- Expanding the limits of isonitrile-mediated amidations: On the remarkable stereosubtleties of macrolactam formation from synthetic seco -cyclosporins
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The scope of isonitrile-mediated amide bond-forming reactions is further explored in this second-generation synthetic approach to cyclosporine (cyclosporin A). Both type I and type II amidations are utilized in this effort, allowing access to epimeric cyclosporins A and H from a single precursor by variation of the coupling reagents. This work lends deeper insight into the relative acylating ability of the formimidate carboxylate mixed anhydride (FCMA) intermediate, while shedding light on the far-reaching impact of remote stereochemical changes on the effective preorganization of seco-cyclosporins.
- Wu, Xiangyang,Stockdill, Jennifer L.,Park, Peter K.,Danishefsky, Samuel J.
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supporting information; experimental part
p. 2378 - 2384
(2012/03/12)
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- POLYMER MICELLE COMPOSITION FOR TREATMENT OF RESISTANT CANCER CELLS
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Disclosed are a polymer micelle composition for treatment of resistant cancer cells that contains an amphiphilic double block copolymer and taxane and a P-glycoprotein inhibitor of cyclosporin as its active ingredients, and a method of preparing the same. Said polymer micelle composition for treatment of cancer resistant cells is accumulated in cancer tissue at high concentrations, and has the advantages that it exhibits superior anti-cancer effects for the cancer cells that have exhibited resistance due to over-expression of P-glycoprotein by the taxane anticancer agent in said cancer tissue, and does not cause hypersensitive reactions due to the use of a solubilizer.
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- Total synthesis of cyclosporine: Access to N-methylated peptides via lsonitrile coupling reactions
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Recent developments in the use of isonitriles to furnish secondary and tertiary amide bond formations have been applied to a novel total synthesis of the important cyclic polypeptide cyclosporine A. Specifically, the disclosed synthetic route demonstrates the utility of microwave-mediated carboxylic acid isonitrile couplings, thioacid isonitrile couplings at ambient temperature, and isonitrile-mediated couplings of carboxylic acids and thioacids with amines to form challenging amide bonds. Copyright
- Wu, Xiangyang,Stockdill, Jennifer L.,Wang, Ping,Danishefsky, Samuel J.
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supporting information; experimental part
p. 4098 - 4100
(2010/05/15)
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- Compositions and methods for enhancing drug delivery across and into epithelial tissues
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This invention provides compositions and methods for enhancing delivery of drugs and other agents across epithelial tissues, including the skin, gastrointestinal tract, pulmonary epithelium, ocular tissues and the like. The compositions and methods are also useful for delivery across endothelial tissues, including the blood brain barrier. The compositions and methods employ a delivery enhancing transporter that has sufficient guanidino or amidino sidechain moieties to enhance delivery of a compound conjugated to the reagent across one or more layers of the tissue, compared to the non-conjugated compound. The delivery-enhancing polymers include, for example, poly-arginine molecules that are preferably between about 6 and 25 residues in length.
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Page column 40; 55
(2010/02/07)
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- LIQUID PHARMACEUTICAL FOR ORAL DELIVERY
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A liquid pharmaceutical for oral delivery wherein at the time of use, a solid unit dosage form is added to the liquid wherein the unit dosage form is comprised of a substrate soluble in the liquid and a particulate pharmaceutically active material in a pharmaceutically effective amount. At the time of use, the unit dosage form is added to the liquid, without requiring measurement of the liquid, and the entire liquid is consumed to provide for oral delivery of the pharmaceutically effective amount of material.
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- Compositions and methods for enhancing drug delivery across and into epithelial tissues
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This invention provides compositions and methods for enhancing delivery of drugs and other agents across epithelial tissues, including the skin, gastrointestinal tract, pulmonary epithelium, ocular tissues and the like. The compositions and methods are also useful for delivery across endothelial tissues, including the blood brain barrier. The compositions and methods employ a delivery enhancing transporter that has sufficient guanidino or amidino sidechain moieties to enhance delivery of a compound conjugated to the reagent across one or more layers of the tissue, compared to the non-conjugated compound. The delivery-enhancing polymers include, for example, poly-arginine molecules that are preferably between about 6 and 25 residues in length.
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- Liquid crystal forms of cyclosporin
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This invention relates to novel, liquid crystal forms of the cyclic peptide cyclosporin and to novel powder formulations of cyclosporin prepared using this novel liquid crystal form of the drug. Methods for preparing and using these formulations are also provided. In particular, the present invention relates to dispersible spray dried particles of cyclosporin suitable for pulmonary delivery.
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- PROCESS OF PURIFICATION OF CYCLOSPORIN
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Object of the invention is a process for the chromatographic preparation of cyclosporin A from a crude product containing cyclosporin complex by using a column filled with silica gel and by the application of multistep chromatography with a column filled with normal phase silica gel and by a solvent mixture containing toluene as the major component.
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- Pharmaceutical composition comprising cyclosporin solid-state microemulsion
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A pharmaceutical composition comprising a cyclosporin solid-state microemulsion is disclosed. In a preferred embodiment, the composition comprises a cyclosporin microemulsion dispersed in an enteric carrier. The composition does not dissolve in external phases such as artificial gastric fluid, but dissolves rapidly in artificial intestinal fluid, whereby it releases the cyclosporin microemulsion, providing rapid delivery of cyclosporin. The composition effectively maintains a therapeutic blood concentration of cyclosporin with once a day dosing, providing for convenience of administration and avoiding adverse effects induced by increasing peak blood cyclosporin concentrations associated with conventional cyclosporin formulations.
