University of Rochester

Research, Incorporated

Other

Innapharma, Inc.

The Dow Chemical Company

Wisconsin Alumni Research Foundation

University of Iowa Research Foundation

Dowelanco

East Carolina University

Andrew S Kende

Yuh-Geng Tsay

James Philip Pearson

Barbara H Iglewski

Richard P Phipps

Roger Smith

Joseph J Hlavka

Matthew R Pincus

Henry B Abajian

Margaret L King

Neil A Feldstein

Dennis P Curran

John E Mills

John Fowler Noble

Lanny S Liebeskind

Frank Hallock Ebetino

Paul C Vosejpka

Bassam S Nader

Ted A Morgan

Jon A Orvik

Norman R Pearson

Howard Hancock Newman

Timothy J Adaway

Larry D Kershner

Anthony P Haag

Christopher A Bradfield

Everett P Greenberg

Everett C Pesci

Noritada Matsuo

Alan P Poland

Edward N Glover

Jared B J Milbank

Weshi Wu

Peter S Rutledge

Takuya Furuta

Novel bacterial quinolone signal molecules and, more particularly,quinolone signal ('PQS') molecules, e.g., 2-heptyl-3-hydroxy-4-quinolone, and analogs and derivatives thereof are described. Therapeutic compositions containing the molecules, and therapeutic methods, methods of for regulating gene expression, methods for identifying modulators of the autoinducer molecules, and methods of modulating quorum sensing signaling in bacteria using the compounds of the invention are also described.

Autoinducer molecules and uses therefor

The present invention relates to an immunogenic conjugate comprising a carrier molecule coupled to an autoinducer of a Gram negative bacteria The immunogenic conjugate, when combined with a pharmaceutically acceptable carrier, forms a suitable vaccine for mammals to prevent infection by the Gram negative bacteria The immunogenic conjugate is also used to raise and subsequently isolate antibodies or binding portions thereof which are capable of recognizing and binding to the autoinducer. The antibodies or binding portions thereof are utilized in a method of treating infections, a method of inhibiting autoinducer activity, and in diagnostic assays which detect the presence of autoinducers or autoinducer antagonists in fluid or tissue samples.

Methods of treating or preventing an infectious disease using an immunogenic conjugate of a gram-negative bacterial autoinducer molecule

The present invention relates to an immunogenic conjugate comprising a carrier molecule coupled to an autoinducer of a Gram negative bacteria. The immunogenic conjugate, when combined with a pharmaceutically acceptable carrier, forms a suitable vaccine for mammals to prevent infection by the Gram negative bacteria. The immunogenic conjugate is also used to raise and subsequently isolate antibodies or binding portions thereof which are capable of recognizing and binding to the autoinducer. The antibodies or binding portions thereof are utilized in a method of treating infections, a method of inhibiting autoinducer activity, and in diagnostic assays which detect the presence of autoinducers or autoinducer antagonists in fluid or tissue samples.

Method for detecting a gram-negative bacterial autoinducer molecule

Antibodies raised against immunogenic conjugates of gram-negative bacterial autoinducer molecules

Immunogenic conjugates of Gram-negative bacterial autoinducer molecules

This invention provides peptidomimetics which bind to T4 or CD4 cell receptors and are useful in inhibiting viral infectivity by viruses which bind to T4 cell receptors. More specifically, peptidomimetics of this invention can alleviate symptoms of AIDS by inhibiting binding of HIV, the virus associated with AIDS, to receptor sites in human cells susceptible to HIV infection. These peptidomimetics, in particular, inhibit binding of HIV to cells of brain membrane and the immune system. They also display substantially longer half-lives in vivo than peptide T. The compounds of this invention which bind to T4 or CD4 receptors and thereby inhibit binding of HIV, alone or in combination with one another, can be used to alleviate AIDS symptoms and ameliorate symptoms of HIV infection, especially neuronal dementias and Kaposi's sarcoma. The compounds of this invention, alone or in combination, can further be used to prevent development of AIDS in persons who might become exposed to HIV.

Peptidomimetics for the treatment of HIV infection

The present invention provides peptides, cyclized peptides and peptidomimetics which inhibit the oncogenic and/or transforming activity of the p21 ras protein, pharmaceutical compositions containing at least one of the ras-inhibiting peptides, cyclized peptides and peptidomimetics, and methods for inhibiting the ras-mediated oncogenic and/or transformation process in mammalian cells or tissues.

Peptidomimetics inhibiting the oncogenic action of p21 ras

The present invention provides peptides and cyclized peptides which inhibit the oncogenic and/or transforming activity of the p21 ras protein, pharmaceutical compositions containing at least one of the ras-inhibiting peptides, cyclized peptides and peptidomimetics, and methods for inhibiting the ras-mediated oncogenic and/or transformation process in mammalian cells or tissues.

Peptides inhibiting the oncogenic action of p21 ras

The present invention is a method of preparing a 4,6-bisarylazoresorcinol comprising reacting an aryldiazonium salt and resorcinol in the presence of a base and a reaction medium containing water and a water-miscible solvent at a temperature in the range of about -5.degree. C to about -60.degree. C. The present invention is also a method of preparing a 2-substituted 4,6-bisarylazoresorcinol comprising reacting an aryldiazonium salt with a 2-substituted resorcinol. The 4,6-bisarylazoresorcinol or 2-substituted 4,6-bisarylazoresorcinol can then be hydrogenated to a 4,6-diaminoresorcinol, which is a precursor to polybisbenzoxazoles (PBOs), polymers which are useful as insulators, solar arrays, and tear-resistant gloves.

