University of Colorado

University Patents, Inc.

Somalogic, Incorporated

Nexstar Pharmaceuticals, Inc.

The United States of America As Represented by the Department of Health

Research Corporation Technologies, Inc.

University Technology Corporation

Consiglio Nazionale Delle Richerche

Tad H Koch

Larry M Gold

Kirk B Jensen

Steven Ringquist

Michael Willis

Brent Atkinson

Giorgio Gaudiano

Barry J Swanson

Benjamin L Barthel

Jonathan Drew Smith

Hang Hubert Yin

Robert P Mahoney

Mace Golden

Jordan W Nafie

Alla Balabanova

Brian T Kalet

Daniel L Rudnicki

Robert J Von Trebra

Steven D Averbuch

Nicholas R Bachur

David J Fenick

David J Burkhart

Dylan J Taatjes

Ryo Tamura

Glen C Post

The present invention includes compounds of the class anthracycline that have been modified to include photo-activated prodrug anthracycline compounds that are useful in the treatment of cancer. One example composition of the invention may include photodoxazolidine which may be synthesized in two steps from 4,5-dimethoxy-2-nitrobenzyl alcohol and doxazolidine. In this embodiment commercial 4,5-dimethoxyl-2-nitrobenzyl alcohol reacts with p-nitrophenylchloroformate to give the p-nitrophenyl carbonate of the benzyl alcohol derivative. The p-nitrophenyl carbonate is then reacted with doxazolidine to give the exemplary photodoxazolidine composition.

Anthracycline prodrugs and methods of making and using the same

The invention provides therapeutically effective compounds for the prevention and treatment of cancer and pharmaceutical compositions containing these compounds as well as methods of using and administering these compounds. The invention also includes methods of activating a prodrug of these therapeutically effective compounds by the administration of a peptide-directed targeting construct that delivers a prodrug-activating enzyme to a target activation site.

Methods of treating cancer with doxazolidine and prodrugs thereof

Monomeric and dimeric anti-cancer drug aldehyde conjugate compounds and pharmaceutically acceptable salts thereof. Specifically, monomeric and dimeric aldehyde conjugates of 1-2, dihetero-substituted anti-cancer drugs, including monomeric and dimeric aldehyde conjugates of anthracyclines, are provided. Also provided are pro-drugs which, after administration, release monomeric aldehyde conjugates. Further provided are pharmaceutical and therapeutic compositions containing anti-cancer drug aldehyde conjugates and methods of treating cancer using the aldehyde conjugates.

Anti-cancer drug aldehyde conjugate drugs with enhanced cytotoxicity compounds, compositions and methods

Methods to obtain nucleic acid ligands that photocrosslink to target molecules associated with a disease state are provided. The methods presented are variations on the photoSELEX methods for obtaining nucleic acid ligands. In one method, a candidate mixture of photocrosslinkable nucleic acids is contacted with a biological substance obtained from a source associated with a disease state suspected of containing a target molecule to form nucleic acid-target molecule complexes, the complexes are irradiated to form crosslinked complexes, the photocrosslinked complexes are partitioned from the remainder of the candidate mixture; and the nucleic acid ligands that photocrosslink to molecule are retained. These nucleic acids are then contacted with a second biological substance of the same type as the first, but obtained from a source not associated with a disease state. This removes nucleic acids with affinity to molecules that are not associated with the disease state. In another method, photocrosslinkable nucleic acids are not incorporated in the initial candidate mixture, but rather are incorporated in an enriched candidate mixture obtained by contacting a biological substance associated with a disease state containing a target molecule to form nucleic acid-target molecule complexes, partitioning the complexes away from the candidate mixture.

Systematic evolution of ligands by exponential enrichment: photoselection of nucleic acid ligands

Methods are described for the identification and preparation of high-affinity nucleic acid ligands to bFGF. Included in the invention are specific DNA ligands to bFGF identified by the photoSELEX method. Also included is a method for determining the position of a nucleic acid ligand-protein photoadduct.

Photoselection of nucleic acid ligands

A method for identifying nucleic acid ligands to target molecules using the SELEX procedure wherein the candidate nucleic acids contain photoreactive groups and nucleic acid ligands identified thereby are claimed. The complexes of increased affinity nucleic acids and target molecules formed in the procedure are crosslinked by irradiation to facilitate separation from unbound nucleic acids. In other methods partitioning of high and low affinity nucleic acids is facilitated by primer extension steps as shown in the figure in which chain termination nucleotides, digestion resistant nucleotides or nucleotides that allow retention of the cDNA product on an affinity matrix are differentially incorporated into the cDNA products of either the high or low affinity nucleic acids and the cDNA products are treated accordingly to amplification, enzymatic or chemical digestion or by contact with an affinity matrix.

