH)2, P(O)(OC1 -6alkyl)2, and C(NH2)^C(CN)2;
X is selected from O, S, NH, and N-Ci-6alkyl;
R5 is selected from the group consisting of NH2, OH, NH(CH2)pAr, NH(CH2)p0H,
(CH2)pOCi-6alkyl, C1-6alkyl, Ci-6alkoxy, NHNH2, NHC(O)NH2, NHC(O)C i-6alkoxy, N-morpholino, and N-pyrrolidino;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, Ci-6alkyl, C1- ealkoxy, NH2, NH-Ci-6alkyl, N(C1-6alkyl)(Ci-6alkyl), SH, S-Ci-6alkyl, NO2, CF3, OCF3, and halo; n is 0 to 4; and p is 1-4; and detecting fluorescent emissions from the cell, wherein fluorescent emissions detected from the cell are indicative of a cancerous state of the cell.
2. A method for identifying a cancer cell, comprising contacting a cell with a compound having a formula:
R1 and R2 are each independently selected from the group consisting of H, OH, Ci-6alkyl, Ci-6alkoxy, Ci-6alkylCO2, NH2, NH-C1-6alkyl, N(C1-6alkyl)(Ci-6alkyl), C1- 6alkyl(C=O)NH, C1-6alkyl(C=O)N(Ci-6alkyl), SH, S-C1-6alkyl, O-Si(C1-6alkyl)(Ci- 6alkyl)(C1-6alkyl), NO2, CF3, OCF3, and halo; or R1 and R2 together represent 0-Ci- 6alkyl-O, thereby forming a ring;
R3 is selected from the group consisting of H, OH, Ci-6alkyl, Ci-6alkoxy, C1-6alkylCO2, NH2, NH-Ci-6alkyl, N(Ci-6alkyl)(Ci-6alkyl), C1-6alkyl(C-O)NH, C1-6alkyl(C=O)N(Ci.
6alkyl), SH, S-C,.6alkyl, O-Si(C1-6alkyl)(C1-6alkyl)(Ci-6alkyl), NO2, halo, and CH2- S-(CH2)nAr;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, Ci-6alkyl, Ci- 6alkoxy, NH2, NH-Ci-6alkyl, NCd-salkylXd-ealkyl), SH, S-Ci-6alkyl, NO2, CF3,
OCF3, and halo;
R6 is selected from the group consisting of Ar, OH, and OC^alkyl; X is selected from O and S; n is 0-4; and p is 1-4; and detecting fluorescent emissions from the cell, wherein fluorescent emissions detected from the cell are indicative of a cancerous state of the cell.
3. A method for identifying a cancer cell, comprising contacting a cell with a compound having a formula:
R1 and R2 are each independently selected from the group consisting of H, OH, Ci-όalkyl,
C1-6alkoxy, C1-6alkylCO2, NH2, NH-C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), C1. 6alkyl(C=O)NH, Ci-6alkyl(C=O)N(C1.6alkyl), SH, S-C1-6alkyl, O-Si(C1-6alkyl)(Ci.
6alkyl)(C1.6alkyl), NO2, CF3, OCF3, and halo; or R1 and R2 together represent 0-C1- 6alkyl-O, thereby forming a ring;
NH-C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), C1-6alkyl(C=O)NH, 6alkyl), SH, S-C,-6alkyl, O-Si(C1-6alkyl)(C1-6alkyl)(C1-6alkyl), NO2, halo, and CH2-
S-(CH2)nAr;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, C1-6alkyl, C1- 6alkoxy, NH2, NH-Ci-6alkyl, N(Ci-6alkyl)(C1-6alkyl), SH, S-C1-6alkyl, NO2, CF3, OCF3, and halo;
R7 is selected from the group consisting of OH, NH2, and OCi-6alkyl; X is selected from O and S; and n is 0-4; and detecting fluorescent emissions from the cell, wherein fluorescent emissions detected from the cell are indicative of a cancerous state of the cell.
4. A method for identifying a cancer cell, comprising contacting a cell with a compound having a formula:
R1, R2, and R3 are each independently selected from H, OH, Ci-βalkyl, Ci^allcoxy,
Ci-6alkyl(CO)O, NH2, NH-Ci-6alkyl, N(C1-6alkyl)(C1-6alkyl), Ci-6alkyl(C=O)NH, Ci- 6alkyl(C=O)N(Ci-6alkyl), SH, S-Ci-6alkyl, NO2, CF3, OCF3, and halo;
R4 is unsubstituted Ar, or Ar substituted with 1-4 substituents, independently selected from d^alkyl, Ci^alkoxy, and halo;
X is selected from (CH2CH2O)n and (CH2)n, and n is 1-4; and detecting fluorescent emissions from the cell, wherein fluorescent emissions detected from the cell are indicative of a cancerous state of the cell.