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- Non-Imuunosuppressive cyclosporins and their use in the prevention and treatment of HIV infection
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Disclosed are cyclosporin analogs having amino acid residue substitutions at positions 1, 3, or 7 of the cyclosporin peptide backbone. Also disclosed are conjugates of these cyclosporin analogs in which an HIV protease inhibitor moiety is conjugated to the position-7 amino acid residue of the cyclosporin. These compounds simultaneously bind to and inhibit cyclophilin and HIV protease. The compounds have good bioavailability and potent HIV inhibitory activity. They are useful in the treatment and prevention of HIV-mediated disorders, including AIDS.
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- Cyclosporin immunoassay
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A method of measuring the amount of cyclosporin in a sample suspected of containing cyclosporin is disclosed. A method of inactivating interfering cross-reactive material in an assay for measuring the amount of cyclosporin in a sample suspected of containing cyclosporin is also disclosed. Compositions wherein cyclosporin is conjugated to an immunogenic carrier or a label, optionally through a linking group, at an alanine nitrogen atom of the cyclic backbone of cyclosporin are also disclosed. Compositions wherein atiocyclosporin is conjugated, optionally through a linking group, to an immunogenic carrier or a label are also disclosed. Where cyclosporin is conjugated to an immunogenic carrier, the conjugates may be used as immunogens for the preparation of antibodies which are capable of recognizing cyclosporin. Where atiocyclosporin is conjugated to an immunogenic carrier, the conjugates may be used as immunogens for the preparation of antibodies which are capable of recognizing interfering cross-reactive material but substantially incapable of recognizing cyclosporin or cyclosporin-label conjugates. Where cyclosporin is conjugated to a label, the conjugates may be used as part of a signal producing system in cyclosporin assays. Both the antibodies and label conjugates are useful in the disclosed assay methods.
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- Process for preparing cyclosporin A
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A process for the isolation of cyclosporin A comprising the steps of: adding a lower alkanol solvent to a culture fluid of a mutant of Tolypocladium inflatum to form a mixture, filtering the mixture to form an extract, transferring the extract to methylene chloride as a solvent therefor, and column chromatographing the resultant product on silica gel.
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- Method for increasing bioavailability of orally administered pharmaceutical compounds
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A method for increasing bioavailability of an orally administered hydrophobic pharmaceutical compound, which comprises orally administering the pharmaceutical compound to a mammal in need of treatment with the compound concurrently with a bioenhancer comprising an inhibitor of a cytochrome P450 3A enzyme or an inhibitor of P-glycoprotein-mediated membrane transport, the bioenhancer being present in sufficient amount to provide bioavailability of the compound in the presence of the bioenhancer greater than the bioavailability of the compound in the absence of the bioenhancer.
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- Cyclosporins
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Nonimmunosuppressant cyclosporin derivatives having cyclophilin-binding activity, for example, the compound, ?MeIle!4 -ciclosporin, are useful in inhibiting HIV-1 replication in treating AIDS and AIDS related disorders.
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- Immunoassay reagents and method for determining cyclosporine
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Cyclosporine derivatives useful as detectable tracer compounds for the immunoassay determination of cyclosporine are disclosed. The cyclosporine derivatives comprise a detectable moiety coupled to the amino acid at the first position (MeBmt) in cyclosporine, the second position (Abu) in cyclosporine, the third position (Sar) in cyclosporine, the eighth position (D-Ala) in cyclosporine, or the tenth position (MeLeu) in cyclosporine. A preferred cyclosporine derivative comprises a fluorescent moiety coupled to the hydroxyl group of the amino acid at the first position in cyclosporine, and is especially useful for the fluorescent polarization immunoassay deterimination of cyclosporine. A fluorescent polarization immunoassay method and test kit are also disclosed.
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- Cyclosporins and their use as pharmaceuticals
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Cyclosporins wherein the residue at the 1-position (typically -MeBmt- or -dihydro-MeBmt-) is 3''O-acylated or 3''-oxo or -C 1-4 alkoxyimino substituted, or wherein the residue at the 2-position is β-O-acyl or β-oxo substituted, or wherein the residue at the 2-position is -Ile-, or wherein the residue at the 11-position is -MeAls-, -MeIle- or -MealloIle- as well as various naturally occurring cyclosporins/dihydro-derivatives thereof, are useful in reversing resistance to chemotherapy, in particular resistance to cytostatic or anti-neoplastic therapy. Various of these cyclosporins and intermediates for their production are novel. Intermediates wherein the residue (e.g. -MeBmt-, -dihydro-MeBmt- etc.) at the 1-position is 8''-alkoxy or 7''-desmethyl-7''-hydrocarbyl substituted are novel and useful as immunosuppressants, anti-inflammatory and anti-parasitic agents.
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- Novel cyclosporins
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Novel cyclosporins having an -Allylgly- residue in the 2-position and/or a -(D)-Ser- residue in the 8-position and process for their production. The novel cyclosporins are useful as pharmaceuticals, e.g. as immunosuppressive and anti-inflammatory agents.
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- Method for the total synthesis of cyclosporins, novel cyclosporins and novel intermediates and methods for their production
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A method for the total synthesis of cyclosporins, in particular Cyclosporin A, cyclosporins produced in accordance with the method of the invention and novel intermediates, in particular novel [1S, 2R, 3R]- and [1R, 2S, 3S]-1-nitrilo-1-carbonyl-3-methyl-2-oxy-heptanes and -hept-5-enes, employed in the method of the invention.
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