Preparation of 4,6-diaminoresorcinol through a bisazoarylresorcinol

A screening assay for recognizing the presence of dioxins (and other related toxins) in a sample is disclosed. In one aspect of the invention, Ah receptor from mice and a radioactively labelled halogenated dioxin are used in a competitive binding assay to test for the presence of toxins. The label is .sup.125 I substituted directly on the main dioxin structure. The relative binding of the toxin in the samples (in competition with labelled dioxin) for Ah receptor can be compared against standard curves. A kit is provided for running such an assay and a preferred .sup.125 I ligand is provided.

Assay for dioxins

A method for preparing substituted phenoxyphenols which are useful in the preparation of herbicidal (phenoxyphenoxy)propionates is disclosed. The process involves the oxidation of substituted phenoxyphenones to the corresponding phenoxyphenyl esters and their conversion to the desired phenoxyphenol. Novel intermediates for the process are similarly disclosed.

Phenoxyphenoxypropionates, intermediates thereof and methods of

New chemical reactions of 1,1,2-trifluoro-1,3-butadiene provide simple access to a series of new fluorinated alkene derivatives. These derivatives provide a simple, general methodology for the stereocontrolled preparation of 2-fluoro-2-alkenoate esters and related monofluoroalkene derivatives which include fluoro analogs of known insecticides, pheromones or pharmaceuticals. A new method for the preparation of 1,1,2-trifluoro-1,3-butadiene is also provided.

Fluorinated butene derivatives and methods for their preparation

The present invention provides compounds having the structure: ##STR1## wherein R.sup.1 represents alkoxy or aralkoxy, R.sup.2 represents hydrogen, alkoxy, aralkoxy, alkyl, aralkyl, or R.sup.1 and R.sup.2 taken together represent the group --O--CH.sub.2 --O--, R.sup.3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I.

Intermediates for the production of picropodophyllin and related

The present invention provides compounds having the structure: ##STR1## wherein R.sup.1 represents alkoxy or aralkoxy, R.sup.2 represents hydrogen, alkoxy, aralkoxy, alkyl, aralkyl, or R.sup.1 and R.sup.2 taken together represent the group --O--CH.sub.2 --O--, R.sup.3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group; and X represents Cl, Br or I. The present invention also provides a process for preparation of compounds VI in a single step wherein X and Y are the same and represent Cl, Br, ,or I, and R.sup.3 is as previously defined except that in this instance, it does not represent a protecting group. According to another aspect of the present invention there are provided compounds VII-a and VII-b having the structure: ##STR2## wherein R.sup.1, R.sup.2 and R.sup.3 are as previously defined, j is an integer having a value of 0 or 1, Z.sup.1 represents a non-reacting electron withdrawing group, and Z.sup.2 represents a non-reacting electron withdrawing group or hydrogen, R.sup.8 and R.sup.9 are the same or different and represent hydrogen, alkyl, aralkyl, alkoxy, or aralkoxy, and R.sup.7 represents hydrogen, alkyl, aralkyl or acyl. Compounds VII-a may be prepared from compounds VI through the use of the process of 'insertion-cyclization' which is provided by another aspect of the present invention. According to a further aspect of the present invention, compounds VII-a are converted into tetralone III-a shown below: ##STR3## wherein R.sup.1, R.sup.2, R.sup.3, Z.sup.1, Z.sup.2, R.sup.7, R.sup.8 and R.sup.9 are as previously defined. Certain of these compounds can, in turn, be readily converted into picropodophyllin and picrosikkimotoxin. The latter can be converted into known antineoplastic agents by known procedures.

The present invention provides compounds having the structure: ##STR1## wherein R.sup.1 represents alkoxy or aralkoxy, R.sup.2 represents hydrogen, alkoxy, aralkoxy, alkyl, aralkyl, or R.sup.1 and R.sup.2 taken together represent the group --O--CH.sub.2 --O--, R.sup.3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group; and X represents Cl, Br or I. The present invention also provides a process for preparation of compounds VI in a single step wherein X and Y are the same and represent Cl, Br, or I, and R.sup.3 is as previously defined except that in this instance, it does not represent a protecting group. According to another aspect of the present invention there are provided compounds VII-a and VII-b having the structure: ##STR2## wherein R.sup.1, R.sup.2 and R.sup.3 are as previously defined, j is an integer having a value of 0 or 1, Z.sup.1 represents a non-reacting electron withdrawing group, and Z.sup.2 represents a non-reacting electron withdrawing group or hydrogen, R.sup.8 and R.sup.9 are the same or different and represent hydrogen, alkyl, aralkyl, alkoxy, or aralkoxy, and R.sup.7 represents hydrogen, alkyl, aralkyl or acyl. Compounds VII-a may be prepared from compounds VI through the use of the process of 'insertion-cyclization' which is provided by another aspect of the present invention. According to a further aspect of the present invention, compounds VII-a are converted into tetralone III-a shown below: ##STR3## wherein R.sup.1, R.sup.2, R.sup.3, Z.sup.1, Z.sup.2, R.sup.7, R.sup.8 and R.sup.9 are as previously defined. Certain of these compounds can, in turn, be readily converted into picropodophyllin and picrosikkimotoxin. The latter can be converted into known antineoplastic agents by known procedures.

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Pittsford, NY, United States of America

Andrew S Kende