Wisconsin Alumni Research Foundation

University of Kentucky Research Foundation

Jon Scott Thorson

Byron R Griffith

Randal D Goff

Jianjun Zhang

Joseph M Langenhan

Richard W Gantt

Peter Anthony Crooks

Stefan Kwiatkowski

Linda P Dwoskin

Guangrong Zheng

David S Watt

Jared T Hammill

Jurgen Rohr

Markos Leggas

Albee Messing

Joseph M Eckenrode

Yang Liu

Woosung Cho

Shannon C Timmons

Ahmed Aqeel

John R Fitzgibbon

Changsheng Zhang

Gavin J Williams

Tyler Huber

Yinan Zhang

Changsgeng Zhang

Khaled Attia Shaaban Mahmoud

Mark Leggas

Na-Ra Lee

Shanteri Singh

Derong Ding

Kip Guy

The present invention relates to methods of treatment of a disease or pathology of the central nervous system, an eating disorder, or substance use disorder, drug dependence/abuse and withdrawal therefrom comprising administering at least one N-phenylalkyl amphetamine derivative and pharmaceutical compositions comprising at least one N-phenylalkyl amphetamine derivative to an individual in need thereof.

Vesicular monoamine transporter-2 ligands and their use in the treatment of psychostimulant abuse

Compounds described herein are mithramycin (MTM) oxide (OX) derivatives and MTM Hydrazine (HY) derivatives. These compounds are useful for treatment of cancers and neuro-diseases.

Mithramycin oxime derivatives having increased selectivity and anti-cancer activity

The present disclosure relates to the synthesis of non-natural analogs of S-adenosyl-L-methionine (SAM) and/or of Se-adenosyl-L-methionine (SeAM) by reacting a methionine analog and adenosine triphosphate (ATP) in the presence of at least one methionine adenosyltransferase (MAT), and to use thereof with downstream SAM and/or SeAM utilizing enzymes. The non-natural analogs of SAM and/or SeAM have the general formula: where X is S or Se, and Ris an alkyl group.

Synthesis of non-natural cofactor analogs of S-adenosyl-L-methionine using methionine adenosyltransferase

The present invention relates to methods of use of glycosyltransferases and related novel compounds. The invention exploits the reversibility of glycosyltransferases to generate new sugars, unnatural biomolecules and numerous one-pot reactions for generation of new biomolecules having varied backbones such as enediynes, vancomycins, bleomycins, anthracyclines, macrolides, pluramycins, aureolic acids, indolocarbazoles, aminglycosides, glycopeptides, polyenes, coumarins, benzoisochromanequinones, calicheamicins, erythromycin, avermectins, ivermectins, angucyclines, cardiac glycosides, steroids or flavinoids. In preferred embodiments, the invention specifically relates to biosynthesis of anticancer (the enediyne calicheamicin, CLM), anthelmintic agents (the macrolides avermectin, ivermectin and erythromycin) and antibiotic (the glycopeptide vancomycin, VCM) natural product-based drugs developed by reversible, bidirectional glycosyltransferase-catalyzed reactions.

Reversible natural product glycosyltransferase-catalyzed reactions, compounds and related methods

The present invention relates to methods of use of glycosyltransferases and related compounds. The invention exploits the reversibility of glycosyltransferases to generate new sugars, unnatural biomolecules and numerous one-pot reactions for generation of new biomolecules having varied backbones such as enediynes, vancomycins, bleomycins, anthracyclines, macrolides, pluramycins, aureolic acids, indolocarbazoles, aminglycosides, glycopeptides, polyenes, coumarins, benzoisochromanequinones, calicheamicins, erythromycin, avermectins, ivermectins, angucyclines, cardiac glycosides, steroids or flavinoids. In preferred embodiments, the invention specifically relates to biosynthesis of anticancer (the enediyne calicheamicin, CLM), anthelmintic agents (the macrolides avermectin, ivermectin and erythromycin) and antibiotic (the glycopeptide vancomycin, VCM) natural product-based drugs developed by reversible, bidirectional glycosyltransferase-catalyzed reactions.