5. A method of claim 4, wherein X is (CH2 )n.
6. A method for identifying a cancer cell, comprising contacting a cell with a compound having a formula: R4
R1, R2, and R3 are each independently selected from H, OH, C^alkyl, Ci-6alkoxy,
C1-6alkyl(CO)O, NH2, NH-Ci-6alkyl, N(C1-6alkyl)(Ci.6alkyl), C1-6alkyl(C=O)NH, C1- 6alkyl(C=O)N(Ci-6alkyl), SH, S-C1-6alkyl, NO2, CF3, OCF3, and halo;
R4 is C1-6alkyl; and n is i -4; and detecting fluorescent emissions from the cell, wherein fluorescent emissions detected from the cell are indicative of a cancerous state of the cell.
7. The method of any one of claims 1 -6, wherein said cell is suspected of being a primary B ALL cell, primary ALL cell, pre B ALL cell, Philadelphia positive ALL cell, breast cancer cell, prostate cancer cell, and kidney cancer cell.
8. The method of any one of claims 1-6, further comprising removing excess compound from extracellular areas where emissions will be detected.
9. The method of any one of claims 1 -6, wherein the cell is contacted with the compound in vitro for 1 to 5 hours.
10. The method of any one of claims 1 -6, wherein the cell is contacted with the compound in vivo for 1 to 48 hours.
11. Use in the manufacture of a medicament for detecting cancer cells of a compound having a structure of the formula:
wherein
R1 and R2 are each independently selected from the group consisting of H, OH, Ci.6alkyl,
Ci-6alkoxy, Ci-6alkylCO2, NH2, NH-C1-6alkyl, N(Ci-6alkyl)(Ci-6alkyl), Ci- 6alkyl(C=O)NH, Ci-6alkyl(C=O)N(C1-6alkyl), SH, S-Ci-6alkyl, O-Si(Ci-6alkyl)(Ci.
6alkyl)(Ci-6alkyl), NO2, CF3, OCF3, and halo; or R1 and R2 together represent 0-Ci- 6alkyl-O, thereby forming a ring;
R3 is selected from the group consisting of H, OH, Ci-6alkyl, Ci-6alkoxy, Ci-6alkylCO2, NH2,
NH-C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), C1-6alkyl(C=O)NH, Ci-6alkyl(C=O)N(Ci. 6alkyl), SH, S-Ci-6alkyl, O-Si(C1-6alkyl)(Ci-6alkyl)(C1-6alkyl), NO2, halo, and CH2-
S-(CH2)nAr;
R4 is selected from the group consisting of C(X)R5, SO3Ar, NH2, NH-Ci-6alkyl, N(Ci- 6alkyl)(C1-6alkyl), P(O)(OH)2, P(O)(OC1-6alkyl)2, and C(NH2)=C(CN)2;
X is selected from O, S, NH, and N-Ci-6alkyl; R5 is selected from the group consisting OfNH2, OH, NH(CH2)pAr, NH(CH2)POH,
(CH2)pOCi-6alkyl, Ci-6alkyl, Ci-6alkoxy, NHNH2, NHC(O)NH2, NHC(O)C i-6alkoxy, N-morpholino, and N-pyrrolidino;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, Ci-6alkyl, Ci- 6alkoxy, NH2, NH-C,-6alkyl, N(C]-6alkyl)(Ci-6alkyl), SH, S-Ci-6alkyl, NO2, CF3,
OCF3, and halo; n is O to 4; and p is 1-4.
12. Use in the manufacture of a medicament for detecting cancer cells of a compound having a structure of the formula:
wherein R1 and R2 are each independently selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylCO2, NH2, NH-C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), C1- 6alkyl(C=O)NH, Ci-6alkyl(C=O)N(C1-6alkyl), SH, S-C1-6alkyl, 6alkyl)(C1-6alkyl), NO2, CF3, OCF3, and halo; or R1 and R2 together represent 0-Ci- 6alkyl-O, thereby forming a ring; R3 is selected from the group consisting of H, OH, Ci-6alkyl, Ci-6alkoxy, Ci-6alkylCO2, NH2, NH-Ci-6alkyl, N(Ci-6alkyl)(Ci-6alkyl), C1-6alkyl(C=O)NH, Ci-6alkyl(C=O)N(Ci. 6alkyl), SH, S-Ci-6alkyl, O-Si(C1-6alkyl)(Ci-6alkyl)(Ci-6alkyl), NO2, halo, and CH2- S-(CH2)nAr;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, Ci-6alkyl, Ci- 6alkoxy, NH2, NH-C1-6alkyl, N(Ci-6alkyl)(Ci-6alkyl), SH, S-Ci-6alkyl, NO2, CF3, OCF3, and halo;
R6 is selected from the group consisting of Ar, OH, and OCi.6alkyl; X is selected from O and S; n is 0-4; and p is 1 -4.