Systematic evolution of ligands by exponential enrichment: photoselection of nucleic acid ligands and solution selex

A method for identifying nucleic acid ligands to target molecules using the SELEX procedure wherein the candidate nucleic acids contain photoreactive groups and nucleic acid ligands identified thereby are claimed. The complexes of increased affinity nucleic acids and target molecules formed in the procedure are crosslinked by irradiation to facilitate separation from unbound nucleic acids. In other methods partitioning of high and low affinity nucleic acids is facilitated by primer extension steps as shown in the figure in which chain termination nucleotides, digestion resistant nucleotides or nucleotides that allow retention of the cDNA product on an affinity matrix arc differentially incorporated into the cDNA products of either the high or low affinity nucleic acids and the cDNA products are treated accordingly to amplification, enzymatic or chemical digestion or by contact with an affinity matrix.

Systematic evolution of ligands by exponential enrichment:

Disclosed herein are new anthracyclines which are derived from conjugation with glutathione, for example from conjugation of adriamycin, daunomycin and menogaril with glutathione: compounds 7 I, 7 II, 8 I, 8 II, 9 I and 9II, are obtained by reduction of the anthracycline followed by reaction of the reduced product with glutathione in aqueous (H.sub.2 O or D.sub.2 O) or organic solvent. The invention also provides salts of these glutathione derivatives, particularly salts formed from anthracycline glutathione anions with anthracycline cations. These anthracycline derivatives are useful as antibiotics, as antitumor agents, and in the treatment of AIDS. These derivatives are particularly useful in the treatment of cancer when multiple drug resistance is present.

Glutathione derivatives of anthracyclines

A method for releasing trialkylamines into the dye circulation stream of a dye laser and a filter cartridge containing a resin bound anion stabilizing agent for insertion into the dye circulation stream of a dye laser improves the performance thereof, especially with respect to excimer and flashlamp pumped coumarin and carbostyryl dye lasers. The resin bears quaternary ammonium groups, and borohydride, bromide, hudroxide or chloride may be used as the counter ion. A resin bound borohydride stabilizing agent is capable of releasing trialkylamine into the dye circulation stream and reducing the carbonyl functional groups of polyarbonyl material in the stream to less light absorbing alcohol functional groups. A resin bound chloride stabilizing agent is capable of releasing trialkylamine into the dye circulation stream as a quencher and radical scavenger.

Cartridge for extending the lifetime of dyes in dye lasers

The present invention discloses a bi(3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl) compound and its efficacy as a rescue agent against anthracycline and mitomycin C induced tissue damage. A method of synthesizing said compound has also been described.

Oxomorpholinyl dimer and rescue of anthracycline and mitomycin C damage

Subjecting 1,4-bis-[(pyrrolin-3-onyl)methylamino]-2-butyne to ultraviolet irradiation effects rearrangement in greater than 80% yield to 1,4-bis-[(isocyanatocyclopropyl)methylamino]-2-butyne. The diisocyanate is useful in the synthesis of polyurethanes and polyureas and also for the in situ photochemical generation of a cross-linking agent for polyurethanes and structurally related polymers.

Photochemical rearrangement of 2-aminopyrrolin-5-ones to

1,4-Diazabicyclo[2.2.2]octane (DABCO) has been shown to extend the lifetime of several organic laser dyes in nitrogen laser pumped and flashlamp pumped dye lasers. With 0.010M DABCO, average power output in coumarin dye lasers remains at better than 90% of initial power at least three times longer than without DABCO.

Stabilizer of organic dye lasers

Subjecting 1,4-bis-[(pyrrolin-3-onyl)methylamino]-2-butyne to ultraviolet irradiation effects rearrangement in greater than 80% yield to 1,4-bis-[(isocyanatocycloprolpyl)methylamino]-2-butyne. The diisocyanate is useful in the synthesis of polyurethanes and polyureas and also for the in situ photochemical generation of a cross-linking agent for polyurethanes and structurally related polymers.

Growing community of inventors

Boulder, CO, United States of America

Tad H Koch