The present invention generally relates to methods and compositions for generating vancomycin analogs. Specifically the invention relates to generating a vancomycin library through chemoselective ligation of a sugar moiety with a vancomycin aglycon. In particular, the present invention provides a library of vancomycin analogs, where the member of the library comprises at least one vancomycin analog selected from 2'-N-acyldecanoyl-glucosyl vancomycin neoglycoside, 3&#x2032;-N-acyldecanoyl-glucosyl vancomycin neoglycoside, 4&#x2032;-N-acyldecanoyl-glucosyl vancomycin neoglycoside, 6&#x2032;-N-acyldecanoyl-glucosyl vancomycin neoglycoside, 2&#x2032;-N-acylbiphenyl-glucosyl vancomycin neoglycoside, 3&#x2032;-N-acylbiphenoyl-glucosyl vancomycin neoglycoside, 4&#x2032;-N-acylbiphenoyl-glucosyl vancomycin neoglycoside and 6&#x2032;-N-acylbiphenoyl-glucosyl vancomycin neoglycoside.

Rapid glycopeptide optimization via neoglycosylation

Using neoglycosylation, the impact of differential glycosylation upon the divergent anticancer and anti-HIV properties of the triterpenoid betulinic acid (BA) was examined. Each member from a library of 37 differentially glycosylated BA variants was tested for anticancer and anti-HIV activities. Enhanced analogs for both desired activities were discovered with the corresponding antitumor or antiviral enhancements diverging, based upon the appended sugar, into two distinct compound subsets.

Enhanced neoglycosides through neoglycosylation and methods of use thereof

The present invention generally relates to materials and methods for exploiting glycosyltransferase reversibility for nucleotide diphosphate (NDP) sugar synthesis. The present invention provides engineered glycosyltransferase enzymes characterized by improved reaction reversibility and expanded sugar donor specificity as compared to corresponding non-mutated glycosyltransferase enzymes. Such reagents provide advantageous routes to NDP sugars for subsequent use in a variety of biomedical applications, including enzymatic and chemoenzymatic glycorandomization.

Glycosyltransferase reversibility for sugar nucleotide synthesis

The present invention provides glycorandomized structures and combinatorial methods for rapidly generating a diverse library of glycorandomized structures, comprising incubating one or more aglycons and a pool of NDP-sugars in the presence of a glycosyltransferase. The glycosyltransferase may be one that is associated with or involved in production of natural secondary metabolites, or one which is putatively associated with or involved in production of natural secondary metabolites. The glycosyltransferase may show significant flexibility with respect to its NDP-sugar donors and/or its aglycons. NDP-sugar donors may be commercially available, or may be produced by utilizing mutant or wild type nucleotidyltransferases significant flexibility with respect to their substrates.

Glycorandomization and production of novel novobiocin analogs

A library of glycosylated chlorambucil analogs which are useful as anti-tumor and/or anti-metastatic agents is disclosed. The glycosylated chlorambucil analogs have the general formula wherein represents a reducing sugar moiety.

Glycosylated chlorambucil analogs and uses thereof

Provided herein are methods of decreasing glial fibrillary acidic protein (GFAP) levels in a cell. Such methods include administering an effective amount of a GFAP lowering compound to the cell. Also provided are compounds useful for the treatment of Alexander disease in subjects at risk of or diagnosed with Alexander disease and methods for the identification of such compounds.

Suppression of glial fibrillary acidic protein

The present invention provides methods of producing compounds with enhanced desirable properties and diminished side effects as well as the compounds produced by the methods. In preferred embodiments, methods of the present invention use a universal chemical glycosylation method that employs reducing sugars and requires no protection or activation. In a preferred embodiment, the invention provides neoglycoside digitoxin analogs that include compounds with significantly enhanced cytotoxic potency toward human cancer cells and tumor-specificity, but are less potent Na/K-ATPase inhibitors in a human cell line than digitoxin.

Neoglycorandomization and digitoxin analogs

The present invention discloses a set of glycosylated warfarin analogs which are useful as anti-tumor or anti-metastatic agents and as reagents for studying sugar uptake in cells.

Glycosylated warfarin analogs and uses thereof

Colchicine neoglycosides, method for their synthesis and methods for their use are disclosed. The invention provides analogs of colchicine glycosylated to include a sugar moiety on a colchicine scaffold that is generally unglycosylated in nature. The colchicine neoglycosides disclosed herein are shown to have cytotoxic effects equivalent to at least the known cytotoxins paclitaxel and doxorubicin. Further, the neoglycosides disclosed according to the invention have physiologic effects not previously recognized in the alkaloid family that includes colchicine but recognized in other cytotoxic drug families such as the taxanes which act by stabilizing tubulin formation.

Growing community of inventors

Middleton, WI, United States of America

Jon Scott Thorson