13. Use in the manufacture of a medicament for detecting cancer cells of a compound having a structure of the formula: wherein
R1 and R2 are each independently selected from the group consisting of H, OH, C^aHcyl,
Ci-6alkoxy, Ci-6alkylCO2, NH2, NH-C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), C1- 6alkyl(C=O)NH, C1-6alkyl(C=O)N(Ci-6alkyl), SH, S-Ci-6alkyl, O-Si(Ci-6alkyl)(Ci.
6alkyl)(Ci-6alkyl), NO2, CF3, OCF3, and halo; or R1 and R2 together represent 0-Ci- 6alkyl-O, thereby forming a ring;
R3 is selected from the group consisting of H, OH, Ci-6alkyl, Ci-6alkoxy, Ci-6alkylCO2, NH2,
NH-Ci-6alkyl, N(C1-6alkyl)(Ci-6alkyl), Ci-6alkyl(C=O)NH, 6alkyl), SH, S-Ci-6alkyl, O-Si(C,-6alkyl)(Ci-6alkyl)(C1-6alkyl), NO2, halo, and CH2-
S-(CH2)nAr;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, Ci-6alkyl, Ci- 6alkoxy, NH2, NH-Ci-6alkyl, N(Ci-6alkyl)(Ci-6alkyl), SH, S-C1-6alkyl, NO2, CF3, OCF3, and halo;
R7 is selected from the group consisting of OH, NH2, and OCi-6alkyl; X is selected from O and S; and n is 0-4.
14. Use in the manufacture of a medicament for detecting cancer cells of a compound having a structure of the formula:
R1, R2, and R3 are each independently selected from H, OH, C1-6alkyl, C^alkoxy,
Ci-6alkyl(CO)O, NH2, NH-Ci-6alkyl, N(Ci-6alkyl)(C1-6alkyl), C1-6alkyl(C=O)NH, C1- 6alkyl(C=O)N(Ci-6alkyl), SH, S-C1-6alkyl, NO2, CF3, OCF3, and halo;
R4 is unsubstituted Ar, or Ar substituted with 1-4 substituents, independently selected from Ci-6alkyl, C1-6alkoxy, and halo;
X is selected from (CH2CH2O)n and (CH2)n, and n is 1-4.
15. A method of claim 14, wherein X is (CH2)n.
16. Use in the manufacture of a medicament for detecting cancer cells of a compound having a structure of the formula:
R1, R2, and R3 are each independently selected from H, OH, C1-6alkyl, Ci-βalkoxy,
Ci-6alkyl(CO)O, NH2, NH-Ci-6alkyl, N(C1-6alkyl)(Ci-6alkyl), C1-6alkyl(C=O)NH, Ci- 6alkyl(C=O)N(C1-6alkyl), SH, S-Ci-6alkyl, NO2, CF3, OCF3, and halo; R is Ci-6alkyl; and n is 1-4.
17. A kit comprising an effective amount of a compound having a structure of the formula:
1 0
R and R are each independently selected from the group consisting of H, OH, Ci-6alkyl, Ci-6alkoxy, Ci-6alkylCO2, NH2, NH-C1-6alkyl, N(Ci-6alkyl)(Ci-6alkyl), C1- 6alkyl(C=O)NH, Ci-6alkyl(C=O)N(C1-6alkyl), SH, S-C1-6alkyl, O-SKCLealkylXd. 6alkyl)(Ci-6alkyl), NO2, CF3, OCF3, and halo; or R1 and R2 together represent 0-C1- 6alkyl-O, thereby forming a ring;
R3 is selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylCO2, NH2, NH-C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), Ci-6alkyl(C=O)NH, 6alkyl), SH, S-C,-6alkyl, O-Si(C1-6alkyl)(C]-6alkyl)(C1-6alkyl), NO2, halo, and CH2- S-(CH2)nAr;
R4 is selected from the group consisting of C(X)R5, SO3Ar, NH2, NH-Ci-6alkyl, N(Ci- 6alkyl)(C1-6alkyl), P(O)(OH)2, P(O)(OC i-6alkyl)2, and C(NH2)=C(CN)2;
X is selected from O, S, NH, and N-C1-6alkyl;
R5 is selected from the group consisting OfNH2, OH, NH(CH2)pAr, NH(CH2)POH, (CH2)pOC1-6alkyl, C]-6alkyl, C1-6alkoxy, NHNH2, NHC(O)NH2, NHC(O)C i-6alkoxy,
N-moφholino, and N-pyrrolidino;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, C1-6alkyl, Ci- 6alkoxy, NH2, NH-Ci-6alkyl, N(Ci-6alkyl)(Ci-6alkyl), SH, S-Ci-6alkyl, NO2, CF3, OCF3, and halo; n is 0 to 4; and p is 1-4; and instructions for using the compound in the diagnosis of cancer by contacting cells with the compound and detecting fluorescent emissions.
18. A kit comprising an effective amount of a compound having a structure of the formula:
wherein R1 and R2 are each independently selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, Ci-6alkylCO2, NH2, NH-C1-6alkyl, N(C1-6alkyl)(Ci-6alkyl), C1- 6alkyl(C=O)NH, C1-6alkyl(C=O)N(C1-6alkyl), SH, S-Ci-6alkyl, O-Si(C1-6alkyl)(Ci. 6alkyl)(Ci-6alkyl), NO2, CF3, OCF3, and halo; or R1 and R2 together represent 0-Ci- 6alkyl-O, thereby forming a ring; R3 is selected from the group consisting of H, OH, Ci-6alkyl, Ci-6alkoxy, Ci-6alkylCO2, NH2, NH-C1-6alkyl, N(C1-6alkyl)(Ci-6alkyl), Ci-6alkyl(C=O)NH, C1.SaIk^(C=O)N(C1- 6alkyl), SH, S-C1-6alkyl, O-Si(Ci-6alkyl)(Ci-6alkyl)(Ci-6alkyl), NO2, halo, and CH2- S-(CH2)nAr;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, Ci-6alkyl, Ci- 6alkoxy, NH2, NH-Ci-6alkyl, N(Ci-6alkyl)(C,-6alkyl), SH, S-Ci-6alkyl, NO2, CF3, OCF3, and halo;
R6 is selected from the group consisting of Ar, OH, and OCi^alkyl; X is selected from O and S; n is 0-4; and p is 1 -4; and instructions for using the compound in the diagnosis of cancer by contacting cells with the compound and detecting fluorescent emissions.
19. A kit comprising an effective amount of a compound having a structure of the formula:
wherein R1 and R2 are each independently selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylCO2, NH2, NH-C1-6alkyl, N(C1-6alkyl)(Ci-6alkyl), C1- 6alkyl(C=O)NH, Ci-6alkyl(C=O)N(C1-6alkyl), SH, S-C1-6alkyl, O-Si(C1-6alkyl)(Ci. 6alkyl)(C1-6alkyl), NO2, CF3, OCF3, and halo; or R1 and R2 together represent 0-C1- 6alkyl-O, thereby forming a ring; R3 is selected from the group consisting of H, OH, d^alkyl, C1-6alkoxy, C1-6alkylCO2, NH2, NH-C1-6alkyl, N(C1-6alkyl)(Ci-6alkyl), Ci-6alkyl(C=O)NH, C1-6alkyl(C=O)N(Ci. 6alkyl), SH, S-C1-6alkyl, O-Si(Ci-6alkyl)(Ci-6alkyl)(C1-6alkyl), NO2, halo, and CH2- S-(CH2)nAr;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, C1-6alkyl, C1- 6alkoxy, NH2, NH-C1-6alkyl, NCd-ealkylXd-ealkyl), SH, S-C1-6alkyl, NO2, OCF3, OCF3 and halo;
R7 is selected from the group consisting of OH, NH2 and OC1-6alkyl; X is selected from O and S; and n is 0-4; and instructions for using the compound in the diagnosis of cancer by contacting cells with the compound and detecting fluorescent emissions.
20. A kit comprising an effective amount of a compound having a structure of the formula:
R1, R2, and R3 are each independently selected from H, OH, C1-6alkyl, C^alkoxy, Ci-6alkyl(CO)O, NH2, NH-C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), Ci-6alkyl(C=O)NH, Ci- 6alkyl(C=O)N(C1-6alkyl), SH, S-C1-6alkyl, NO2, CF3, OCF3, and halo;
R4 is unsubstituted Ar, or Ar substituted with 1-4 substituents, independently selected from Ci-6alkyl, Ci-6alkoxy, and halo;
X is selected from (CH2CH2O)n and (CH2)n, and n is 1-4; and instructions for using the compound in the diagnosis of cancer by contacting cells with the compound and detecting fluorescent emissions.
21. A method of claim 20, wherein X is (CH2)n.
R1, R2, and R3 are each independently selected from H, OH, C1-6alkyl, C1-6alkoxy,
C1-6alkyl(CO)O, NH2, NH-C1-6alkyl, N(Ci-6alkyl)(C1-6alkyl), C1-6alkyl(C=O)NH, C1- 6alkyl(C=O)N(C1-6alkyl), SH, S-C1-6alkyl, NO2, CF3, OCF3, and halo;
R4 is C1-6alkyl; and n is 1-4; and instructions for using the compound in the diagnosis of cancer by contacting cells with the compound and detecting fluorescent emissions.
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